Genetic Basis of Oral Health Conditions [1st ed. 2019] 978-3-030-14484-5, 978-3-030-14485-2

Table of contents :
Front Matter ....Pages i-ix
Inheritance in Oral Health Conditions (Alexandre Rezende Vieira)....Pages 1-8
Genetic Basis of Enamel and Dentin Defects (Alexandre Rezende Vieira)....Pages 9-21
Genetic Basis of Tooth Agenesis, Supernumerary Teeth, and Other Dental Abnormalities (Alexandre Rezende Vieira)....Pages 23-31
Genetic Basis of Dental Caries and Periapical Pathology (Alexandre Rezende Vieira)....Pages 33-42
Genetic Basis of Periodontitis and Tooth Loss (Alexandre Rezende Vieira)....Pages 43-50
Genetic Basis of Dental Implant Failure and Alveolar Ridge Resorption (Alexandre Rezende Vieira)....Pages 51-58
Genetic Basis of Craniofacial Deformities and Malocclusion, Oral Clefts, and Craniosynostosis (Alexandre Rezende Vieira)....Pages 59-72
Genetic Basis of Lichen Planus and Oral Cancer (Alexandre Rezende Vieira)....Pages 73-79
Genetic Basis of Orofacial Pain and Temporomandibular Joint Dysfunction (Alexandre Rezende Vieira)....Pages 81-92
Genetic Influence on Behavior and the Impact on Oral Health Conditions (Alexandre Rezende Vieira)....Pages 93-104

Citation preview

Genetic Basis of Oral Health Conditions Alexandre Rezende Vieira 

123

Genetic Basis of Oral Health Conditions

Alexandre Rezende Vieira

Genetic Basis of Oral Health Conditions

Alexandre Rezende Vieira Oral Biology University of Pittsburgh Pittsburgh, PA USA

ISBN 978-3-030-14484-5    ISBN 978-3-030-14485-2 (eBook) https://doi.org/10.1007/978-3-030-14485-2 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

Human genetics is the discipline that deals with inheritance as it occurs in human beings. It has components of classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics, and genetic counseling, and to the list we can now add epigenetics. My main purpose in writing this book is to document the content of 12 years of developing a Craniofacial Genetics course for dental students. The course, as is this book, is designed to use the clinical conditions that interest dentists to present genetic concepts. In that sense, this book brings information that is not typically found in other genetic textbooks or dental textbooks. Similarly to how the course addresses inheritance of dental conditions, the book focuses on inheritance, which is a topic not really explored in publications of the conditions highlighted in the following chapters. This text is the result of more than 20 years of interactions with a number of very talented dental and craniofacial scientists, dentists, and physicians from all continents. I thank Lindsay Carol Brown, Jacob I.  Khan, Daryna A.  Koval, and Catherine A.  Roberts who took my Craniofacial Genetics course and then accepted the challenge to carefully revise the text for grammar, style, and flow so it resembles closely the discussions that happen in the classroom. Chapter 1 is the introduction of all other chapters and although the following chapters are structured to stand alone in their respective subspecialties of dentistry; concepts that can be relevant to all conditions are described throughout in the book. In that sense, this book can be read as a novel. Since multifactorial inheritance is the best explanation for most of the conditions presented in the book, this concept is highlighted in all chapters and the repetition is done purposely. There are also other obviously related topics. Individuals interested in cariology, which is discussed in Chap. 4, will find interesting and relevant content in Chaps. 2, 5, 6, and 10. Craniofacial and dental development disturbances are discussed in Chaps. 2, 3, and 7 and have relevant overlap with Chap. 8 that deals with cancer. Orofacial pain, in Chap. 9, can be complemented by Chaps. 4, 5, 8, and 10. In writing this volume, I have attempted to produce a comprehensive but at the same time concise, well-referenced text on the genetics of selected dental conditions, each area combined in a separate chapter with depth provided by selecting a few ideas we published for detailed consideration, including a few instances of original data.

v

Preface

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Readers who should find this volume of interest include dentists, dental hygienists, craniofacial, oral, and maxillofacial surgeons, craniofacial biologists, psychologists, sociologists, anthropologists, students, and others with special interest in dental, oral, and craniofacial structures. Pittsburgh, PA, USA 2019

Alexandre Rezende Vieira

Contents

1 Inheritance in Oral Health Conditions������������������������������������������   1 1.1 Introduction������������������������������������������������������������������������������   1 1.2 Complex Inheritance����������������������������������������������������������������   1 1.3 Single Gene Disorders��������������������������������������������������������������   4 1.4 Chromosomal Abnormalities����������������������������������������������������   7 References������������������������������������������������������������������������������������������   7 2 Genetic Basis of Enamel and Dentin Defects��������������������������������   9 2.1 Introduction������������������������������������������������������������������������������   9 2.2 From Monogenic to Complex Forms of Enamel and Dentin Alterations��������������������������������������������������������������   9 2.3 Molar-Incisor Hypomineralization (MIH)��������������������������������  18 2.4 Dental Caries and Erosive Tooth Wear ������������������������������������  18 2.5 Dental Fluorosis������������������������������������������������������������������������  19 References������������������������������������������������������������������������������������������  20 3 Genetic Basis of Tooth Agenesis, Supernumerary Teeth, and Other Dental Abnormalities����������������������������������������������������  23 3.1 Introduction������������������������������������������������������������������������������  23 3.2 Tooth Agenesis��������������������������������������������������������������������������  23 3.3 Supernumerary Teeth����������������������������������������������������������������  26 3.4 Other Dental Abnormalities������������������������������������������������������  26 3.5 Genetic Testing ������������������������������������������������������������������������  28 References������������������������������������������������������������������������������������������  30 4 Genetic Basis of Dental Caries and Periapical Pathology������������  33 4.1 Introduction������������������������������������������������������������������������������  33 4.2 Genes Influence Dental Caries Risks����������������������������������������  34 4.3 Dental Caries Progression��������������������������������������������������������  36 4.4 Genomic Biomarkers for Dental Caries������������������������������������  37 References������������������������������������������������������������������������������������������  41 5 Genetic Basis of Periodontitis and Tooth Loss������������������������������  43 5.1 Introduction������������������������������������������������������������������������������  43 5.2 Periodontitis Is Difficult to Measure����������������������������������������  43 5.3 Evidence for a Genetic Contribution����������������������������������������  44 5.4 Interleukin 1 Alpha and Beta����������������������������������������������������  46 5.5 Tooth Loss as an Outcome��������������������������������������������������������  47

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5.6 The Impact of Oral Health on Overall Health��������������������������  48 References������������������������������������������������������������������������������������������  49 6 Genetic Basis of Dental Implant Failure and Alveolar Ridge Resorption������������������������������������������������������������������������������  51 6.1 Introduction������������������������������������������������������������������������������  51 6.2 Risk Factors for Dental Implant Failure ����������������������������������  51 6.3 BRINP3 (Bone Morphogenetic Protein/Retinoic Acid Inducible Neural Specific 3)��������������������������������������������  53 6.4 A Changing Paradigm��������������������������������������������������������������  54 6.5 Alveolar Ridge Resorption ������������������������������������������������������  54 References������������������������������������������������������������������������������������������  57 7 Genetic Basis of Craniofacial Deformities and Malocclusion, Oral Clefts, and Craniosynostosis��������������������������������������������������  59 7.1 Craniofacial Deformities and Malocclusions����������������������������  59 7.1.1 An Unconventional Myosin������������������������������������������  60 7.1.2 Sprinters Versus Marathon Runners������������������������������  61 7.1.3 Facial Asymmetry ��������������������������������������������������������  62 7.1.4 Orthodontic Tooth Movement��������������������������������������  63 7.2 Oral Clefts��������������������������������������������������������������������������������  63 7.2.1 Oral Clefts Frequency Worldwide��������������������������������  63 7.2.2 Left Versus Right����������������������������������������������������������  64 7.2.3 Maternal Cigarette Smoking ����������������������������������������  64 7.2.4 Dental Development ����������������������������������������������������  65 7.2.5 Severity of Oral Clefts��������������������������������������������������  67 7.2.6 Cancer ��������������������������������������������������������������������������  68 7.3 Craniosynostosis ����������������������������������������������������������������������  69 References������������������������������������������������������������������������������������������  70 8 Genetic Basis of Lichen Planus and Oral Cancer ������������������������  73 8.1 Lichen Planus����������������������������������������������������������������������������  73 8.2 Oral Cancer ������������������������������������������������������������������������������  73 8.3 Oral Mucositis��������������������������������������������������������������������������  74 8.4 Radiation Caries������������������������������������������������������������������������  76 8.5 Precision������������������������������������������������������������������������������������  76 References������������������������������������������������������������������������������������������  78 9 Genetic Basis of Orofacial Pain and Temporomandibular Joint Dysfunction ����������������������������������������������������������������������������  81 9.1 Orofacial Pain ��������������������������������������������������������������������������  81 9.2 Variation in the Ability to Respond to Pain Relief Strategies����  83 9.3 Congenital Insensitivity to Pain������������������������������������������������  84 9.4 Temporomandibular Joint Dysfunction (TMD)������������������������  84 9.4.1 Mitochondria and Temporomandibular Joint Dysfunction (TMD) ��������������������������������������������  85 9.5 Stress and Inflammation������������������������������������������������������������  85 References������������������������������������������������������������������������������������������  91

Contents

ix

10 Genetic Influence on Behavior and the Impact on Oral Health Conditions��������������������������������������������������������������  93 10.1 Introduction����������������������������������������������������������������������������  93 10.2 The Interplay of Genes and Environment: Measuring Intelligence������������������������������������������������������������  93 10.3 Sexual Orientation: A Behavioral Genetics Case Study ��������  95 10.3.1 Measuring Heterosexual–Homosexual Orientation ��  95 10.3.2 Height as a Model ����������������������������������������������������  96 10.3.3 Sexual Orientation Distribution in a Population ������  96 10.3.4 Lack of Evolutionary Pressure����������������������������������  97 10.4 Decision-Making Genes����������������������������������������������������������  98 10.5 Risk-Taking Genes������������������������������������������������������������������ 100 10.6 Altruism, Cooperation, and Fear�������������������������������������������� 100 10.7 Belief in the Supernatural ������������������������������������������������������ 102 References������������������������������������������������������������������������������������������ 102

1

Inheritance in Oral Health Conditions

1.1

Introduction

Inheritance of human conditions (both traits and diseases, including those of the craniofacial region) can be divided into three main groups. The vast majority are complex or multifactorial. These are the conditions that are defined by more than one gene, and which can be influenced by the environment (Fig. 1.1; Manolio et al. 2008). Some examples of these conditions include dental caries, periodontitis, dental abnormalities of number and structure, most cases of cleft lip and palate, malocclusion, orofacial pain, oral cancer, and temporomandibular joint dysfunction. The mode of inheritance most people relate to is the one defined by a major single gene, which is called monogenic or Mendelian (Fig.  1.1; Manolio et al. 2008). The reason most know of this type of mode of inheritance is because this is the type typically taught in high school and university curricula. Certain forms of cleft lip, cleft palate, and tooth agenesis are monogenic. The third type refers to conditions that are the result of chromosomal abnormalities. To complicate matters further, there are plenty of exceptions to these three groups. The etiology and progression of all human diseases likely have a genetic and an environmental component, even if we do not have the tools to identify them. If one lined up all human conditions, three main groups can be identified (Fig.  1.2). At one end of the line, we would © Springer Nature Switzerland AG 2019 A. R. Vieira, Genetic Basis of Oral Health Conditions, https://doi.org/10.1007/978-3-030-14485-2_1

see a group of diseases that have a very important genetic component, whereas at the opposite extreme, a group of conditions that have a very important environmental component, and in the vast majority of scenarios, there will be diseases that have both significant genetic and environmental contributions. This chapter will thus aim to describe the main concepts underlying complex inheritance, single gene inheritance, and chromosomal abnormalities. These concepts relate to changes in the DNA sequence and do not include therefore epigenetic changes, which are modifications of gene expression that are not due to alterations of the genetic code itself.

1.2

Complex Inheritance

Complex modes of inheritance explain the large majority of the conditions affecting oral, dental, and craniofacial structures. Most forms of oral cancer, cleft lip and palate, craniosynostosis, craniofacial deformities, malocclusion, periodontitis, dental caries, orofacial pain, temporomandibular joint dysfunction, and developmental dental abnormalities have complex inheritance. Furthermore, various traits such as height (Fig. 1.3), weight, blood pressure, glycemia, response to vaccines, intelligence, behaviors, sexual orientation, and cognition also have a complex mode of inheritance. 1

1  Inheritance in Oral Health Conditions

2

Fig. 1.1  A complex or COMPLEX multifactorial inheritance [CATEGORY NAME] model is the one caused by more than one gene, each [CATEGORY NAME] having a relatively small [CATEGORY NAME] effect. These effects can be [CATEGORY NAME] additive and they can be influenced by environmental factors. A [CATEGORY NAME] [CATEGORY NAME] single gene model is determined by a major gene effect, which can be [CATEGORY NAME] [CATEGORY NAME] dominant or recessive, depending if one copy or two is needed of an altered allele to express the GENE 5 [CATEGORY NAME] phenotype. This expression can vary from individual to [CATEGORY NAME] [CATEGORY NAME] individual even within the same family, and this [CATEGORY NAME] variation can be understood as modulated by other genes and/or SINGLE GENE modified by the environment ENVIRONMENT GENE 4 GENE 3 GENE 2

GENE 1

Conditions that have a complex mode of inheritance have characteristics (Fraser 1970) that can only be fully explained when one assumes that more than one gene, where each individual gene has a relatively small overall effect individually are involved. These characteristics include:

4. The condition is more likely to reoccur in a family when the family has more than one affected individual. 5. The chance of recurrence is higher in first-­ degree relatives of affected individuals than in either second-degree relatives or in relatives that are further removed.

1. Variations in frequency of a trait, depending on the geographic origin (Table 1.1). 2. The condition is more likely to reoccur in a family if the phenotype is more severe. 3. The condition is more likely to reoccur in a family if the individual affected is of the sex less commonly affected.

Since more than one gene is involved in the occurrence of a condition with complex inheritance, it is reasonable to assume that the series of events that lead to such a complex condition can differ case by case. Ignoring variations in the phenotype may then be a deterrent in the effort of mapping genes for these conditions.

1.2 Complex Inheritance Diseases with strong genetic component

3 Diseases with strong environmental component

Influences on diseases Genetics

Environment

All human diseases

Fig. 1.2  The amount of genetic and environmental influences in human diseases can vary immensely. If all human diseases are aligned on the X-axis, the disease closest to the vertex would have a major genetic effect and very little environmental effect, and conversely, the disease further away from the Y-axis would have a major environmental component and a very small genetic influence. The vast majority of diseases have a sizeable amount of influence from both genetics and environment. As an example, across many individuals born with Down syndrome, the ones more likely to survive or have improved quality of life are the ones that will receive more stimuli. The amount of stimulus can be understood as the environmental influ-

ence of Down syndrome, which itself is determined by a chromosomal defect. On the other hand, a gastrointestinal infection is the direct result of exposure to contaminated food, but some individuals may experience more or less severe vomiting and diarrhea. This variable individual response, despite having been exposed to similar amounts of contaminated food, is related to each person’s immune system, which is primarily genetically controlled. The vast majority of diseases that affect many individuals within populations and create a heavy burden to the medical system have sizeable amounts of influence of genetics and the environment

Another reason why it is important to understand the framework that underlies complex inheritance (Fig. 1.3) is that it helps in the interpretation of the effects of a given intervention. When individuals are exposed to fluoride for the prevention of dental caries (be that in drinking water, toothpaste, professional interventions, or added to foods), this leads to a shift to the left of the curve shown in Fig. 1.4 due to a decrease of risk—most of the people in the population will be less likely to present the phenotype. However, the position of each individual in this risk landscape is not likely to change significantly. In other words, the segment of the population with a lower risk to initially will continue to have the lowest risk, while the high-risk group will also remain at a higher risk level. However, everyone would have a lower risk after the intervention. A lower frequency and severity of the phenotype is expected.

Normal traits, such as height, weight, blood pressure, and levels of sugar in the blood, also have a multifactorial inheritance resulting in a continuum of phenotypes rather than an either/or dichotomy. Table  1.2 shows the mean and standard deviations of the maxillary tooth diameters of 150 subjects, aged 18–24  years, from Suazo et al. (2008). Figure 1.5 shows the estimated distribution of buccolingual diameters of right second maxillary molars in females, males, and all individuals. Females have slightly smaller teeth, and thus their curve is shifted to the left. Multiple genes, as in the case of height, likely contribute to the final first maxillary molar dimension, and some of these genes are probably located on the X chromosome, hence the evidence from the literature that in the case of females mosaic for missing one X chromosome (45,X/46,XX, Varrela et al. 1988), tooth sizes of affected individuals are smaller. Females thus likely have smaller teeth,

1  Inheritance in Oral Health Conditions

Frequency

4

m

8

ft

0

153

161

7

169 177 185 Height (cm) m

2

m

201

7 2 6 5

2 6

4

4 1

5

3

4

2 1 1

3 2

3

1

2

0

ft 8

7

5

0

ft 8

6

1

193

0

0

1

dwarfism 0

0

gigantism normal growth

Fig. 1.3  Risks for traits or diseases with complex or multifactorial inheritance accumulate in populations similarly to a normal distribution. When a continuous measurement can be used (x-axis), most individuals are one standard deviation around the mean of the population assessed and essentially the entirety of the population will be within three standard deviations from the mean. Very large devia-

tions from the mean of 4, 5, 6 or more standard deviations are likely due to very strong genetic effects. If one takes height as an example, dwarfism, as well as gigantism, are explained by single gene models and result in a dramatic change in the expected phenotype as based on the population to which these individuals belong

Table 1.1  Frequency of complex traits based on geographic origin

the same way they tend to be shorter than males, due to unique interactions with different hormonal levels and possibly unique gene expressions.

Condition Severe periodontitis Oral clefts (cleft lip only + cleft lip and palate + cleft palate only) Tooth agenesis

Asians Blacks Whites Reference 12.1% 15.6% 6.8% Eke et al. (2015) Vanderas 1.47 0.61 2.03 (1987) per per per 1000 1000 1000

6.9%

3.9%

5.5%

Polder et al. (2004)

1.3

Single Gene Disorders

Monogenic or Mendelian conditions have distinguishable patterns when segregating in families, contrary to what is typically seen in conditions with multifactorial inheritance

1.3 Single Gene Disorders

5

After intervention Before intervention

Fig. 1.4  Distribution of risks of a condition that fits a complex or multifactorial mode of inheritance before and after an intervention that aims to modify those risks. In red, the distribution of the population before the intervention. The amount of risks, including genetic risks, accumulates in the x-axis with most individuals in the population within one standard deviation from the mean risk of the population. After the

intervention (blue curve), all individuals shift to the left and there was an overall impact on risk. However, individuals that had low risk continue to be at the low-risk end of the curve, and individuals that had high risk also continue to be at the high-­risk end of the curve. This suggests that any particular intervention might not be enough for high-risk individuals to avoid developing a particular condition

Table 1.2  Descriptive statistics of mesiodistal and buccolingual diameters of maxillary teeth of 150 males and females between 18 and 24 years

Tooth Right second molar Right first molar Right second premolar Right first premolar Right canine

Sex Male Female Male Female Male Female Male Female Male Female Right lateral Male incisor Female Right central Male incisor Female Left central Male incisor Female Left lateral Male incisor Female Left canine Male Female Left first Male premolar Female Left second Male premolar Female Left first molar Male Female Left second Male molar Female

N 66 77 62 79 62 79 55 71 67 82 66 81 66 83 66 83 67 81 67 83 54 71 62 79 62 81 66 80

Mean in mm Mesiodistal 10.0062 9.8291 10.6784 10.4761 7.0965 6.9629 7.056 6.9172 8.0488 7.9113 7.1021 6.8502 8.6927 8.4707 8.6939 8.5437 6.9455 6.8504 7.9243 7.8360 7.2283 7.0800 6.949 6.7851 10.3897 10.3052 9.8397 9.8548

Standard deviation (mm) 0.74872 0.98408 0.73422 0.68209 0.90884 11.01901 0.7077 0.66066 0.62420 0.60871 0.70753 0.63383 0.73973 0.74266 0.64982 0.74805 0.57821 0.75118 0.61450 0.67230 0.60851 0.59415 0.701 0.71388 0.88912 0.78168 0.82406 0.80418

p-value with alpha 0.05 0.234 0.093 0.420 0.259 0.177 0.024 0.071 0.199 0.397 0.407 0.174 0.175 0.547 0.897

Mean Standard (mm) deviation (mm) Buccolingual 11.3859 0.68071 10.9927 0.63676 11.408 0.77397 11.1157 0.58303 9.5805 0.706 9.4654 0.72221 9.5162 0.78887 9.2907 0.79735 8.3651 0.88795 8.0587 0.7813 6.719 0.7851 6.4 0.8197 7.1748 0.74135 6.9022 0.65968 7.1892 0.75498 7.0743 0.72853 6.6487 0.74567 6.4173 0.81136 8.128 0.9701 7.94 0.7563 9.448 0.872 9.21 0.7856 9.554 0.91451 9.3352 0.88877 11.4069 0.85932 11.1223 0.73839 11.4338 0.94515 11.1762 0.67659

p-value with alpha 0.05 0.001 0.01 0.343 0.119 0.026 0.018 0.019 0.346 0.074 0.185 0.111 0.154 0.033 0.058

1  Inheritance in Oral Health Conditions

6

Distribution of bucolingual diameter of maxillary tooth(1.7) of 150 males and females between 18 and 24 years 7

6

Number of individuals

5

4

3

2

1

0

8

9

10

11

12

13

14

Tooth sizes (mm) Male Female Male+Female

Fig. 1.5  Tooth dimensions fit a complex or multifactorial mode of inheritance. Females have slightly smaller teeth than males, and hence their curve is shifted to the left. This is not surprising, since females tend to be shorter

than their male counterparts. Most individuals are within one standard deviation of the mean, and curves are narrow since tooth sizes in the sample did not vary much

(Fig. 1.5). If having one copy of an altered allele is enough for a given phenotype to be expressed, they are called dominant. Conversely, if both alleles need to be altered for a phenotype to be expressed, they are called recessive. If these alleles are located in any of the genes in one of each of the non-sex chromosome types, they are called autosomal. If they are located in one of the sex chromosomes, X or Y, they are called sex-linked. Since very few genes are located on the Y chromosome, most of the sex-linked conditions are X-linked. There is great variation in the clinical presentation of monogenic conditions, which may complicate the interpretation of these segregation patterns. Certain conditions, even within the same family, can have a range of clinical expressions from very mild to very severe, which is

referred to as having variable expressivity. Such variations in expression may be explained by other genes that attenuate or aggravate the clinical presentation (Fig. 1.1; Manolio et al. 2008). Further, individuals may be carrying the altered allele that leads to a monogenic condition but do not have the condition; this phenomenon is called incomplete penetrance. Penetrance is the proportion of individuals in the population that carry the altered alleles (mutations) and indeed express the disease. Furthermore, there are many instances in which parents do not carry the mutation; the causal mutation arises solely in the affected individual, which we refer to as a de novo mutation, and these cases are referred to as sporadic. Sporadic cases are not limited to monogenic conditions, but can also be seen in conditions of multifactorial inheritance.

References

1.4

7

Chromosomal Abnormalities

Finally, disease may arise from problems in the number (aneuploidy) or structure of the chromosomes. These conditions tend to be more severe and have cognitive involvement, since chromosomal defects may impact several genes simultaneously. These mechanisms also explain a large percentage of spontaneous abortions, which can be as high as 11–35.5% in the population (Wilcox et al. 1988; Wang et al. 2003; Lohstroh et al. 2005). Nondisjunction during meiosis is the likely mechanism explaining many chromosomal aneuploidies. The frequency of nondisjunction increases as women approach the age of 45 (Table 1.3). This maternal age effect in aneuploidies is well documented. Of interest are the cases of younger women with pregnancies that resulted in aneuploidy, as a genetic predisposition may exist (Lister and Frota-Pessoa 1980) due to the inheritance of chromosomal translocations. Advanced paternal age does not typically lead to chromosomal abnormalities, but older males have a higher frequency of point mutations being Table 1.3  Risk of trisomy 21 depending on gestational age (Snijders et al. 1999) Maternal age (years) 20 25 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

Risk of trisomy 21 (down syndrome) at 40 weeks of gestational age 1/1527 1/1352 1/895 1/776 1/659 1/547 1/446 1/356 1/280 1/218 1/167 1/128 1/97 1/73 1/55 1/41 1/30 1/23

transmitted and therefore a higher frequency of certain specific syndromes, including Pfeiffer syndrome, Crouzon syndrome, Apert syndrome, achondroplasia, and thanatophoric dysplasia (Toriello et al. 2008). Aneuploidies compatible with life typically occur for chromosomes 13 (Patau syndrome), 18 (Edwards syndrome), 21 (Down syndrome), and the sex chromosomes [Turner syndrome (X0), Klinefelter syndrome (XXY), trisomy X (XXX), XYY, and XXY]. Aneuploidy in any other chromosome is typically not compatible with life and those instances make up a large percentage of instances of miscarriages.

References Eke PI, Dye BA, Wei L, Slade GD, Thornton-Evans GO, Borgnakke WS, Taylor GW, Page RC, Beck JD, Genco RJ.  Update on prevalence of periodontitis in adults in the United States: NHANES 2009-2012. J Periodontol. 2015;86(5):611–22. Fraser FC. The genetics of cleft lip and cleft palate. Am J Hum Genet. 1970;22(3):336–52. Lister TJ, Frota-Pessoa O. Recurrence risks for down syndrome. Hum Genet. 1980;55(2):203–8. Lohstroh PN, Overstreet JW, Stewart DR, Nakajima ST, Cragun JR, Boyers SP, Lasley BL. Secretion and excretion of human chorionic gonadotropin during early pregnancy. Fertil Steril. 2005;83(4):1000–11. Manolio TA, Brooks LD, Collins FS. A HapMap harvest of insights into the genetics of common disease. J Clin Invest. 2008;118(5):1590–605. Polder BJ, Van’t Hof MA, Van der Linden FPGM, Kuijpers-­ Jagtman AM.  A meta-analysis of the prevalence of dental agenesis of permanent teeth. Community Dent Oral Epidemiol. 2004;32(3):217–26. Snijders RJ, Sundberg K, Holzgreve W, Henry G, Nicolaides KH.  Maternal age- and gestation-specific risk for trisomy 21. Ultrasound Obstet Gynecol. 1999;13(3):167–70. Suazo GI, Cantín LM, López FB, Sandoval MC, Torres MS, Gajardo RP, Gajardo RM.  Sexual dimorphism in mesiodistal and buccolingual tooth dimensions in Chilean people. Int J Morphol. 2008;26(3):609–14. Toriello HV, Meck JMM, Professional Practice Guidelines Committee. Statement on guidance for genetic counseling in advanced paternal age. Genet Med. 2008;10(6):457–60. Vanderas AP. Incidence of cleft lip, cleft palate, and cleft lip and palate among races: a review. Cleft Palate J. 1987;24(3):216–25.

8 Varrela J, Towssend G, Alvesalo L. Tooth crown size in human females with 45,X/46,XX chromosomes. Arch Oral Biol. 1988;33(5):291–4. Wang X, Chen C, Wang L, Chen D, Guang W, French J. Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril. 2003;79(3):577–84. Vivaldi.

1  Inheritance in Oral Health Conditions Wilcox AJ, Weinberg CR, O’Connor JF, Baird DD, Schalatterer JP, Canfield RE, Armstrong EG, Nisula BC.  Incidence of early loss of pregnancy. N Engl J Med. 1988;319(4):189–94.

2

Genetic Basis of Enamel and Dentin Defects

2.1

Introduction

Tooth development is a highly regulated process that can be defined as having a complex or multifactorial pattern of inheritance—tooth development is defined by more than one gene and can also be influenced by the environment (Table 2.1; Thesleff 2003). The understanding of this process is accelerated by the molecular characterization of gene defects resulting in monogenic forms of dental enamel (Table 2.2) and dentin (Table 2.3) abnormalities. These conditions are caused by mutations in a single gene out of the many that are involved in otherwise normal dental enamel or dentin development. The phenotypes of these conditions are severe. It is believed that alleles resulting in less dramatic alterations may play a role in milder disruptions in the development of dental enamel and dentin. This may become meaningful when conditions that increase the risk of dental caries or erosive tooth wear are present. This chapter examines single gene models, such as amelogenesis imperfecta, dentinogenesis imperfecta, and dentin dysplasia, as tools with which to understand the pathogenesis of conditions with complex inheritance, such as dental caries (both incipient lesions in enamel and deep lesions in dentin), enamel hypoplasia (in particular, molar-incisor hypomineralization), erosive tooth wear, and fluorosis.

© Springer Nature Switzerland AG 2019 A. R. Vieira, Genetic Basis of Oral Health Conditions, https://doi.org/10.1007/978-3-030-14485-2_2

2.2

 rom Monogenic to Complex F Forms of Enamel and Dentin Alterations

Monogenic or Mendelian forms of enamel or dentin defects have distinguishable patterns when segregating in families and can be autosomal or X-linked, and dominant or recessive in nature. The identification of mutations leading to enamel or dentin defects thus provided a venue toward understanding the mechanisms involved in dental development. This is an important practical concept as dental development is a complex trait, defined by more than one gene, and possibly more than 200 genes are involved in dental development (Gene expression in tooth 1996-2007), in addition to being potentially influenced by the environment. However, amelogenesis imperfecta, dentinogenesis imperfecta, and dentin dysplasia are monogenic conditions, and the identification of the mutated gene immediately gives a clue on the mechanisms and pathways that determine dental enamel or dentin formation. Therefore, studying these conditions is important, not only for the effort of identifying individual mutations, but also for the understanding of the role genes play during dental development.

9

Bmp7 Bono1 Btrc Cd44 Cdkn1a CNR-cluster Ctgf/Fisp12 Cyp26C1 Dab1 Dll1 Dlx2 Dlx3 Dlx4 Dlx5 Dlx6 Ectodin Eda Edar Egr1 Fgf1 Fgf10

Arnt Axin1 Axin2 Barx1 BEN/DM-GRASP/SC1 Bmp2 Bmp3 Bmp4 Bmp5 Bmp6 Bmp7 Bono1 Bpag1 Btrc C-Myb cadherin 1 catenin beta Cd44 CNR-cluster collagen type I collagen type III

Aquaporin4 Aquaporin5 Aquaporin9

Bmp4 Bmp5 Bmp6 Aquaporin4 Aquaporin5 Aquaporin9 Axin1 Axin2 Barx1 BEN/DM-GRASP/SC1 Bmp2 Bmp3 Bmp4 Bmp5 Bmp6 Bmp7 Bono1 Bpag1 brevican C-Myc cadherin 1 catenin beta Cd44 cerebroglycan

Aquaporin1 Aquaporin2 Aquaporin3

antizyme 1 appican

Aquaporin2 Aquaporin3

Axin2 Barx1 BEN/ DM-GRASP/SC1 Bmp2 Bmp3 Bmp4 Bmp5 Bmp6 Bmp7 Bono1 Bpag1 Btrc cadherin 1 catenin beta Cd44 Cdkn1a Cdkn1a CNR-cluster collagen type I collagen type III collagen type IV Crabp1 Ctgf/Fisp12 Dab1

alkaline phosphatase amelogenin

Bell stage activin beta A aggrecan 1 Ahr

antizyme 1 Aquaporin1

Cap stage activin beta A alkaline phosphatase amelogenin

Barx1 BEN/ DM-GRASP/SC1 Bmp2 Arnt Bmp3 Axin1

Bud stage activin beta A Ahr alkaline phosphatase amelogenin antizyme 1

Initiation stage activin beta A Axin1 Axin2

Table 2.1  Genes expressed during dental development by dental development stage

Aquaporin2 Aquaporin3 Aquaporin4 Aquaporin5 Aquaporin9 Axin1 Axin2 Barx1 Bax Bcl2 biglycan Bmp2 Bmp3 Bmp4 Bmp5 Bmp6 Bmp7 Bono1 Bpag1 brevican Btrc

amelogenin amelogenin and enamelin antizyme 1 appican Aquaporin1

alkaline phosphatase ameloblastin

Differentiation stage activin beta A aggrecan 1 Ahr

Aquaporin5 Arnt Bax Bcl2 biglycan Bmp2 Bmp3 Bmp4 Bmp5 Bmp6 Bmp7 Bono1 brevican C-Cam C-ErbB2 cadherin 1 cerebroglycan clusterin collagen type I collagen type I collagen type III

ameloprotease-I appican Aquaporin4

amelogenin amelogenin and enamelin

alkaline phosphatase ameloblastin

Secretory stage activin beta A aggrecan 1 Ahr

collagen type III collagen type VI dentin sialoprotein enamelin ErbB3 fibromodulin lumican Mmp9 Msx1 Msx2 osteocalcin osteopontin Runx2 secreted phosphoprotein 1 Sonic hedgehog Timp1

cadherin 1 collagen type I collagen type I

Bmp7 Bono1

Bmp3 Bmp4

Root development amelogenin appican Bmp2

10 2  Genetic Basis of Enamel and Dentin Defects

Edar Edaradd

fibulin 2 follistatin

forkhead Gdnf Gfr alpha-1 Gfr alpha-2 Gli1

Lhx6 Lhx8 Mfng MFrp2 MFrzb1

EGFR Egr1 EphA7 ErbB3 ErbB4

collagen type III collagen type IV collagen type VI collagen type VII Crabp1 Ctgf/Fisp12 Cyp26C1 cytokeratin 1 cytokeratin 10 cytokeratin 13 cytokeratin 18 cytokeratin 19 cytokeratin 4 cytokeratin 5 cytokeratin 7 cytokeratin 8 Dab1 desmoglein Dll1 Dlx1 Dlx2 Dlx3 Dlx4 Dlx5 Dlx6 Ectodin Eda

desmoglein Dll1 Dlx1 Dlx2 Dlx3 Dlx4 Dlx5 Dlx6 Ectodin Eda Edar Egr1 ErbB3 ErbB4 Fadd Fas Fgf10 Fgf3 Fgf4 Fgf7 Fgf8 Fgf9 Fgfr1 Fgfr2 Fgfr3 Fgfr4 fibulin 1

Fgf2 Fgf3 Fgf4 Fgf7 Fgf8 Fgf9 Fgfr1 Fgfr2 Fgfr3 Fgfr4 fibulin 1 fibulin 2 forkhead Gas1 Gli1 Gli2 Gli3 Hand1 IKBA IKKA IKKB integrin beta 5 Islet1 Jag2 laminin 5 alpha 3 laminin 5 beta 3 laminin 5 gamma 2 Lef1 Lfng Dlx5 Dlx6 Ectodin Eda Edar

Dlx3 Dlx4

collagen type I collagen type I collagen type II collagen type III collagen type III collagen type IV collagen type VI collagen type VII connexin43 Crabp1 Cspg4 Ctgf/Fisp12 cyclin A Cyp26C1 cytokeratin 1 cytokeratin 10 cytokeratin 13 cytokeratin 18 cytokeratin 19 cytokeratin 4 cytokeratin 5 cytokeratin 7 cytokeratin 8 decorin Dermo1 desmoglein Dlx2 decorin dentin sialophosphoprotein dentin sialoprotein desmoglein Dlx2 Dlx3 Dlx4

C-Cam cadherin 1 Calb1 catenin beta Cd24 Cd44 cerebroglycan clusterin CNR-cluster collagen type I collagen type I collagen type III collagen type III collagen type IV collagen type V collagen type VI collagen type VII Crabp1 Cspg4 Ctgf/Fisp12 cyclin A Cyclin D1 Cyp26C1 cytokeratin 1 cytokeratin 19 cytokeratin 8 Dab1

Gfr alpha-1 Gfr alpha-2 glypican Has Hspb1

follistatin Gdnf

collagen type III collagen type IV collagen type V collagen type VII connexin43 Cspg4 Ctgf/Fisp12 cyclin A decorin dentin phosphoprotein dentin sialophosphoprotein dentin sialoprotein EGFR Egr1 enamelin enamelysin ErbB3 ErbB4 Fgf1 Fgf2 Fgf9 Fgfr1 Fgfr2 Fgfr3 Fgfr4 fibronectin fibronectin

(continued)

2.2  From Monogenic to Complex Forms of Enamel and Dentin Alterations 11

Raf1 Rara Rarb Rarg Rbp1

Initiation stage MFz6 midkine Mmp2 Msx1 Msx2 Netrin1 Netrin3 Neuropilin1 Neuropilin2 Ngf Ngfr Notch1 Notch2 Notch3 Ntf3 Ntf5 Ntrk1 Ntrk3 Oasis Pace4 Patched 1 Pax9 Pcdh-gamma pigpen Pitx2 Prrx1 Prrx2 Rab23

Bud stage Gli2 Gli3 Hand1 Hand2 heparan sulfate Hes1 Hes5 IKBA IKKA IKKB integrin alpha 4 integrin alpha 6 integrin alpha v integrin beta 1 integrin beta 4 integrin beta 5 Irx1 Irx2 Irx3 Irx4 Irx5 Irx6 Islet1 Jag1 Jag2 laminin 5 alpha 3 laminin 5 beta 3 laminin 5 gamma 2 laminin alpha 1 laminin alpha 2 laminin alpha 3a laminin alpha 3b laminin alpha 5

Table 2.1 (continued)

Hes1 Hes5 Hgf Hip1 IKBA

Cap stage Fadd Fas Fgf1 Fgf10 Fgf2 Fgf3 Fgf4 Fgf7 Fgf8 Fgf9 Fgfr1 Fgfr2 Fgfr3 Fgfr4 fibronectin fibronectin fibulin 1 fibulin 2 follistatin Gdnf Gfr alpha-1 Gfr alpha-2 Gli1 Gli2 Gli3 Hand1 Hand2 heparan sulfate Hspg2 integrin alpha 4 integrin alpha 6 integrin alpha v integrin beta 1

Bell stage Egf EGFR Egr1 endothelin Fadd Fas Fgf1 Fgf10 Fgf3 Fgf4 Fgf7 Fgf8 Fgf9 Fgfr1 Fgfr2 Fgfr3 Fgfr4 fibronectin fibronectin fibulin 1 fibulin 2 follistatin glypican Hand1 Hand2 Has heparan sulfate Hgf Gfr alpha-1 Gfr alpha-2 glypican Hand1 Hand2

Differentiation stage Dlx5 Dlx6 Ectodin Eda Edar EGFR Egr1 enamelysin endothelin ErbB3 ErbB4 Fgf1 Fgf10 Fgf2 Fgf3 Fgf4 Fgf7 Fgf8 Fgf9 Fgfr1 Fgfr1 Fgfr2 Fgfr3 Fgfr4 fibronectin fibronectin follistatin Gdnf Ntrk3 Oasis Occludin onnexin32 osteocalcin

Secretory stage Hspg2 Igf1 Islet1 K-glypican Kallikrein 4 laminin laminin 5 alpha 3 laminin 5 beta 3 laminin 5 gamma 2 laminin alpha 1 laminin alpha 3b laminin alpha 5 Lfng Lhx6 Lhx8 midkine Mmp2 Mmp9 Msx1 Nestin neuroglycan Ngf Ngfr Notch1 Notch2 Notch3 Nrg1 Ntrk1

Root development

12 2  Genetic Basis of Enamel and Dentin Defects

Lef1 Lfng Lhx6 Lhx8 membrane metallo endopeptidase Mfng MFrp2 MFrzb1 MFz6 midkine Mmp13 Mmp14 Mmp2 Mmp3 Mmp9 Msx1 Msx2

Netrin1 Netrin3 Neuropilin1 Neuropilin2 Ngf Ngfr Nlrr3 Notch1

Notch2 Notch3 Nrg1 Ntf3 Ntf5 Ntrk1 Ntrk3

Rxra Rxrb Rxrg Sema3a Sema3b Sema3c Sema3f Slit1 Slit2 Slit3 Smo Sonic hedgehog

Sp6 syndecan 1 syndecan 2 tenascin C Tfap2a Tfap2c Tgfb1 Timp1

Timp3 Tlx1 Tnfrsf19 Traf1 Traf2 Traf3 Traf4

Reelin Rfng Robo1 Robo2 Runx2

laminin alpha 3b laminin alpha 4 laminin alpha 5 Lef1 Lfng Lhx6 Lhx8 membrane metallo endopeptidase Met proto-oncogene Mfng MFrp2 MFrzb1 MFz6 midkine mlarp

integrin beta 4 integrin beta 5 Islet1 Jag1 Jag2 laminin laminin 5 alpha 3 laminin 5 beta 3 laminin 5 gamma 2 laminin alpha 1 laminin alpha 2 laminin alpha 3a

IKKA IKKG integrin alpha 6 integrin alpha v integrin beta 1

Msx1 Msx2 N-myc Netrin1 Netrin3 neuroglycan Neuropilin1

laminin 5 alpha 3 laminin 5 beta 3 laminin 5 gamma 2 laminin alpha 1 laminin alpha 2 laminin alpha 3a laminin alpha 3b laminin alpha 5 Lef1 Lhx6 Lhx8 membrane metallo endopeptidase Met proto-oncogene MFrp2 MFrzb1 MFz6 midkine Mmp14 Mmp2 Mmp9

integrin beta 4 integrin beta 5 Islet1 K-glypican laminin

Neuropilin1 Neuropilin2 Ngf Ngfr Notch1 Notch2 Notch3

Met proto-oncogene midkine Mmp14 Mmp2 Mmp9 Msx1 Msx2 neuroglycan

Islet1 K-glypican laminin laminin 5 alpha 3 laminin 5 beta 3 laminin 5 gamma 2 laminin alpha 1 laminin alpha 2 laminin alpha 3b laminin alpha 5 Lhx6 Lhx8

heparan sulfate Hgf Hip1 Hspg2 integrin beta 5

tenascin tenascin C Tgfb1 Timp1 Timp2 Timp3 Tjp1

Rxrg secreted phosphoprotein 1 Sonic hedgehog Spock1 syndecan 1 syndecan 2 syndecan 3 syndecan 4

Pthlh Pthr1 Rara Rarb Rarg Reelin Ret Runx1 Runx2 Runx3 Rxra Rxrb

osteopontin P-cadherin Pcna phosphacan Plp1

(continued)

2.2  From Monogenic to Complex Forms of Enamel and Dentin Alterations 13

Initiation stage Traf6 trkB.FL trkB.T1 trkB.T2 Trp63 Wnt10a Wnt10b Wnt3 Wnt4 Wnt5a Wnt6 Wnt7b Wt1

Bud stage Oasis Odc Ofd1 P-cadherin p21 Pace4 Patched 1 Patched 2 Pax9 Pcdh-gamma pigpen Pitx2 plakoglobin Prrx1 Prrx2 Rab23 Raf1 Rbp1 Reelin Ret Rfng Robo1 Robo2 Runx1 Runx2 Runx3 Rxrb Sema3a Sema3b Sema3c Sema3f Slit1 Slit2 Slit3 Slitrk6

Table 2.1 (continued)

Cap stage Mmp14 Mmp2 Mmp9 Msx1 Msx2 N-myc Ndr1 Netrin1 Netrin3 Neuropilin1 Neuropilin2 Ngf Ngfr Noggin Notch1 Notch2 Notch3 Nrg1 Ntf3 Ntf5 Ntrk1 Ntrk3 Oasis Occludin Odc Osr2 P-cadherin p21 Pace4 Patched 1 Patched 2 Pax9 Pcdh-gamma pigpen Pitx2

Bell stage Neuropilin2 Ngf Ngfr Notch1 Notch2 Notch3 Ntf3 Ntf5 Ntrk1 Ntrk3 Oasis Occludin Odc P-cadherin p21 Pace4 Patched 1 Patched 2 Pax9 phosphacan pigpen Pitx2 plakoglobin Prrx2 Pthlh Pthr1 Pvrl1 Rara Rarb Rarg Rbp1 Robo1 Robo2 Runx1 Runx2

Differentiation stage Nrg1 Ntf3 Ntf5 Ntrk1 Ntrk3 Oasis Occludin Odc onnexin32 osteocalcin P-cadherin p21 Pace4 Patched 1 Pcdh-gamma Pcna phosphacan plakoglobin procollagen type III Rab23 Raf1 Rara Rarb Rarg Rbp1 Reelin Ret Robo1 Robo2 Runx1 Runx2 Runx3 Rxra Rxrb Rxrg

Secretory stage Tjp2 Tjp3 trkB.FL trkB.T2 tuftelin versican vimentin Wt1

Root development

14 2  Genetic Basis of Enamel and Dentin Defects

Smo Snai1 Rarg Sonic hedgehog Sox9 Sp6 Spry1 Spry4 syndecan 1 syndecan 2 Tac1 Tbx1 Tcf1 tenascin tenascin C Tfap2a Tgfb1 Tgfb2 Tgfb3 Tgfbr2 Timp1 Timp2 Timp3 Tjp1 Tjp2 Tjp3 Tlx1 Tnfrsf19 Tnfsf6 Traf1 Traf2 Traf3 Traf4 Traf6 trkB.FL

plakoglobin pleiotrophin Plu1 Prrx2 Rab23 Raf1 Rara Rarb Sema3f Slit1 Slit2 Ret Rfng Robo1 Robo2 Ror1 Ror2 Runx1 Runx2 Runx3 Rxra Rxrb Rxrg Sema3a Sema3b Sema3c Slit3 Smo Sonic hedgehog Sp4 Sp6 Spry1 Spry2 Spry4 syndecan 1

Runx3 Rxra Rxrb Rxrg Sema3a Sema3b Sema3c Sox9 Sp6 Spock1 Slit3 Sonic hedgehog syndecan 1 syndecan 2 syndecan 3 syndecan 4 Tac1 tenascin tenascin C Tgfb1 Tgfb3 Tgfbr2 Timp Timp1 Timp2 Timp3 Tjp1 Tjp2 Tjp3 Tlx1 Tnfrsf19 Tnfsf6 Traf1 Traf2 Traf3

Sema3a Sema3b Sema3c Sema3f Slit1 Slit2 Slit3 Sonic hedgehog syndecan 1 syndecan 2 syndecan 3 syndecan 4 tenascin tenascin C Tgfb1 Tgfb2 Tgfb3 Timp Timp1 Timp2 Timp3 Tjp1 Tjp2 Tjp3 trkB.FL trkB.T1 trkB.T2 tuftelin versican Wt1

(continued)

2.2  From Monogenic to Complex Forms of Enamel and Dentin Alterations 15

Initiation stage

Bud stage trkB.T1 trkB.T2 Wnt10a Wnt10b Wnt3 Wnt4 Wnt5a Wnt6 Wnt7b Wt1

Table 2.1 (continued)

Cap stage syndecan 2 Tac1 Tcf1 tenascin tenascin C Tgfb1 Tgfb3 Timp Timp1 Timp2 Timp3 Tjp1 Tjp2 Tjp3 Tlx1 Tnfrsf19 Tnfsf6 Traf1 Traf2 Traf3 Traf4 Traf6 trkB.FL trkB.T1 trkB.T2 vimentin Wnt10a Wnt10b Wnt3 Wnt4 Wnt5a Wnt6 Wnt7b Wt1

Bell stage Traf4 Traf6 trkB.FL trkB.T1 trkB.T2 tuftelin versican vimentin Wnt10b Wnt3 Wnt4 Wnt5a Wnt6 Wnt7b Wt1

Differentiation stage

Secretory stage

Root development

16 2  Genetic Basis of Enamel and Dentin Defects

2.2  From Monogenic to Complex Forms of Enamel and Dentin Alterations

17

Table 2.2  Monogenic forms of amelogenesis imperfecta (Smith et al. 2017; Kim et al. 2019) Additional anomalies or traits Mechanism (OMIM #) Approximately 90% of total enamel matrix protein secreted by ameloblasts in AMELX Ameloblastin (AMBN) Part of the remaining 10% of total enamel matrix protein secreted by ameloblasts Enamelin (ENAM) Part of the remaining 10% of total enamel matrix protein secreted by ameloblasts Matrix metalloproteinase 20 (MMP20) Enamel matrix proteases that cleaves enamel matrix proteins during the secretory stage Kallikrein related peptidase 4 (KLK4) Enamel matrix proteases that degrades enamel matrix proteins during the maturation stage Cell-surface adhesion receptor that Integrin, β6 (ITGB6) mediates cell–cell and cell–extra cellular matrix interactions Laminin, alpha 3 (LAMA3), laminin, beta Ameloblast adhesion to the enamel Epidermolysis bullosa (226650) surface 3 (LAMB3), and collagen type XVII alpha 1 (COL17A1) Amelotin (AMTN) Facilitates attachment between maturation stage ameloblasts and the mineralizing enamel Helps stabilizing epithelial cells Family with sequence similarity 83, member H (FAM83H) WD repeat domain 72 (WDR72) Transport and removal of proteins Transport of Ca2+ ions from Solute carrier family 24 (sodium/ Skin, hair, eye pigmentation (blond/ potassium/calcium exchanger), member 4 ameloblasts into the enamel matrix brown hair, blue/green eyes) (SLC24A4) (210750) during maturation G protein-coupled receptor 68 (GPR68) Calcium release from intracellular stores Chromosome 4 open reading frame 26 Promotes hydroxyapatite (C4orf26) nucleation and crystal growth Acid phosphatase, testicular (ACPT) Supplies phosphate during dentin formation eliciting odontoblast differentiation and mineralization Family with sequence similarity 20, Phosphorylates secreted proteins Raine syndrome (259775) member A (FAM20C) Distal-less homeobox 3 (DLX3) Binds to AMELX and ENAM Trichodentosseous syndrome (190320) Gap junction protein (GJA1) Building blocks of gap junction Oculodentodigital dysplasia channels (164200 and 257850) Claudin 16 (CLDN16) Reabsorption of divalent cations Hypomagnesemia 3 (248250) Claudin 19 (CLDN19) Regulatory barrier that separates Hypomagnesemia 5 (248190) fluid compartments Mediates coupled movement of Renal tubular acidosis (604278) Solute carrier family 4 (sodium sodium and bicarbonate ions bicarbonate cotransporter), member 4 (SLC4A4) Family with sequence similarity 20, Modulates secretion Enamel-renal syndrome (204690) member A (FAM20A) Lysosomal N-acetylgalactosamine-sulfate Catabolism of keratan and Mucopolysaccharidosis IVA sulfatase (GALNS) chondroitin sulfate (253000) Peroxisome biogenesis factor 1 and 6 Restore peroxisomes Heimler syndrome (234580 and (PEX1 and PEX6) 616617) Gene mutated Amelogenin (AMELX)

2  Genetic Basis of Enamel and Dentin Defects

18 Table 2.2 (continued) Gene mutated Solute carrier family 13 (sodium-­ dependent citrate transporter), member 5 (SLC13A5) Latent transforming growth factor-beta-­ binding protein 3 (LTBP3) Receptor expressed in lymphoid tissues (RELT)

Mechanism Transporter with preference for citrate

Additional anomalies or traits (OMIM #) Epileptic encephalopathy (615905)

Modulates TGF-beta bioavailability Dental anomalies and short stature (601216) Binds to members of the tumor necrosis factor (TNF) superfamily

Table 2.3  Monogenic forms of dentinogenesis imperfecta and dentin dysplasia (Chen et al. 2019) Gene Dentin sialophosphoprotein (DSPP) (SPARC)-related modular calcium-binding protein-2 (SMOC2) Vacuolar protein sorting 4B (VPS4B) Ssu-2 homolog (SSUH2)

Mechanism Hardening of collagen Unknown

Condition Dentinogenesis imperfecta and dentin dysplasia type II Dentin dysplasia I

Unknown Unknown

Dentin dysplasia I Dentin dysplasia I

Table 2.4  Gene–gene interactionsa in MIH (Bussaneli et al. 2019) Gene–gene interactions IL4-TUFT1 IL4-BMP2 IL4-AMELX IL17A-AMELX IL10-AMELX IL1A-AMELX STAT1-AMELX

Marker alleles CT (rs2070874-rs7526319) CG (rs2070874-rs2355767) CT (rs2070874-rs6654939) GT (rs2275913-rs6654939) GT (rs1800872-rs6654939) GT (rs1800587-rs6654939) GT (rs3771300-rs6654939)

Number of informative heterozygotes 22 19 27 27 23 26 27

p-value 0.03 0.001 0.006 0.003 0.009 0.03 0.009

The gene–gene interaction analyses were made by observing the transmission of the marker alleles (one of immune response and another of tooth development) from heterozygous parents for both of the markers (Vieira et al. 2004)

a

2.3

Molar-Incisor Hypomineralization (MIH)

MIH, which affects the permanent first molars and incisors, was originally described as an idiopathic defect (Weerheijm 2003) but it actually fits the framework of a multifactorial genetic condition (Vieira and Kup 2016), meaning more than one gene is likely involved which can all be influenced by the environment. The same genes, that when mutated can lead to amelogenesis imperfecta (Jeremias et  al. 2013; see also the list of these genes in Table 2.2), likely contribute to the expression of MIH.  This genetic contribution appears to also involve genes

related to inflammatory responses (Table  2.4). Inflammatory genes interacting with the presence of infection may be a model explaining a portion of MIH cases (Bussaneli et al. 2019).

2.4

 ental Caries and Erosive D Tooth Wear

When genes involved in enamel or dentin development are mutated lead to profound consequences and visible disruptions of these structures (e.g., amelogenesis imperfecta or dentinogenesis imperfecta). The case can be made that genetic variation leading to microscopic disruptions of

2.5  Dental Fluorosis

19

dental enamel could also increase individual susceptibility to mineral loss under low-pH conditions. Acidic conditions in the oral cavity, whether brought on by bacterial metabolism of sugars or an inherently acidic diet, can precipitate development of dental caries or erosive tooth wear. The exposure to these acidic conditions in combination with dental enamel that is overall more susceptible to mineral loss motivated testing the hypothesis that dental enamel formation genes are associated with dental caries and erosive tooth wear. Amelogenin (AMELX) has been consistently associated with both dental caries (Vieira et al. 2014; Nibali et al. 2017) and erosive tooth wear (Søvik et al. 2015; Uhlen et al. 2016). Transgenic mice overexpressing Amelx are more resistant to artificial dental caries, whereas Amelx-knockout mice showed a greater level of demineralization (Vieira et al. 2015). Genetic variation in AMELX contributes to dental enamel defects ranging from amelogenesis imperfecta due to complete inactivation of the gene, through milder phenotypes such as MIH, to individual susceptibility to dental caries or erosive tooth wear (Fig. 2.1).

2.5

Dental Fluorosis

Dental fluorosis is characterized by degrees of intrinsic tooth alterations that are visible to the naked eye. The window of time in which someone can develop signs of dental fluorosis ranges from 4 months in utero through 8 years old, and even beyond if one considers all the posterior teeth (Warren et al. 2001; O’Mullane et al. 2016). It must be noted however that dental fluorosis is considered as a side effect of chronic excessive ingestion of fluoride, rather than an adverse health concern (Zohoori and Maguire 2018). The frequency of fluorosis at any severity is reported to be 55% in fluoridated areas and 27% in non-­ fluoridated areas (McGrady et  al. 2012). These figures suggest it is not very difficult to reach levels of fluoride exposure that can alter dental development. The susceptibility to dental fluorosis can thus be understood as having a multifactorial mode of inheritance, similar to that of MIH or dental caries. Exposure to levels of fluoride twice as high as the optimum in the drinking water increases the prevalence of dental fluorosis; however, upon further exploration of the genetic

AMELX expression

Dental Caries and erosive tooth wear: 0.1% to 10% of AMELX inactive

Molar-incisor hypomineralization: 10% to 50% of AMELX inactive

Sugar-rich diet Acidic diet Microbiota

Infection

Amelogenesis imperfecta: 50% or more of AMELX inactive

Amelogenin spectrum

Fig. 2.1  AMELX is linked to amelogenesis imperfecta, molar-incisor hypomineralization (MIH), dental caries, and erosive tooth wear depending on the amount of gene impairment

20

impact attributed to dental fluorosis, it was revealed that individuals carrying the G allele of aquaporin 5 (AQP5) rs296763 are protected against this disruption of dental development (Sezgin et  al. 2018). AQP5 is a water channel protein that is implicated in the production of saliva, tears, and pulmonary secretions. AQP5 is expressed during dental development in the dental lamina, inner dental enamel epithelium, stratum intermedium, stellate reticulum, and the outer dental enamel epithelium (Felszeghy et  al. 2004). It has been shown to be associated with dental caries experience (Wang et  al. 2012; Anjomshoaa et al. 2015), the formation of incipient artificial lesions in enamel (Vieira et al. 2017), and interacts with dental enamel formation genes (Anjomshoaa et al. 2015). Thus, suggesting AQP5 impacts the characteristics of the enamel structure, making it more prone to the carious attack. There was also evidence that the expression of AQP5 in saliva was associated with lower caries experience scores and that an excess of fluoride in the drinking water inhibited this positive protective effect of AQP5 on the dental caries experience (Anjomshoaa et al. 2015). Data from mice (Charone et al. 2019) suggest that additional genes that have a role in enamel development also play a role in modulating the clinical presentation of dental fluorosis, further demonstrating that a multifactorial or complex mode of inheritance in the best fit to describe the genetics contribution to dental fluorosis in humans.

References Anjomshoaa I, Briseño-Ruiz J, Deeley K, Poletta FA, Mereb JC, Leite AL, Barreta PA, Silva TL, Dizak P, Ruff T, Patir A, Koruyucu M, Abbasoğlu Z, Casado PL, Brown A, Zaky SH, Bayram M, Küchler EC, Cooper ME, Liu K, Marazita ML, Tanboğa İ, Granjeiro JM, Seymen F, Castilla EE, Orioli IM, Sfeir C, Ouyang H, Buzalaf MA, Vieira AR.  Aquaporin 5 interacts with fluoride and possibly protects against caries. PLoS One. 2015;10:e0143068. Bussaneli DG, Restrepo M, Fragelli CMB, Santos-Pinto L, Jeremias F, Cordeiro RCL, Bezamat M, Vieira AR, Scarel-Caminaga RM. Genes regulating immune response and amelogenesis interact in increasing the

2  Genetic Basis of Enamel and Dentin Defects susceptibility to molar-incisor hypomineralization. Caries Res. 2019;53:217–27. Charone S, Kūchler EC, Leite AL, Fernandes MS, Pelá VT, Martini T, Brondino BM, Magalhāes AC, Dionisio TJ, Santos CF, Buzalaf MAR.  Analysis of polymorphisms in genes differentially expressed in the enamel of mice with different genetic susceptibilities to dental fluorosis. Caries Res. 2019;953:228–33. Chen D, Li X, Lu F, Wang Y, Xiong F, Li Q. Dentin dysplasia type I-A dental disease with genetic heterogeneity. Oral Dis. 2019;25(2):439–46. Felszeghy S, Módis L, Németh P, Hagy G, Zelles T, Agre P, Laurikkala J, Fejerskov O, Thesleff I, Nielsen S.  Expression of aquaporin isoforms during human and mouse tooth development. Arch Oral Biol. 2004;49:247–57. Gene expression in tooth (WWW database). http://bite-it. helsinki.fi. Developmental Biology Programme of the University of Helsinki, 1996-2007. Jeremias F, Koruyucu M, Küchler EC, Bayram M, Tuna EB, Deeley K, Pierri RA, Souza JF, Fragelli CMB, Paschoal MAB, Gencay K, Seymen F, Caminaga RMS, Santos-Pinto L, Vieira AR.  Genes expressed in dental enamel development are associated with molar-incisor hypomineralization. Arch Oral Biol. 2013;58:1434–42. Kim JW, Zhang H, Seymen F, Koroyucu M, Hu Y, Kang J, Kim YJ, Ikeda A, Kasimoglu Y, Byram M, Zhang C, Kawasaki K, Bartlett JD, Saunders TL, Simmer JP, Hu JCC.  Mutations in RELT cause autosomal recessive amelogenesis imperfecta. Clin Genet. 2019;95(3):375–83. McGrady MG, Ellwood RP, Maguire A, Goodwin M, Boothman N, Pretty IA.  The association between social deprivation and the prevalence and severity of dental caries and fluorosis in population with and without water fluoridation. BMC Public Health. 2012;12:1122. Nibali L, Di Iorio A, Tu Y-K, Vieira AR.  Host genetics role in the pathogenesis of periodontal disease and caries. J Clin Periodontol. 2017;44(Suppl 18):S52–78. O’Mullane DM, Baez RJ, Jones S, Lennon MA, Petersen PE, Rugg-Gunn AJ, Whelton H, WhiCord GM.  Fluoride and oral health. Community Dent Health. 2016;33:69–99. Sezgin BT, Onur ŞG, Menteş A, Okutan AE, Haznedaroğlu E, Vieira AR. Two-fold excess of fluoride in the drinking water has no obvious health effects other than dental fluorosis. J Trace Elem Med Biol. 2018;50:216–22. Smith CEL, Poulter JA, Antanaviciute A, Kirkham J, Brookes SJ, Inglehearn CF, Mighell AJ. Amelogenesis imperfecta; genes, proteins, and pathways. Front Physiol. 2017;8:435. Søvik JB, Vieira AR, Tveit AB, Mulic A. Enamel formation genes associated with dental erosive wear. Caries Res. 2015;49:236–42. Thesleff I.  Epithelial-mesenchymal signaling regulating tooth morphogenesis. J Cell Sci. 2003;116(9):1647–8. Uhlen M-M, Stenhagen KR, Dizak PM, Holme B, Mulic A, Tveit AB, Vieira AR. Genetic variation may explain

References why females are less susceptible to dental erosion. Eur J Oral Sci. 2016;124:426–32. Vieira AR, Kup E. On the etiology of molar-incisor hypomineralization. Caries Res. 2016;50:166–9. Vieira AR, Meira R, Modesto A, Murray JC.  MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. J Dent Res. 2004;83:723–7. Vieira AR, Modesto A, Marazita ML.  Caries: review of human genetics research. Caries Res. 2014;48:491–506. Vieira AR, Gibson CW, Deeley K, Xue H, Li Y. Weaker dental enamel explains dental decay. PLoS One. 2015;19(4):e0124236. Vieira AR, Bayram M, Seymen F, Sencak R, Lippert F, Modesto A. In vitro acid-mediated initial dental enamel loss is associated with genetic variants

21 previously linked to caries experience. Front Physiol. 2017;8:104. Wang X, Willing MC, Marazita ML, Wendell S, Warren JJ, Broffitt B, Smith B, Busch T, Lidral AC, Levy SM.  Genetic and environmental factors associated with dental caries in children: the Iowa fluoride study. Caries Res. 2012;46:177–84. Warren JJ, Levy SM, Kanellis MJ.  Prevalence of dental fluorosis in primary dentition. J Public Health Dent. 2001;61:87–91. Weerheijm KL. Molar incisor hypomineralization (MIH). Eur J Paediatr Dent. 2003;4:114–20. Zohoori FV, Maguire A.  Are there good reasons for fluoride labelling of food and drink? Br Dent J. 2018;224:215–7.

3

Genetic Basis of Tooth Agenesis, Supernumerary Teeth, and Other Dental Abnormalities

3.1

Introduction

Table 3.1  Genes associated with isolated forms of tooth agenesis (modified from Williams and Letra 2018) Gene AXIN2 ANTXR1 COL17A1 DKK1 EDA EDAR EDARADD

Alterations in number and/or structure of the dentition are the most common craniofacial congenital anomalies in humans. Dental development is regulated by hundreds of genes (Thesleff 2003) and conditions affecting the dentition can be defined as complex or multifactorial, although several monogenic forms of dental abnormalities have also been identified. The most common alteration in number of the dentition is tooth agenesis. Since it is the most common, a great deal is known about tooth agenesis in comparison to other dental abnormalities.

3.2

FGFR1 GREM2 IRF6 KDF1a MSX1

Tooth Agenesis

Tooth agenesis is the congenital lack of one or more of the deciduous or permanent teeth. Clinically, tooth agenesis is typically described as hypodontia or oligodontia. Oligodontia is the agenesis of six or more permanent teeth, whereas absence of less than six teeth is referred to as hypodontia. Anodontia refers to the absence of all deciduous and permanent teeth. The extent to which tooth agenesis is manifested varies widely and it can be present as the only phenotypic feature (isolated, Table  3.1), or associated with other anomalies or as part of a syndrome (Table 3.2). Further, tooth agenesis may involve specific groups of teeth. For instance, as a group, © Springer Nature Switzerland AG 2019 A. R. Vieira, Genetic Basis of Oral Health Conditions, https://doi.org/10.1007/978-3-030-14485-2_3

LAMA3 LRP6 LTBP3 PAX9 SMOC2 TGFAb WNT10A WNT10B

Locus 17q24.1 2p13.3 10q25.1 10q21.1 Xq13.1 2q13 1q42-­ q43 8p11.23 1q43

Phenotypes Hypodontia, Oligodontia Hypodontia, Oligodontia Hypodontia Hypodontia Hypodontia, Oligodontia Hypodontia, Oligodontia Hypodontia, Oligodontia

Hypodontia Hypodontia, Microdontia, Taurodontia 1q32.2 Hypodontia, lip pits, cleft lip and palate 1p36.11 Oligodontia, dens Invaginatus 4p16.2 Hypodontia, Oligodontia, cleft lip and palate 18q11.2 Hypodontia 12p13.2 Oligodontia 11q13.1 Hypodontia, Oligodontia 14q13.3 Hypodontia, Oligodontia, Microdontia 6q27 Oligodontia, Microdontia, abnormal morphology 2p13 Hypodontia, cleft lip and palate 2q35 Hypodontia, Oligodontia 12q13.12 Hypodontia, Oligodontia

Zeng et al. (2019) Callahan et al. (2009)

a

b

the third molars are congenitally absent so often that surveys of tooth agenesis, dental caries, and periodontitis frequently exclude these teeth for consideration entirely. Third molar agenesis is 23

3  Genetic Basis of Tooth Agenesis, Supernumerary Teeth, and Other Dental Abnormalities

24

Table 3.2  Genes associated with syndromic forms of tooth agenesis (modified from Williams and Letra 2018) Gene Locus ADAMTS2 5q35.3 ANTXR1 2p13.3

Syndrome Ehlers–Danlos syndrome Growth retardation, alopecia, pseudoanodontia, and optic atrophy (GAPO) syndrome 17q24.1 Oligodontia-colorectal cancer syndrome 17q21.33 Osteogenesis imperfecta type 1 16p13.3 Rubinstein–Taybi syndrome

Dental phenotypes Hypodontia, microdontia, tooth discoloration Hypodontia, delayed eruption

AXIN2

Oligodontia

Hypodontia, oligodontia Hypodontia, retrognathia, micrognathia, arched/ narrow palate, talon cusps, dental crowding, screwdriver incisors, cross bite, and enamel hypoplasia EDA Xq13.1 Ectodermal dysplasia, hypohidrotic Anodontia, hypodontia, misshapen teeth, microdontia EDAR 2q13 Ectodermal dysplasia, hypohidrotic/ Anodontia, hypodontia, oligodontia hair/tooth type Ectodermal dysplasia, hypohidrotic/ Anodontia, hypodontia, taurodontism, microdontia EDARADD 1q42-­ q43 hair/tooth type EVC 4p16.2 Ellis–van Creveld syndrome and Natal teeth, enamel abnormalities, hypodontia, Weyers acrofacial dysostosis microdontia EVC2 4p16.2 Ellis–van Creveld syndrome and Natal teeth, enamel abnormalities, hypodontia, Weyers acrofacial dysostosis oligodontia, microdontia Hypodontia (maxillary incisors), microdontia, FGF10 5p12 Lacrimoauriculodentodigital syndrome delayed eruption, enamel dysplasia FGFR1 8p11.23 Kallmann syndrome Hypodontia, cleft lip/palate FGFR2 10q26.13 Lacrimoauriculodentodigital Hypodontia (maxillary incisors), microdontia peg syndrome or Apert syndrome laterals, delayed eruption, enamel dysplasia or Hypodontia (maxillary canines), enamel opacities, ectopic eruptions, gingival hyperplasia FGFR3 4p16.3 Crouzon syndrome with acanthosis Hypodontia, malocclusion, cementomas, delayed nigricans eruption, midface hypoplasia FLNB 3p14.3 Larsen syndrome Hypodontia, delayed dental development, class III occlusion, morphological anomalies FOXC1 6p25.3 Axenfeld–Rieger syndrome type 3 Hypodontia, microdontia, taurodontism GJA1 6q22.31 Oculodentodigital dysplasia Microdontia, enamel hypoplasia, hypodontia, delayed eruption GRHL2 8q22.3 Ectodermal dysplasia/short stature Delayed eruption, hypodontia, enamel hypoplasia syndrome IRF6 1q32.2 van der Woude syndrome Hypodontia, cleft lip/palate JAG1 20p12.2 Alagille syndrome Hypodontia, enamel hypoplasia and opacities, hypomineralization KDM6A Xp11.3 Kabuki syndrome 2 High-arched palate, malocclusion, microdontia, a small dental arch, hypodontia, severe maxillary recession, conical teeth KMT2D 12q13.12 Kabuki syndrome 1 High-arched palate, malocclusion, microdontia, a small dental arch, hypodontia, severe maxillary retrognathia, conical teeth KREMEN1 22q12.1 Ectodermal dysplasia, hair/tooth Oligodontia, hypodontia, alveolar ridge deficiency, type increased palatal depth MKKS 20p12.2 Bardet–Biedl syndrome Dental crowding, high-arched palate, hypodontia, malocclusion, enamel hypoplasia, retrognathia MSX1 4p16.1 Witkop syndrome or cleft lip and Hypodontia, oligodontia palate/oligodontia syndrome NEMO Xq28 Incontinentia pigmenti Hypodontia, anodontia, microdontia NSD1 5q35.3 Sotos syndrome I Hypodontia, enamel defects, malocclusion OFD1 Xp22.2 Oro-facio-digital syndrome I Hypodontia, missing lateral incisors, canine malposition, micrognathia COLA1/2 CREBBP

3.2 Tooth Agenesis

25

Table 3.2 (continued) Gene P63

Locus 3q28

PITX2 PVRL1

4q25 11q23.3

Syndrome Rapp-Hodgkin, and Ectrodactyly, ectodermal dysplasia, and cleft lip/ palate syndrome

RECQL4 RSK2

Axenfeld–Rieger syndrome, type 1 Cleft lip/palate-ectodermal dysplasia 8q24.3 Rothmund–Thomson syndrome Xp22.12 Coffin–Lowry syndrome

SHH

7q36.3

TBX3 TCOF1

12q24.21 Ulnar-mammary syndrome 5q32-­ Treacher Collins syndrome q33 6p12.3 Char syndrome

TFAP2B

Holoprosencephaly

Trisomy 21 21q22.13 Down syndrome

TSPEAR UBR1 WNT10A

21q22.3 15q15.2 2q35

Ectodermal dysplasia Johanson–Blizzard syndrome Odontoonychodermal dysplasia or Schopf–Schulz–Passarge syndrome

quite common, reported to range from 12.6% to 51.1% (García-Hernández et al. 2008; Celikoglu and Kamak 2012). This prevalence is substantially higher than agenesis reported for the rest of the dentition, which can range from 0.3% to 11.2% (Celikoglu et al. 2011). There has been discussion regarding the indiscriminate removal of third molars. Historically it has been suggested that third molars, whether or not impacted, lead to sufficient harm and their extraction is justified. The common reasoning given for prophylactic removal of third molars include (1) eruption is unpredictable, (2) adjacent teeth could be damaged, (3) the teeth may be source of periodontal pathogens, (4) eruption may lead to tooth misalignment, and (5) they are easier to extract when patient is an adolescent. These reasons are not supported by any scientific evidence (American Public Health Association 2008). The evidence that exists suggests that there is no increased harm when third molars are present (Stanley et al. 1988; Ahlqwist and Gröndahl

Dental phenotypes Hypodontia, enamel hypoplasia, extensive dental caries, hypodontia of the mandibular canines, generalized microdontia, prominent marginal ridges of permanent maxillary incisors, round-shaped permanent molars, and barrel-shaped permanent maxillary central incisors Hypodontia, microdontia, enamel hypoplasia Hypodontia, cleft lip and palate, abnormal dental morphology, microdontia Hypodontia, microdontia, hypoplastic teeth High narrow palate, midline lingual furrow, hypodontia, and microdontia Cleft lip and palate, single central incisor, micrognathia Hypodontia, ectopic and hypoplastic canines Hypodontia, micrognathia, malocclusion, spaced teeth Oligodontia, hypodontia, thick lips, retention of primary teeth Hypodontia, delayed eruption, barrel-shaped permanent maxillary central incisors, localized bone loss/periodontitis Hypodontia, microdontia Oligodontia Oligodontia, hypodontia, microdontia

1991; Valmaseda-Castellon et al. 2001; Friedman 2007). Third molar agenesis has been associated with other dental anomalies (number and/or structure variations) (Celikoglu et al. 2011), cleft lip and palate (Fernandez et al. 2018), and other malformations (García-Hernández et  al. 2008), and was even associated with Angle Class I malocclusion and hyper-divergent growth patterns (Fernandez et al. 2018), Angle Class II malocclusion (Pitekova and Satko 2009), and mandibular prognathism (Liu et al. 2004; Chung et al. 2008; Celikoglu and Kamak 2012; Alam et  al. 2014). Studies that examined whether third molar agenesis is associated with crowding in the lower arch have been inconclusive (Antanas and Giedrè 2006; Karasawa et al. 2013). Forms of oligodontia with monogenic patterns of inheritance provided the first tool for the studies aiming to identify gene mutations (Vieira 2003). These cases contrasted with the most common forms of tooth agenesis which involved only one or two congenitally missing teeth. Whereas

26

3  Genetic Basis of Tooth Agenesis, Supernumerary Teeth, and Other Dental Abnormalities

some oligodontia cases appeared to be monogenic, the vast majority of cases of tooth agenesis fit better with a multifactorial or complex mode of inheritance (Vieira et al. 2004). Such predictions were later verified when genomic DNA sequencing was implemented (Dinckan et  al. 2018a, b) on a larger scale to study cases without these gene alterations (Table 3.1). The association of tooth agenesis with colorectal cancer provided a new dimension to the studies of the etiology of the condition. While studying the family’s medical records of a child with familial oligodontia and had a mutation in AXIN2, a history of familial adenomatous polyposis was also discovered. AXIN2 is a negative regulator of the Wnt signaling pathway, and there is extensive evidence of the expression of AXIN2 in colorectal tissues leading to carcinomas (Lammi et al. 2004). Overall, the occurrence of cancer in families reporting tooth agenesis appears to be increased over baseline risk. In a cohort of 82 cases with hypodontia, in comparison to 328 individuals without hypodontia or a family history of tooth agenesis, a positive history of cancer was determined to be 55% among the affected and just 31% among the unaffected with tooth agenesis (Küchler et al. 2013). In particular, the odds of brain cancer appear to be increased 12 times, breast cancer three times, and prostate cancer three and a half times. These data suggest there may be potential for dental clinical markers to be utilized as a cancer screening tool. There are several reports in the literature of families segregating tooth agenesis which do not include ascertainment for cancer. Upon follow-­up with a family that was originally studied for their history of oligodontia, the occurrence and onset of forms of neurological cancer (Fig. 3.1) could be determined.

3.3

Supernumerary Teeth

In comparison to tooth agenesis, genetic studies of supernumerary teeth in humans are still scarce. The condition is also less frequent than tooth agenesis, with rates varying from 0.04% to 2.29% (Pippi 2014). Cleidocranial dysplasia is a syndrome that presents with supernumerary teeth and is caused by mutations in RUNX2, but

not many entities have been described as having supernumerary teeth as part of the overall phenotype (Table  3.3). Sequencing of individuals affected with supernumerary teeth has suggested a number of genes may play a role in their formation (Bae et al. 2017; Takahashi et al. 2017; Arikan et  al. 2018; Table  3.4). These data suggest a multifactorial or complex mode of inheritance is the best framework to interpret genetic contributions to supernumerary teeth.

3.4

Other Dental Abnormalities

The genetics of isolated forms of structural abnormalities other than dental enamel and dentin defects are even less studied. The obvious reason for this lack of data is that such conditions are less common even than supernumerary teeth. These cases, however, likely fit the same multifactorial inheritance framework. They occasionally appear to be associated with each other (i.e., dens evaginatus and dens invaginatus, Tannure et al. 2008), suggesting that they share some of the same genetic contributors. One good example is taurodontism, the frequency of which varies from 0.3% to 11.3%, depending on the definition of taurodontism used (Küchler et al. 2008). Taurodontism appears to be associated with more severe forms of tooth agenesis (e.g., oligodontia) (Lai and Seow 1989; Seow and Lai 1989; Schalk-­van der Weid et  al. 1993). It is also part of the phenotype of amelogenesis imperfecta caused by mutations in DLX3 (Dong et al. 2005). However, taurodontism has not been associated with hypodontia (Küchler et al. 2008). In individuals born with cleft lip and palate, taurodontism is seen more frequently than in individuals born without clefts and typically more teeth are affected in these individuals than in individuals born without clefts (Fig. 3.2). Disruptions in dental development are relatively common, since they depend on the role of more than 200 genes (Thesleff 2003), which means there are many possibilities for disruption. Assuming a multifactorial or complex mode of inheritance for disturbances in tooth development, there is then the potential that the environment also can help disrupt development. That would include maternal viral infections affecting the

3.4 Other Dental Abnormalities

27

I.

1

2

II.

1

2

3

5

4

6

7

III.

1 Subject

Teeth Missing

I.1

1,16,17,20,32 (astrocytoma)

I.2

1,7,10,16,17,32 (ependymoma)

II.1 II.2

1,4,7,10,13,16,17,29,32

II.3

1,17,32

II.4

1,2,4,7,10,13,15,16,17,18,20,21,29,31,32

II.5

1,2,3,4,7,10,13,14,16,17,18,20,23,29,31,32

II.6 II.7 III.1

Fig. 3.1  Family segregating oligodontia. Squares indicate males, circles females. Blue indicates affected individuals (details of affection status below). Individuals I.2, II.2, II.4, and II.6 have severe forms of oligodontia. Individual I.1 has only five teeth missing (hypodontia indicated by a shade under the blue color) and individual II.3 hypodontia of three teeth (marked as stripped blue). All individuals with blue color are heterozygous for the

WNT10A mutation F228I.  The individual II.3 does not carry a WNT10A mutation, indicating his hypodontia has a different etiology. Individual II.6, marked with the black arrow requested genetic counseling and was originally advised her chance of having a child with oligodontia was 50%. Fédération Dentaire Internationale (FDI) tooth numbering system. Individuals I.1 and I.2 have their cancer types noted

28

3  Genetic Basis of Tooth Agenesis, Supernumerary Teeth, and Other Dental Abnormalities

Table 3.3  Syndromes and conditions with supernumerary teeth as part of the phenotype (modified from Lu et al. 2017) Syndrome Amelogenesis imperfecta Bloch-Sulzberger syndrome Cleft lip and palatea Cleidocranial dysplasia Craniosynostosis Crouzon syndrome Ehlers-Danlos type III Ehlers-Danlos type IV Ellis–Van Creveld Fabry disease Gardner syndrome Hallermann-Streiff Nance-Horan Noonan syndrome Oro-facio-digital type I Rothmund–Thomson syndrome Robinow Anophthalmia syndrome Trichorhinophalangeal Letra et al. (2007)

a

OMIM # 204690 308300 Several 119600 614188 123500 130020 225400 225500 301500 175100 234100 302350 163950 311200 268400 180700 184429 190350

Gene FAM20A IKBKG Several RUNX2 IL11RA FGFR2 COL3A1 PLOD EVC, EVC2 GLA APC Unknown NHS PTPN11 OFD1 RECQL4 ROR2 SOX2 TRPS1

development of the primary dentition (Fig.  3.3) and any other risk factors that can potentially disrupt tooth development, such as fluoride levels leading potentially to fluorosis. The challenge of studying these dental development-­ related phenotypes is that they do not affect health and are not routinely fully described. To be able to study these conditions more efficiently, descriptions must be made more accurately across a diagnostic standard, so that when an individual’s genomic information is made accessible, the etiology of these phenotypes can be fully tested.

3.5

Genetic Testing

The number of different gene mutations that have been linked to oligodontia would allow for designing a panel to test for their presence in cases of tooth agenesis. This service could be

Table 3.4 Genesa associated with isolated forms of supernumerary teeth based on being mutated in more than one family, suggesting supernumerary teeth is multifactorial (modified from Takahashi et al. 2017) Gene AIMIL AGRN ATXN1 CDH26 C21orf58 CFB EFCAB5 EXOC3L4 FAM186A FANCE FMNL1 FXYD4 HMCN1 IGSF9B KIAA1614 LOC100652824 MGA PLCH2 PKD1L2 RNF207 SSPO TEX15 TKTL1 TUSC1

Presence of gene variants in families Family 1 Family 2 X X X X X X X X X X X X X X X X X X X X X X X X X X X

Family 3 X X X X X X X X X X X X X X X X X X X X X

Another gene that can be added to this list is SOSTDC1 (Arikan et al. 2018)

a

Family 4

X

3.5 Genetic Testing

29

Prenatal

5 mo iu 1 mo iu

Prenatal

3 years 32 mo 28 mo 24 mo 20 mo 16 mo 12 mo 8 mo 4 mo Birth

1 mo iu 5 mo iu Birth

Postnatal

Fig. 3.3  Timing of preand postnatal development of the dentition. Dashed lines over the dental crowns indicate amount of developed structure at birth. Occlusal radiographic views allowed for the evaluation of the coronary portion of anterior primary teeth (incisors and canines). One can see evidence for the presence of dental germs of all maxillary teeth. Red lines indicate expected amount of dental development by 4–5 months of age, which corresponds to when radiographs were taken. Black lines in the central and lateral incisors and canines indicate the amount of developed structure in patients born with microcephaly that was associated with maternal infection by the Zika virus. This analysis suggests the babies born with microcephaly that was associated with maternal infection by the Zika virus have delayed dental development (radiographic images courtesy of Arnoldo Filho)

Postnatal

Fig. 3.2 Individual born with cleft lip and palate with multiple teeth with enlarged pulp chambers (radiographic image courtesy of Rosa Helena Wanderley Lacerda)

4 mo 8 mo 12 mo 16 mo 20 mo 2 years 26 mm 28 mm 3 years

3  Genetic Basis of Tooth Agenesis, Supernumerary Teeth, and Other Dental Abnormalities

30 Target Population

Patients with oligodontia 0.3% of all tooth agenesis cases Patients with tooth agenesis 1-10% of the population (20-25% if 3rd molars are included)

Target Professionals

Genetinc testing

Genetic testing

Dental

On site genetic counseling

Professionals

Individuals with family history of tooth agenesis Individuals with family history of colon cancer

Remote Genetic Counseling

Remote Genetic Counseling

Fig. 3.4  Tooth agenesis genetic testing targeting consumers

offered directly to patients, as well as dentists, and researchers in the field (Fig. 3.4). Based on the frequency of tooth agenesis and assuming a total population of 300 million people, it can be projected that close to 100,000 people may have some form of oligodontia. Furthermore, more than 30 million people could have agenesis of at least one tooth. These conditions can potentially cause great distress to affected individuals and families, with the link between AXIN2 and colorectal cancer indicating that early detection of AXIN2 mutations will have the potential to impact colorectal cancer morbidity and mortality. In that sense, the general dentist can play a crucial role in long-term patient quality of life, especially because dentists see their patients regularly at 6-month intervals, or far more often than the rate at which patients see their primary care providers (Vieira and Babb 2012).

References Ahlqwist M, Gröndahl HG. Prevalence of impacted teeth and associated pathology in middle-aged and older Swedish women. Community Dent Oral Epidemiol. 1991;19(2):116–9. Alam MK, Hamza MA, Khafiz MA, Rahman SA, Shaari R, Hassan A. Multivariate analysis of factors affecting presence and/or agenesis of third molar tooth. PLoS One. 2014;9(6):e101157. American Public Health Association. Opposition to prophylactic removal of third molars (wisdom teeth). Policy Statement Database Policy Number 20085; 2008.

Antanas S, Giedrè T.  Effect of the lower third molars on the lower dental arch crowding. Stomatologija. 2006;8(3):80–4. Arikan V, Cumaogullari O, Ozgul BM, Oz FT. Investigation of SOSTDC1 gene in non-syndromic patients with supernumerary teeth. Med Oral Patol Oral Cir Bucal. 2018;23(5):e531–9. Bae DH, Lee JH, Song JS, Jung HS, Choi HJ, Kim JH.  Genetic analysis of non-syndromic familial multiple supernumerary premolars. Acta Odontol ­ Scand. 2017;75(5):350–4. Callahan N, Modesto A, Deeley K, Meira R, Vieira AR. Transforming growth factor alpha (TGFA), human tooth agenesis, and evidence of segmental uniparental isodisomy. Eur J Oral Sci. 2009;117:20–6. Celikoglu M, Kamak H. Patterns of third-molar agenesis in an orthodontic patient population with different skeletal malocclusions. Angle Orthod. 2012;82(1):165–9. Celikoglu M, Bayram M, Nur M. Patterns of third-molar agenesis and associated dental anomalies in an orthodontic population. Am J Orthod Dentofac Orthop. 2011;140(6):856–60. Chung CJ, Han J-H, Kim K-H. The pattern and prevalence of hypodontia in Koreans. Oral Dis. 2008;14(7):620–5. Dinckan N, Du R, Akdemir ZC, Bayram Y, Jhangiani SN, Doddapaneni H, Hu J, Muzny DM, Guven Y, Aktoren O, Kayserili H, Boerwinkle E, Gibbs RA, Posey JE, Lupski JR, Uyguner ZO, Letra A. A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis. Am J Med Genet A. 2018a;176(4):1015–22. Dinckan N, Du R, Petty LE, Coban-Akdemir Z, Jhangiani SN, Paine I, Baugh EH, Erdem AP, Kayserili H, Doddapaneni H, Hu J, Muzny DM, Boerwinkle E, Gibbs RA, Lupski JR, Uyguner ZO, Below JE, Letra A. Whole-exome sequencing identifies novel variants for tooth agenesis. J Dent Res. 2018b;97(1):49–59. Dong J, Amor D, Aldred MJ, Gu T, Escamilla M, MacDougall M. DLX3 mutation associated with autosomal dominant amelogenesis imperfecta with taurodontism. Am J Med Genet A. 2005;133(2):138–41.

References Fernandez CCA, Pereira CVCA, Luiz RR, Faraco IM Jr, Marazita ML, Arnaudo M, de Carvalho FM, Poletta FA, Mereb JC, Castilla EE, Orioli IM, Costa MC, Vieira AR.  Third molar agenesis as a potential marker for craniofacial deformities. Arch Oral Biol. 2018;88:19–23. Friedman JW.  The prophylactic extraction of third molars: a public health hazard. Am J Public Health. 2007;97(9):1554–9. García-Hernández F, Toro YO, Veja VM, Verdejo MM.  Agenesia del tercer molar en jóvenes entre 14 y 20 ānos de edad, Antofagasta, Chile. Int J Morphol. 2008;26(4):825–32. Karasawa LH, Rossi AC, Groppo FC, Prado FB, Caria PHF.  Cross-sectional study of correlation between mandibular incisor crowding and third molars in young Brazilians. Med Oral Patol Oral Cir Bucal. 2013;18(3):e505–9. Küchler EC, Risso PA, Costa MC, Modesto A, Vieira AR. Assessing the proposed association between tooth agenesis and taurodontism in 975 pediatric subjects. Int J Paediatr Dent. 2008;18:231–4. Küchler EC, Lips A, Tannure PN, Ho B, Costa MC, Granjeiro JM, Vieira AR.  Tooth agenesis association with self-reported family history of cancer. J Dent Res. 2013;92(2):149–55. Lai PY, Seow WK. A controlled study of the association of various dental anomalies with hypodontia of permanent teeth. Pediatr Dent. 1989;11(4):291–6. Lammi L, Arte S, Somer M, Jarvinen H, Lahermo P, Thessleff I, Pirinen S, Nieminen P.  Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet. 2004;74(5):1043–50. Letra A, Menezes R, Granjeiro JM, Vieira AR. Defining subphenotypes for oral clefts based on dental development. J Dent Res. 2007;86(10):986–91. Liu X, Chen J, Liu J, Xu H, Fan C. A statistic analysis on absence of third molar germs in orthodontic patients. West China J Stomatol. 2004;22(6):493–5. Lu X, Yu F, Liu J, Cai W, Zhao Y, Zhao S, Liu S.  The epidemiology of supernumerary teeth and the associated molecular mechanism. Organogenesis. 2017;13(3):71–82.

31 Pippi R. Odontomas and supernumerary teeth: is there a common origin? Int J Med Sci. 2014;11(12):1282–97. Pitekova L, Satko L.  Controversy of the third molars. Bratisl Lek Listy. 2009;110(2):110–1. Schalk-van der Weid Y, Steen WH, Bosman F.  Taurodontism and length of teeth in patients with oligodontia. J Oral Rehabil. 1993;20(4):401–12. Seow WK, Lai PY.  Association of taurodontism with hypodontia: a controlled study. Pediatr Dent. 1989;11(3):214–9. Stanley HR, Alattar M, Colett WK, Stringfellow HR Jr, Spiegel EH.  Pathological sequelae of “neglected” impacted third molars. J Oral Pathol. 1988;17(3):113–7. Takahashi M, Hosomichi K, Yamaguchi T, Yano K, Funatsu T, Adel M, Haga S, Maki K, Tajima A. Whole-­ exome sequencing analysis of supernumerary teeth occurrence in Japanese individuals. Hum Genome Var. 2017;4:16046. Tannure PN, Küchler EC, Pedro RL, Costa MC, Vieira AR.  Dens evaginatus associated with dens invaginatus: a rare case with affected maxillary lateral incisors. Pediatric Dent J. 2008;18(2):192–5. Thesleff I.  Epithelial-mesenchymal signaling regulating tooth morphogenesis. J Cell Sci. 2003;116(9):1647–8. Valmaseda-Castellon E, Berini-Aytes L, Gay-Escoda C.  Inferior alveolar nerve damage after lower third molar surgical extraction: a prospective study of 1117 surgical extractions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001;92(4):377–83. Vieira AR. Oral clefts and syndromic forms of tooth agenesis as models for genetics of isolated tooth agenesis. J Dent Res. 2003;82:162–5. Vieira AR, Babb LM. Detection of carotid artery plaque in the dental setting. Open J Stomatol. 2012;2:136–9. Vieira AR, Meira R, Modesto A, Murray JC.  MSX1, PAX9, and TGFA contribute to tooth agenesis in humans. J Dent Res. 2004;83:723–7. Williams MA, Letra A.  The changing landscape in the genetic etiology of human tooth agenesis. Genes (Basel). 2018;9(5):255. Zeng B, Lu H, Xiao X, Yu X, Li S, Zhu L, Yu D, Zhao W. KDF1 is a novel candidate gene of non-syndromic tooth agenesis. Arch Oral Biol. 2019;97(1):131–6.

4

Genetic Basis of Dental Caries and Periapical Pathology

4.1

Introduction

Cariology is likely the most prolix field of dental research, and the pathogenesis of dental caries is very well understood. The occurrence of the disease requires that a susceptible host be exposed to cariogenic microbiota and carbohydrates at the same time and for relatively prolonged periods of time (Fig.  4.1). When microbiota break down sugars, the pH lowers and minerals are lost from the tooth subsurface. If this process goes

Fig. 4.1  The triad originally described by Keyes (1962) is influenced by factors pertaining to the individual, the family of the individual, and where the person lives (modified from Fisher-Owens et al. 2007). At the host level, genetics influences their susceptibility to dental caries. Factors such as oral hygiene habits and type of diet are shared in the same household and may mimic genetic influences

unchecked for too long, the loss of minerals can no longer be reversed anymore and the surface collapses. Interventions have focused on the use of fluoride, dietary modifications, oral hygiene practices, and microbial inhibition. For a century, very little was done to understand the role of the host in the process of dental caries initiation and progression. In part, this can be justified by the difficulties of studying populations, knowledge at the time, and lack of tools to explore the role of the host. This scenario changed dramatically

societal influences

family influences

Individual influences microbiota

susceptible host genetics

sugar-rich diet

© Springer Nature Switzerland AG 2019 A. R. Vieira, Genetic Basis of Oral Health Conditions, https://doi.org/10.1007/978-3-030-14485-2_4

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when the role of DNA was better understood and studies exploring and questioning genetic susceptibility to disease became mainstream.

4.2

 enes Influence Dental G Caries Risks

Heritability is an estimate of the degree of variation in a phenotypic trait (in this case, a surrogate of dental caries) in a population that is due to genetic variation between individuals in that population. Heritability of dental caries is likely to be not more than 50%, though depending on how it is measured investigators have suggested higher percentages (Table  4.1). Classically, better estimates of heritability are obtained from Table 4.1  Heritability estimates of dental caries in different studies Study site (references) USA (Horowitz et al. 1958) USA (Goodman et al. 1959) China (Gao 1990) China (Liu et al. 1998) Brazil (Bretz et al. 2005a) Brazil (Bretz et al. 2005b) Brazil (Bretz et al. 2006)

Brazil (Corby et al. 2007)

India (Kuppan et al. 2017) UK, Denmark, Netherlands, Germany, Finland, Australia, and the USA (Haworth et al. 2018) India (Anu et al. 2018)

Surrogate for dental caries Presence of caries Presence of caries At least one caries lesion At least one caries lesion Surface-based caries prevalence rates Depth of dentinal lesions Surface-based caries prevalence rates adjusted by age and sex Infection by 10 specific oral microbial species Early childhood caries At least one caries lesion

Heritability estimate 63

Caries experience

87.8

85 8.7 30 76.3

56.2 64.6

56–80

15 6

individuals with biological relationships (twins, siblings, parents, and offspring), rather than from unrelated less similar subjects. On the other hand, shared environments may confound estimates of heritability, and similar habits may mimic a genetic component. The heritability estimates shown in Table  4.1 have a pattern. Studies that utilized twins and a more sophisticated caries definition show higher estimates of heritability. Studies that utilized very unsophisticated caries measurements (having no caries lesions versus having at least one caries lesion) show lower estimates of heritability. This distinction can be understood on the basis of the pathogenesis of dental caries. Individuals with a dental caries experience affecting 1 or 2 teeth likely had a very different trajectory of disease than someone who had 10 or 20 teeth affected. Those differences are simply ignored when analysis is done comparing individuals who are caries free with individuals with any number of caries lesions. Similarly, the noninclusion of instances where teeth were extracted due to caries eliminates individuals with more severe presentations of the disease. Those arbitrary decisions are made to facilitate genetic analysis in cases of genome-wide association genotyping data but disregarding differences in clinical presentation and the pathogenesis of the disease. This likely impacted the results of the genome-wide association studies published to date. The data included in the meta-analysis presented by Haworth et al. (2018) have these characteristics and also include instances where individuals self-reported having had dental caries. The large sample sizes do not compensate for the systematic oversimplification of the caries phenotype. Since dental caries is so prevalent in populations, genetic variation may be more prevalent than the variability of disease, and heritability estimates taking these additional criteria into account will likely look low. The bottom line is that dental caries has a genetic component that may be easily overcome by environmental factors, making it difficult to study. In that sense, it fits well in the multifactorial or complex mode of inheritance framework. Since the most common measure of dental caries counts past experience of disease, the most sig-

4.2 Genes Influence Dental Caries Risks

35

nificant measures take into consideration levels of severity corrected by age (Table 4.2), since it is known that dental caries experience scores will increase with age if other conditions such as periodontitis, trauma, and extensive restorative work Table 4.2  Definition of caries experience level based on age and DMFT scores of a population with high caries experience (Vieira et al. 2008) Caries experience level Children (up to 12 years of age) 1.  Very low caries experience: DMFT = 0–1 2.  Low caries experience: DMFT = 2 3.  Moderate caries experience: DMFT = 3–4 4.  High caries experience: DMFT = 5 or higher Teenagers (from 13 to 18 years of age) 1.  Very low caries experience: DMFT = 0–2 2.  Low caries experience: DMFT = 3–5 3.  Moderate caries experience: DMFT = 6–8 4.  High caries experience: DMFT = 9 or higher Adults (20 years of age and older) 1.  Very low caries experience: DMFT = 0–5 2.  Low caries experience: DMFT = 5–8 3.  Moderate caries experience: DMFT = 9–13 4.  High caries experience: DMFT = 14 or higher

12

10

8 DMFT/dmft

Fig. 4.2  Decayed, missing due to caries, filled teeth (DMFT/dmft) scores at specific ages (5, 12, 14, 16, and 17 years of age). Some individuals remain caries free (Patient C), whereas others continuously have increases in the number of teeth affected by caries (either quite dramatic like in Patient D, or a steadier increase like in Patient B). Patient A had a higher caries experience in primary dentition and an increase toward the end of adolescence (from Weber et al. 2018)

that led to tooth loss are included in the number of teeth or surfaces missing due to caries. Another interesting aspect is that early childhood caries is likely less impacted by any potential genetic factor, protective, or otherwise. The most meaningful ways to measure dental caries for the identification of genetic contributors may be longitudinally. When dental caries experience can be assessed in the same individuals over time, different trajectories of the disease process are apparent (Fig.  4.2). Whereas some individuals remain caries free, others steadily continue to increase their dental caries experience and some have more dramatically increases over a relatively short period of time. Another way to measure dental caries includes assessing preclinical mineral loss using dental enamel microhardness measurements (Shimizu et al. 2012; Weber et  al. 2014; Bayram et  al. 2015; Vieira et  al. 2017a), with the hypothesis that some individuals are more susceptible to dental caries because their dental enamel is “softer.” This hypothesis was tested using a series of mice that expressed amelogenin at different levels (Fig. 4.3). The data

6

4

2

0 5

12

14 Patient A Patient B Patient C Patient D

16

17

4  Genetic Basis of Dental Caries and Periapical Pathology

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Fig. 4.3  These animals were used to show that developing enamel with less or without amelogenin decreases the hardness of the dental enamel, which was interpreted as being more susceptible to demineralization (Vieira et  al.

Diet • What to eat? • When to eat? Oral Hygiene • When? • How often?

2015a). Left image shows a heterozygote for a knockout allele of amelogenin (teeth formed with 50% of the amount of amelogenin) in comparison to animals with teeth formed with 100% of amelogenin (image on the right)

“diet preference” genes “decision making” genes ”behavioral” genes “personality” genes

Dental Development “development” genes • Structure • Position in the arch

Socioeconomic status and education

Dental Care • Access • When to seek help? • Why seeking help?

Saliva • Composition • Flow

“saliva” genes

Immune System “immune response” genes Microbial Colonization

Fig. 4.4  Host factors influencing dental caries (modified from Vieira 2016)

showed that dental enamel formed in the absence of, or with less, amelogenin is easier to be demineralized by the use of artificial caries protocols (Vieira et al. 2015a, b). This provides strong evidence for the rationale that certain individuals will be more prone to mineral loss under low pH conditions whereas others might be more resistant under the same circumstances. Genes that may influence dental caries are likely the ones that modify its pathogenesis (Fig. 4.4). The most studied genes regarding dental caries are related to dental enamel formation and the data are quite convincing that they modify

individual risks (based on replication on multiple populations). Other genes that can be included in this list are aquaporin 5 and ESRRB (reviewed in Vieira et al. 2014; Nibali et al. 2017).

4.3

Dental Caries Progression

Another interesting aspect of genetic influences in dental caries is the velocity at which the lesion progresses through dentin. It has been hypothesized that some individuals are more prone to the formation of periapical lesions,

4.4 Genomic Biomarkers for Dental Caries

due to deep caries lesions in dentin than others and that would be due to genetic contributions from matrix metalloproteinases (MMPs) (Menezes-Silva et al. 2012). Indeed, it appears that MMP2 in particular, a gelatinase, increases the risk of having the formation of periapical lesions (Menezes-Silva et  al. 2012) and/or the loss of extensive composite resin restorations (Vieira et al. 2017b). When the pH lowers from 7.0  in an exposed dentin, apatite is dissolved thus exposing the organic matrix to degradation by dentin MMPs and this process continues even when the pH returns to 7.0 (Tjäderhane et  al. 1998). Some individuals are likely more prone to enhanced MMP activity and would be more susceptible to caries lesion progression through the dentin and potential formation of periapical lesions, and to failures of adhesivebased restorative systems. The problem of systematically defining dental caries for genetic studies has been approached by considering multiple disease presentations as a continuum. When individuals who had caries experience subsequently developed periapical lesions were analyzed as a group, associations with multiple markers in RHEB were found (Bezamat et al. 2018). This gene is also involved in pathways that control several cellular processes. It is mutated in certain types of cancer

37

(Lawrence et  al. 2014) and neurological malformations (Salinas et  al. 2018), therefore, we do not expect to see mutations in this gene that lead to rapid dental caries progression in dentin or formation of periapical lesions. However, similarly to our proposal for amelogenin, genetic ­variations in this gene that are common in the population may predispose some to quicker dentin and bone destruction in the presence of oral bacteria and at lower pH.  Considering multiple phenotypic presentations, which allows for better definition of the phenotype to be studied, by taking into consideration what is known of the pathogenesis of dental caries may allow for better opportunities to identify relevant genetic contributors to the disease in the future.

4.4

Genomic Biomarkers for Dental Caries

The accumulated data that show consistent associations between common genetic variation in the population and dental caries may be considered as biomarkers (Table 4.3), as a measure of a normal or pathological state, or as a response to intervention. Such variants are associated with dental caries in multiple independent cohorts and were analyzed under hypothesis-driven designs rather

Table 4.3  Common variants with the potential of genomic biomarkers for dental caries or tooth loss Gene/locus Genetic marker AMELX/Xp22.2 rs946252 may be a good marker to test

Other relevant condition When mutated causes amelogenesis imperfecta MMP20/11q22.2 Protective effect, rs946252 may be a good marker When mutated causes to test amelogenesis imperfecta MMP2/16q12.2 Deep lesions in dentin, rs9923304 may be a good Same marker may marker to test predispose to the formation of periapical lesions ESRRB/14q24.3 rs55835922 may be a good marker to test Hearing impairment AQP5/12q13.12 IL1/2q14.1

Protective effect, rs296763 may be a good marker Dental fluorosis to test Along with smoking, diabetes, hypertension, and Periodontitis genotypes of IL1α (rs1800587) and IL1β (rs1143634) may be a good predictor of tooth loss

Reference Shimizu et al. (2012) Filho et al. (2017) Vieira et al. (2017b) Weber et al. (2014) Anjomshoaa et al. (2015) Vieira et al. (2015b)

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than hypothesis-free and took into consideration the different severities of dental caries presentation. Direct to the consumer products marketed to the public for ancestry self-­knowledge could inform customers about the status of these variants. This is a much more viable model than the assumption that individual genetic testing for certain dental caries risks can be marketed with success.

Dental Caries: An Evolutionary Thought

“But how did we evolve to have dental caries?” is a question that has been posed to me many a time. One misconception regarding natural selection is that we are evolving to become more fit, and or somehow “better.” Bone, as an example, evolved to be a though mineralized structure, but it is not unbreakable because it does not need to be. Under regular circumstances, the mineral density of bone in humans is sufficient for humans to survive. Fatal events involving bone fractures did not occur often enough to impact the survival of our species nor lead to favor the ones that can survive long falls. If we frame the question of bone strength as a function of bone metabolism, we seldom survived past young adult life and the consequences of aging and osteopenia were never an issue. In regards to teeth, natural selection shaped our dentition to allow humans to obtain nutrients from solid foods, in turn allowing the brain and other organs to become more sophisticated. Roots and raw vegetables required a powerful tool to be broken down. To make teeth harder, the easy solution was using calcium, which is the third most abundant metal in Earth’s crust (fifth most common element) after iron and aluminum. Calcium reacts slowly with water but dissolves readily in dilute or concentrated acids. Individuals with softer teeth (a lesser

calcium content) probably had difficulties in gaining satisfactory levels of nutrition, had more fractures, and were less likely to survive whereas individuals with harder teeth were probably more successful. The ultimate consequence of this process resulted in hard calciumrich teeth, which is highly susceptible to acidic solutions. This was never an issue for humans until our diet changed dramatically with the introduction of refined sugars, which led to the dramatic increase in dental decay and tooth loss due to decay (Fig. 4.5).

Fig. 4.5 Specimen from the skull collection of the University of Pittsburgh School of Dental Medicine (Rose and Vieira 2008). This individual lived between the end of the nineteenth century and beginning of the twentieth century. Molars show areas of exposed dentin that suggests a diet of hard food. Signs of cavitation of the occlusal surface of the left second mandibular molars appear to have not progressed. This person was likely an exception to the typical dental caries experience of the time

4.4 Genomic Biomarkers for Dental Caries

The Holy Grail of Dental Caries

Is dental caries an infectious disease? Dental caries is not an infectious disease if Koch’s postulates are to be satisfied. The microorganisms causing dental caries need to be (1) found in all cases of the disease at the site of the lesions; (2) grown on artificial media; and (3) generate a subculture that can produce the disease in a susceptible animal. Is dental caries a contagious disease? The idea of calling dental caries transmissible came with the evidence that the same strains of Streptococcus mutans seen in an affected child would be found in the mother, leading to the conclusion the mother transmitted the bacteria to the affected child. However, the exposure to the mother also leads to the colonization of bacteria in the skin, and guts of a child, not only her mouth. A transmissible disease is diagnosed by the presence of the microorganism, the microorganism is not present in health, satisfies Koch’s postulates, and the disease can be passed from person to person. Clearly, dental caries does not satisfy these principles. Does dental caries occur in the absence of microorganisms? It does not. Microorganisms are necessary but not sufficient for the disease to happen. Dental caries should be referred to as a bacteria-­ mediated disease. The daily disturbance of biofilm will be sufficient to prevent dental caries in all individuals. Does dental caries occur in the absence of sugars? It does not. Sugars from the diet are the source of energy for microorganisms and the consequence is the production of acids that if not removed constantly will lead to demineralization of tooth services. This imbalance is the disease. Are there individuals more susceptible to dental caries than others? Yes. Individual susceptibility is modulated by a number of

39

factors that include socioeconomic status, ability to find dental care, oral hygiene habits, dietary habits, and individual biological influences that modulated enamel and dental formation, immune responses, and saliva amount and composition. In the case of dental caries, these biological factors are probably easily overcome by other factors. Why dental caries has not been eradicated? Despite more than a century of knowledge of the pathogenesis of dental caries, a large portion of populations continue to suffer from the disease. Interventions at the population level such as fluoridation of water or fluoridation of toothpastes dramatically decreased the number of lesions experienced by individuals but did not bring those numbers to zero (Table 4.4). Similarly, providing oral hygiene instructions or dietary interventions are not effective enough to eradicate dental caries. Studying dental caries with emphasis on the biological component of the host has provided a new venue for exploring an alternative to identify the individuals that continue experiencing most of the disease in the population. There is enough evidence that the final product of enamel development is not exactly the same in all individuals, resulting that some may be more prone to demineralization under specific conditions than others. This complexity has been ignored by the field that continues to not translate the vast in vitro work into clinical interventions.

Dental Caries Secondary to Orthodontic Treatment: A Case Study (Fig. 4.6)

Poor oral hygiene associated with fixed orthodontic treatment is a combination known to increase dental caries risk. Individuals with dental enamel more

4  Genetic Basis of Dental Caries and Periapical Pathology

40

prone to demineralization can be potentially at higher risk. Two siblings that had orthodontic treatment show the sequelae of demineralization around the brackets and this familial aggregation suggest a genetic component or a behavioral component that is shared in the same household and mimics a genetic component. It is clear, however, that one sibling was more severely affected than the other. Further investigation showed that they did not practice rigorous oral hygiene but the most severely affected sibling had signs of autism spectrum disorder. This case exemplifies that dental caries has a multifactorial mode of inheritance and can be understood as a gene-environmental model. The two siblings were similarly susceptible to demineralization and the orthodontic treatment precipitated the installation of the disease process in both of them but the one with the underlying autism spectrum disorder, due to poorer oral hygiene control, had more severe mineral losses.

Fig. 4.6  Two siblings showing signs of demineralization after orthodontic treatment was concluded. One is more severely affected whereas the other show signs of demineralization only in the maxillary lateral incisors and canines. Both of them were susceptible to demineralization but the one with underlying autistic spectrum disorder was more severely affected since poorer oral hygiene

Table 4.4 Trends in prevalence of cavitated dentine and caries experience in selected parts of the world (Frencken et al. 2017) Prevalence (%) of dentine caries DMFT mean Country and period lesions South Africa (14 to 17-year-old children living in urban settings) 1977 95 7.5 2002 50 2.0 Brazil (12 to 13-year old children) 1971 98 9.2 2011 37 0.7 Norway (12-year-old children) 1985 81 3.4 2004 60 1.7 United Kingdom (15-year-old children) 1973 97 8.4 2013 42 1.2 Poland (12-year-old children) 1978 98 6.3 2012 84 3.5

exacerbated the risk. Dental caries is a disease that innate individual susceptibility can be readily overcome by poor oral hygiene and a diet rich in sugars. Conversely, despite these conditions, some individuals may be more resistant to demineralization and show milder signs of mineral loss or remain caries free (images courtesy of Lily Hartsock)

References

References Anjomshoaa I, Briseño-Ruiz J, Deeley K, Poletta FA, Mereb JC, Leite AL, Barreta PA, Silva TL, Dizak P, Ruff T, Patir A, Koruyucu M, Abbasoğlu Z, Casado PL, Brown A, Zaky SH, Bayram M, Küchler EC, Cooper ME, Liu K, Marazita ML, Tanboğa İ, Granjeiro JM, Seymen F, Castilla EE, Orioli IM, Sfeir C, Ouyang H, Buzalaf MA, Vieira AR.  Aquaporin 5 interacts with fluoride and possibly protects against caries. PLoS One. 2015;10:e0143068. Anu V, Arsheya GS, Anjana V, Annison GK, Aruna MRL, Alice AP, Aishwarya BA.  Dental caries experience, dental anomalies, and morphometric analysis of canine among monozygotic and dizygotic twins. Contemp Clin Dent. 2018;9(Suppl 2):S314–7. Bayram M, Deeley K, Reis MF, Trombetta VM, Ruff TD, Sencak RC, Hummel M, Dizak PM, Washam K, Romanos HF, Lips A, Alves G, Costa MC, Granjeiro JM, Antunes LS, Küchler EC, Seymen F, Vieira AR. Genetic influences on dental enamel that impact caries differ between the primary and permanent dentitions. Eur J Oral Sci. 2015;123:327–34. Bezamat M, Deeley K, Khaliq S, Letra A, Scariot R, Silva RM, Weber ML, Bussaneli D, Trevilatto PC, Almarza AJ, Ouyang H, Vieira AR. Are mTOR and ER stress pathway genes associated with oral and bone diseases? Caries Res. 2018;53(3):235–41. Bretz WA, Corby PM, Hart TC, Costa S, Coelho MQ, Weyant RJ, Robinson M, Schork NJ.  Dental caries and microbial acid production in twins. Caries Res. 2005a;39(3):168–72. Bretz WA, Corby PM, Schork NJ, Robinson M, Coelho M, Costa S, Melo Filho MR, Weyant RJ, Hart TC.  Longitudinal analysis of heritability for dental caries traits. J Dent Res. 2005b;84(11):1047–51. Bretz WA, Corby PM, Melo MR, Coelho MQ, Costa SM, Robinson M, Schork NJ, Drewnowski A, Hart TC.  Heritability estimates for dental caries and sucrose sweetness preference. Arch Oral Biol. 2006;51(12):1156–60. Corby PM, Bretz WA, Hart TC, Schork NJ, Wessel J, Lyons-Weiler J, Paster BJ. Heritability of oral microbial species in caries-active and caries-free twins. Twin Res Hum Genet. 2007;10(6):821–8. Filho AV, Calixto MS, Deeley K, Santos N, Rosenblatt A, Vieira AR. MMP20 rs1784418 protects certain populations against caries. Caries Res. 2017;51(1):46–51. Fisher-Owens SA, Gansky SA, Platt LJ, Weintraub JA, Soobader MJ, Bramlett MD, Newacheck PW. Influences on children’s oral health: a conceptual model. Pediatrics. 2007;120(3):e510–20. Frencken JE, Sharma P, Stenhouse L, Green D, Laverty D, Dietrich T. Global epidemiology of dental caries and severe periodontitis—a comprehensive review. J Clin Periodontol. 2017;44 Suppl 18:S94–S105. https://doi. org/10.1111/jcpe.12677. Gao XJ.  Dental caries in 280 pairs of same-sex twins. Zhonghua Kou Qiang Yi Xue Za Zhi. 1990;25(1): 18–20, 61.

41 Goodman HO, Luke JE, Rosen S, Hackel E. Heritability in dental caries, certain oral microflora and salivary components. Am J Hum Genet. 1959;11(3):263–73. Haworth S, Shungin D, van der Tas JT, Vucic S, Medina-­ Gomez C, Yakimov V, Feenstra B, Shaffer JR, Lee MK, Standl M, Thiering E, Wang C, Bønnelykke K, Waage J, Jessen LE, Nørrisgaard PE, Joro R, Seppälä I, Raitakari O, Dudding T, Grgic O, Ongkosuwito E, Vierola A, Eloranta AM, West NX, Thomas SJ, McNeil DW, Levy SM, Slayton R, Nohr EA, Lehtimãki T, Lakka T, Bisgaard H, Pennell C, Kühnisch T, Marazita ML, Melbye M, Geller F, Rivadeneira F, Wolvius EB, Franks PW, Johansson I, Timpson NJ.  Consortium-­ based genome-wide meta-analysis for childhood dental caries traits. Hum Mol Genet. 2018;27(17):3113–27. Horowitz SL, Osbourne RH, DeGeorge FV. Caries experience in twins. Science. 1958;128(3319):300–1. Keyes PH.  Recent advances in dental caries research. Bacteriology. Bacteriological findings and biologic implications. Int Dent J. 1962;12:443–64. Kuppan A, Rodrigues S, Samuel V, Ramakrishnan M, Halawany HS, Abraham NB, Jacob V, Anil S. Prevalence and heritability of early childhood caries among monozygotic and dizygotic twins. Twin Res Hum Genet. 2017;20(1):43–52. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, Meyerson M, Gabriel SB, Lander ES, Getz G.  Discovery and saturation analysis of cancer genes across 21 tumor types. Nature. 2014;505(7484):495–501. Liu H, Deng H, Cao CF, Ono H. Genetic analysis of dental traits in 82 pairs of female-female twins. Chin J Dent Res. 1998;1(3):12–6. Menezes-Silva R, Khaliq S, Deeley K, Letra A, Vieira AR. Genetic susceptibility to periapical disease: conditional contribution of MMP2 and MMP3 genes to the development of periapical lesions and healing response. J Endod. 2012;38:604–7. Nibali L, Di Iorio A, Tu YK, Vieira AR. Host genetics role in the pathogenesis of periodontal disease and caries. J Clin Periodontol. 2017;44(Suppl 18):S52–78. Rose EK, Vieira AR.  Caries and periodontal disease: insights from two US populations living a century apart. Oral Health Prev Dent. 2008;6:23–8. Salinas V, Vega P, Piccirilli MV, Chicco C, Ciraolo C, Christiansen S, Consalvo D, Perez-Maturo J, Medina N, González-Morón D, Novaro V, Perrone C, García MDC, Agosta G, Silva W, Kauffman M. Identification of a somatic mutation in the RHEB gene through high depth and ultra-high depth next generation sequencing in a patient with hemimegalencephaly and drug resistant epilepsy. Eur J Med Genet. 2018. [Epub ahead of print]. Shimizu T, Ho B, Deeley K, Briseño-Ruiz J, Faraco IM Jr, Schupack BI, Brancher JA, Pecharki GD, Küchler EC, Tannure PN, Lips A, Vieira TC, Patir A, Yildirim M, Poletta FA, Mereb JC, Resick JM, Brandon CA, Orioli IM, Castilla EE, Marazita ML, Seymen F, Costa MC, Granjeiro JM, Trevilatto PC, Vieira AR. Enamel formation genes influence enamel microhardness before and after cariogenic challenge. PLoS One. 2012;7:e45022.

42

4  Genetic Basis of Dental Caries and Periapical Pathology

Tjäderhane L, Larjava H, Sorsa T, Uitto VJ, Larmas M, Salo T.  The activation and function of host matrix metalloproteinases in dentin matrix breakdown in caries lesions. J Dent Res. 1998;77(8):1622–9. Vieira AR.  Genetic influences on dental caries. eLS.  Chichester: Wiley; 2016. http://www.els.net https://doi.org/10.1002/9780470015902.a0024258. Vieira AR, Marazita ML, Goldstein-McHenry T. Genome-­ wide scan finds suggestive caries loci. J Dent Res. 2008;87(5):435–9. Vieira AR, Modesto A, Marazita ML.  Caries: review of human genetics research. Caries Res. 2014;48:491–506. Vieira AR, Gibson CW, Deeley K, Xue H, Li Y. Weaker dental enamel explains dental decay. PLoS One. 2015a;10:e0124236. Vieira AR, Hilands KM, Braun TW. Saving more teeth—a case for personalized care. J Pers Med. 2015b;5(1):30–5. Vieira AR, Bayram M, Seymen F, Sencak R, Lippert F, Modesto A. In vitro acid-mediated initial dental enamel loss is associated with genetic variants pre-

viously linked to caries experience. Front Physiol. 2017a;8:104. Vieira AR, Silva MB, Souza KA, Filho AVA, Rosenblatt A, Modesto A.  A pragmatic study shows failure of dental composite fillings is genetically determined: a contribution to the discussion on dental amalgams. Front Med (Lausanne). 2017b;4:186. Weber ML, Hsin H-Y, Kalay E, Brožková DS, Shimizu T, Bayram M, Deeley K, Küchler EC, Forella J, Ruff TD, Trombetta VM, Sencak RC, Hummel M, Briseño-Ruiz J, Revu SK, Granjeiro JM, Antunes LS, Abreu FV, Costa MC, Tannure PN, Koruyucu M, Patir A, Poletta FA, Mereb JC, Castilla EE, Orioli IM, Marazita ML, Ouyang H, Jayaraman T, Seymen F, Vieira AR. Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay. BMC Med Genet. 2014;15:81. Weber M, Bogstad Søvik J, Mulic A, Deeley K, Tveit AB, Forella J, Shirey N, Vieira AR. Redefining the phenotype of dental caries. Caries Res. 2018;52(4): 263–71.

5

Genetic Basis of Periodontitis and Tooth Loss

5.1

Introduction

Studying the genetic basis of periodontitis has been a challenge for various reasons. Periodontitis has historically been an ill-defined disease, with a wide variance in phenotype, which presents a difficult problem in constructing genetic studies. These factors have tempered the field and most of the work focuses on pathogens and serologic markers. Genetic studies, initially focusing on specific genes and later scanning genotypes spread throughout the genome, have not provided any conclusive insights. This has motivated many to question the role of genetics in periodontitis. In this chapter, we present periodontitis, and its ultimate consequence of tooth loss (noting that dental caries also leads to tooth loss), as complex conditions that follow a multifactorial mode of inheritance.

5.2

 eriodontitis Is Difficult P to Measure

Periodontitis fits very well in a framework of multiple genes with relatively small addictive effects each and that can be influenced by environmental factors (the definition of multifactorial inheritance, Fig. 5.1). The clinical presentation of periodontitis varies and scientists in the field have suggested different ways to define it over time. Up until 1993, periodontitis was defined based © Springer Nature Switzerland AG 2019 A. R. Vieira, Genetic Basis of Oral Health Conditions, https://doi.org/10.1007/978-3-030-14485-2_5

on the age of onset and rates of progression, and was classified as prepubertal, juvenile (localized and generalized), adult, and rapidly progressive (American Academy of Periodontology 1989; Caton 1989). This classification was revisited in 1993 and simplified to adult and earlyonset periodontitis (European Federation of Periodontology 1993). This simplified classification was revisited 3 years later and ultimately not altered (Papapanou 1996). However, in 1999 periodontitis was classified as chronic, aggressive (localized and generalized), necrotizing, or as a manifestation of systemic disease (Lang et al. 1999a, b; Lindhe et al. 1999a, b). The distinction between chronic and aggressive periodontitis motivated investigators to further differentiate patients within these two groups and treat them as two distinct conditions. The search for etiological factors and the definition of treatment protocols were proposed based on this distinction. The ability to investigate molecular markers also motivated studies, which took into consideration whether the periodontitis in question was chronic or aggressive. Using these parameters, we showed that variation in BRINP3, a gene that when expressed increases vascular inflammation, was associated with aggressive periodontitis (Carvalho et al. 2010) but not with chronic periodontitis (Ribeiro et  al. 2012; Feng et al. 2014). However, when global gene expression was used to define chronic versus aggressive periodontitis, 43

5  Genetic Basis of Periodontitis and Tooth Loss

44 Fig. 5.1  The complex interplay between genetic and environmental factors (modified from a personal communication by Dr. Eduardo Tinoco)

Behaviors

Genetic Factors

Socioeconomic status smoking

Bacteria

stress

Host response

Diabetes, AIDS

Bone

Clinical

connective

signs of

tissue

disease

Genetic factors

patterns of gene expression in gingival biopsies showed no obvious distinct pattern between them (Kebschull et al. 2013) despite their distinct clinical presentations, suggesting that these conditions are one and the same. This evidence motivated another revisitation of the disease classification (Caton et al. 2018), proposing that chronic and aggressive periodontitis are indeed the same entity. Periodontitis is now characterized by a multidimensional staging and grading system that consider both the severity and progression of the disease. This lack of consistency in defining the condition obviously has made it difficult to definitively study periodontitis. The consequences of this historical lack of consistency are inconclusive and unconvincing studies aiming to define a genetic contributor to periodontitis and a general sense that genetics has an unimportant role in the etiology of periodontitis.

5.3

Evidence for a Genetic Contribution

The best evidence for a genetic contribution to periodontitis continues to be the data unveiled by the classic studies with Sri Lankan tea plant-

ers. Four hundred and eighty men were initially enrolled in a study that successfully followed 161 of them for 15  years. Five clinical assessments computed the progression of their periodontal disease. It was found that 8% of the tea planters had rapid progression, 81% had moderate progression, and 11% exhibited no progression of the disease despite no intervention (Löe et al. 1986). These results begged the question: What was protecting these people from showing any signs of progressive periodontal loss despite no oral hygiene (Fig. 5.2)? There are instances in which there is evidence of familial aggregation of periodontitis, including evidence of discordance in identical twins (Fig.  5.3; Grech 2015), suggesting a genetic component to periodontitis. When the data on heritability of periodontitis was revisited in more than 50,000 individuals from twin, family and case-­ control studies, it was found that a substantial proportion of the phenotypic variance of periodontitis in populations was due to genetics (7–38%). Furthermore, heritability tended to be higher for severe, early-onset traits and younger individuals (Nibali et  al. 2019). It thus appears that the heritability of periodontitis has common pathways to that of other inflammatory/chronic

5.3 Evidence for a Genetic Contribution Fig. 5.2  Specimens from the skull collection of the University of Pittsburgh School of Dental Medicine (Rose and Vieira 2008). These individuals lived between the end of the nineteenth century and beginning of the twentieth century. There are different levels of bone loss both in anterior and posterior areas despite no obvious differences in diet and oral hygiene habits

45

5  Genetic Basis of Periodontitis and Tooth Loss

46

Fig. 5.3  Nuclear family with several cases of chronic periodontitis (modified from Grech 2015). Affected individuals are marked in blue

diseases. Therefore, associations between periodontitis and diseases of other systems (e.g., cardiovascular disease, see Mucci et al. 2009) may be detected in cohorts of individuals who happen to share similar inflammatory responses (Loos 2015; Chapple et al. 2017). It is important to stress that heritability is a concept related to relative contribution in a population, meaning that if certain environmental factors in a population considerably increase the risk of disease, then the relative contribution of genetics would be smaller. As such, no direct inference can be derived in terms of management of the single patient. However, dental health professionals can expect susceptibility to periodontitis and perhaps also periodontitis treatment response to be largely influenced by genetic variants. For example, individuals who respond less favorably to treatment (due to their accentuated genetic predisposition) would benefit from more intense therapeutic regimes or more frequent recalls, which may require changes in policy related to health insurance fees and reimbursements, and will likely affect important stakeholder practices. Since the search for the specific genomic loci where this

heritability lies has so far proved quite elusive (Nibali et al. 2017), collaborative efforts including consortium meta-analyses of several studies and hundreds of thousands of individuals, as well as examination of “refined” biologically informed traits (that may be more homogeneous) could help elucidate the biological basis and heritability of periodontal disease.

5.4

Interleukin 1 Alpha and Beta

Interestingly, the association between genetic variation in interleukin 1 alpha and beta (IL1A and IL1B) and periodontitis was the first one to be translated to a “genetic test.” The composite less common allele of IL1A − 889 and less common allele of IL1B + 3953 was associated with severe periodontitis in nonsmokers (Kornman et al. 1997). This composite genotype is as common as 30% in Northern Europeans of unknown periodontal status. The application was then patented with the motivation that these genetic markers could be used as a risk indicator for patients who did not smoke. This was without regard for the level of bacterial challenge, and who could

5.5 Tooth Loss as an Outcome

47

potentially progress to more severe forms of the disease. Whereas it is relatively easy to identify moderate-to-severe periodontal bone loss, a predictor for the development of severe forms of the disease in individuals who do not smoke and have mild periodontitis or are still relatively young could be useful. This product was released in the market but is not widely used because the prediction of an increase in risk has little practical value in the context of a multifactorial inheritance framework.

5.5

Tooth Loss as an Outcome

A discussion considering the value of this particular interleukin 1 genetic test was renewed by a report that looked at 16 consecutive years of data from dental insurance claims during the peak age of incident periodontitis (Giannobile et  al. 2013). Patients with low risk status, as determined by nonsmoking, no history of diabetes, and absence of IL1A − 889 and IL1B + 3953 less common alleles, did not have their risk for tooth loss reduced by having two annual preventive visits (going to the dentist every 6 months) in comparison to just one annual visit. Conversely, two annual preventive dental visits may not be sufficient to reduce tooth loss in patients with more than one risk factor. This report sparked an interesting debate and a subsequent publication (Diehl et al. 2015) reanalyzed the same data to show that genetic testing is not useful for rationing preventive dental care. This question is relevant because rationing preventive dental care

to focus on high-­risk individuals could reduce the cost of dental care by US$4.8 billion annually in the USA. The reanalysis also suggested that a “positive” result on the genetic test did not have an effect on risk of tooth loss, therefore, the use of the genetic test to determine risk was not warranted. A similar experiment was performed with 4137 subjects from the University of Pittsburgh School of Dental Medicine Dental Registry and DNA Repository project (Vieira et  al. 2015). Four risk factors (smoking, diabetes, high blood pressure, and presence of IL1A  −  889 and IL1B + 3953 less common alleles) were considered in regard to tooth loss as the main outcome. It is clear that as individuals accumulate risk factors (Fig. 5.4), the more tooth loss they have. The variants IL1A  −  889 and IL1B  +  3953 are relatively common in populations and a relevant question is whether there is a real need to test them to infer risk of tooth loss. Out of the total 4137 subjects, 881 had the genotypes of interleukin 1 alpha and beta available and 128 (14.5%) had none of the four risk factors and on average, lost five teeth. This figure jumped to nine lost teeth when one risk factor was present, 10 lost teeth for two risk factors, 11 lost teeth for three risk factors, and 13 lost teeth for the individuals with all four risk factors. If we exclude genetic variation in interleukin 1 alpha and beta as a risk factor, the number of individuals classified as having no risk factors for tooth loss was 2229 out of 4137 (54%) and they on average had three lost teeth. In all likelihood, a subset of those individuals may be at higher risk for tooth loss and

Tooth loss average

Tooth loss average vs number of risk factors (RF) 14 12 10 8 6 4

0 RF

1 RF

2 RF

3 RF

4 RF

Any RF

Fig. 5.4  Tooth loss accumulates as individuals accumulate risk factors (RF). The RF were smoking, diabetes, high blood pressure, and presence of IL1A − 889 and IL1B + 3953 less common alleles (from Vieira et al. 2015)

5  Genetic Basis of Periodontitis and Tooth Loss

48

would have been put in a group of lower risk. Disregarding the genetic variation in interleukin 1 alpha and beta may not be the answer and it might be better to design a strategy that focuses on identifying the 14.5% that may be at lower risk for tooth loss. Tooth loss is the ultimate negative outcome of dental caries or periodontitis if they are left untreated or if treatments fail and it is a relevant measure that associates with mortality (Koka and Gupta 2018).

5.6

 he Impact of Oral Health T on Overall Health

Associations between periodontitis and a number of systemic conditions, cardiovascular diseases, arthritis, upper respiratory infections, and premature birth to name a few (Martelli et al. 2017; Cardoso et  al. 2018) have suggested that oral health may be more important than just for preserving teeth. Data suggesting individuals with periodontitis are more likely to have a number of

systemic diseases motivated many to offer models that suggest periodontitis directly impacts the risk for those conditions (Fig.  5.5). Other data, however, appear to suggest the opposite: that poor overall health leads to poorer oral health (Ravindramurthy and Vieira 2018; Henn et  al. 2019). Therefore, a more likely model shows that those associations can be explained by a common form of response the individual has to challenges in all systems (Fig.  5.6). Since episodes of bacteremia are so common in our daily lives (simple tooth brushing potentially causes oral bacterial to go to the circulating bloodstream), we believe it is more likely that overall health has a much bigger effect on oral health than vice versa. The evidence that providing periodontal treatment to pregnant women or to patients with rheumatoid arthritis does not decrease the risk of premature births (Michalowicz et al. 2006) or does not improve rheumatoid arthritis (Monsarrat et al. 2019) further suggests that the effect of oral health on overall health is likely to be less important than what has been proposed.

Oral bacteria…

Increase the risk for heart disease

Increase the risk for Alzheimer’s disease, Dementia, and stroke

Increase the risk for pneumonia and bronchitis

Can lead to stomach ulcers Linked to kidney failure Increase the risk for premature birth

Increase the risk for arthritis

Fig. 5.5  Model suggesting periodontitis directly impacts other systems

Can complicate diabetes and has been linked to pancreatic cancer

References

49 Inflammatory response chronification

activation

genetics

activity trigger

resolution

time

Fig. 5.6  Model suggesting inflammation is the common denominator explaining associations between periodontitis and other systemic conditions. Inflammatory response is modulated by individual genetic background and per-

References American Academy of Periodontology. Consensus report on diagnosis and diagnostic aids. In: World workshop in clinical periodontics. Chicago: American Academy of Periodontology; 1989. p. 123–131. Cardoso EM, Reis C, Manzanares-Céspedes MC. Chronic periodontitis, inflammatory cytokines, and ­interrelationship with other chronic diseases. Postgrad Med. 2018;130(1):98–104. Carvalho FM, Tinoco EM, Deeley K, Duarte PM, Faveri M, Marques MR, Mendonça AC, Wang X.  FAM5C contributes to aggressive periodontitis. PLoS One. 2010;5(4):e10053. Caton J.  Periodontal diagnosis and diagnostic aids. In: World workshop in clinical periodontics. Chicago: American Academy of Periodontology; 1989. p. 1–122. Caton JG, Armitage G, Berglundh T, Chapple ILC, Jepsen S, Kornaman KS, Mealey BL, Papapanou PN, Sanz M, Tonetti MS. A new classification scheme for periodontal and peri-implant diseases and conditions—introduction and key changes from the 1999 classification. J Clin Periodontol. 2018;45(Suppl 20):S1–8. Chapple IL, Bouchard P, Cagetti MG, Campus G, Carra MC, Cocco F, Nibali L, Hujoel P, Laine ML, Lingstrom P, Manton DJ, Montero E, Pitts N, Rangé H, Schlueter N, Teughels W, Twetman S, Van Loveren C,

sistent inflammation in more than one site or organ is likely to happen in individuals who are prone to chronification of inflammation

Van der Weijden F, Vieira AR, Schulte AG. Interaction of lifestyle, behaviour or systemic diseases with dental caries and periodontal diseases: consensus report of group 2 of the joint EFP/ORCA workshop on the boundaries between caries and periodontal diseases. J Clin Periodontol. 2017;44 Suppl 18:S39–51. Diehl SR, Kuo F, Hart TC. Interleukin 1 genetic tests provide no support for reduction of preventive dental care. J Am Dent Assoc. 2015;146(3):164–73. European Federation of Periodontology. Proceedings of the 1st European workshop on periodontics. London: Quintessence; 1993. Feng P, Wang X, Casado PL, Küchler EC, Deeley K, Noel J, Kimm H, Kim JH, Haas AN, Quinelato V, Bonato LL, Granjeiro JM, Susin C, Vieira AR. Genome wide association scan for chronic periodontitis implicates novel locus. BMC Oral Health. 2014;14:84. Giannobile WV, Braun TM, Caplis AK, Doucette-­ Stamm L, Duff GW, Kornman KS.  Patient stratification for preventive care in dentistry. J Dent Res. 2013;92(8):6894–701. Grech SC.  Chronic periodontitis with familial aggregation and discordant identical twins. Dent 3000. 2015;3(1):44–6. Henn IW, Fernandez CCA, Ravindramurthy S, Bussaneli DG, Alanis LRA. Oral health management in patients with depression. Clin Oral Investig. 2019;23(2): 975–7.

50 Kebschull M, Guarnieri P, Demmer RT, Boulesteix AL, Pavlidis P, Papapanou PN. Molecular differences between chronic and aggressive periodontitis. J Dent Res. 2013;92(12):1081–8. Koka S, Gupta A.  Association between missing tooth count and mortality: a systematic review. J Prosthodont Res. 2018;62(2):134–51. Kornman KS, Crane A, Wang HY, di Giovini FS, Newman MG, Pirk FW, Wilson TG Jr, Higginbottom FL, Duff GW.  The interlukin-1 genotype as a severity f­actor in adult periodontal disease. J Clin Periodontol. 1997;24:72–7. Lang N, Bartold M, Cullinan M, Jeffcoat M, Mombelli A, Murakami S, Page R, Papapanou P, Tonetti M, Van Dyke T.  Consensus report: aggressive periodontitis. Ann Periodontol. 1999a;4(1):53. Lang N, Soskolne WA, Greenstein G, Cochran D, Corbet E, Meng HX, Newman M, Novak MJ, Tenenbaum H. Consensus report: necrotizing periodontal diseases. Ann Periodontol. 1999b;4(1):78. Lindhe J, Ranney R, Lamster I, Charles A, Chung CP, Flemming T, Kinane D, Listgarten M, Löe H, Schoor R, Seymour G, Somerman M.  Consensus report: chronic periodontitis. Ann Periodontol. 1999a; 4(1):38. Lindhe J, Ranney R, Lamster I, Charles A, Chung CP, Flemming T, Kinane D, Listgarten M, Löe H, Schoor R, Seymour G, Somerman M. Consensus report: periodontitis as a manifestation of systemic diseases. Ann Periodontol. 1999b;4(1):64. Löe H, Amnerud A, Boysen H, Morrison E. Natural history of periodontal disease in man. Rapid, moderate and no loss of attachment in Sri Lankan laborers 14 to 46 years of age. J Clin Periodontol. 1986;13:431–40. Loos BG, Papantonopoulos G, Jepsen S, Laine ML. What is the contribution of genetics to periodontal risk? Dent Clin North Am. 2015;59(4):761–80. Martelli ML, Brandi ML, Martelli M, Nobili P, Medico E, Martelli F. Periodontal disease and women’s health. Curr Med Res Opin. 2017;33(6):1005–15.

5  Genetic Basis of Periodontitis and Tooth Loss Michalowicz BS, Hodges JS, DiAngelis AJ, Lupo VR, Novak MJ, Ferguson JE, Buchanan W, Bofill J, Papapanou PN, Mitchell DA, Matseoane S, Tschida PA. Treatment of periodontal disease and risk of preterm birth. N Engl J Med. 2006;355:1885–94. Monsarrat P, de Grado GF, Constantin A, Willmann C, Nabet C, Sixou M, Cantagrel A, Barnetche T, Mehsen N, Schaeverbeke T, Arrivé E, Vergnes JN, EaSPERA Group. The effect of periodontal treatment on patients with rheumatoid arthritis: the ESPERA ramdomised controlled trial. Joint Bone Spine. 2019. [Epub ahead of print]. Mucci LA, Hsieh CC, Williams PL, Arora M, Adami HO, de Faire U, Douglass CW, Pedersen NL. Do genetic factors explain the association between poor oral health and cardiovascular disease? A prospective study among Swedish twins. Am J Epidemiol. 2009;170(5):615–21. Nibali L, Di Iorio A, Tu YK, Vieira AR. Host genetics role in the pathogenesis of periodontal disease and caries. J Clin Periodontol. 2017;44(Suppl 18):S52–78. Nibali L, Bayliss-Chapman J, Almofareh SA, Zhou Y, Divaris K, Vieira AR. What is the heritability of periodontitis? A systematic review. J Dent Res. 2019;98(6):632–41. Papapanou PN. Periodontal diseases: epidemiology. Ann Periodontol. 1996;1:1–36. Ravindramurthy S, Vieira AR. Depression and its effects on the success of resin-based restorations. Spec Care Dentist. 2018;38(4):266–8. Ribeiro FV, Santos VR, Bastos MF, Miranda TS, Vieira AR, Figueiredo LC, Duarte PM. A preliminary study of FAM5C expression in generalized chronic periodontitis. Oral Dis. 2012;18(2):147–52. Rose EK, Vieira AR.  Caries and periodontal disease: insights from two US populations living a century apart. Oral Health Prev Dent. 2008;6:23–8. Vieira AR, Hilands KM, Braun TW. Saving more teeth—a case for personalized care. J Pers Med. 2015;5(1):30–5.

6

Genetic Basis of Dental Implant Failure and Alveolar Ridge Resorption

6.1

Introduction

Dental implants have evolved over the years into a safe procedure with high success rates. What has been consistently seen despite advances in the field, is approximate 3.5% failure rates (Esposito et al. 1998; Hickin et al. 2017), which cannot be easily attributed to the operator, material used, or any particular risk factor related to the patient. Dental implant failure thus fits well to a multifactorial mode of inheritance (likely contributions of multiple genes each with a small effect, which can be modulated by the environment). Identifying the genetic variants that may contribute to dental implant failure could provide a tool for determining which individuals are at higher risk for implant loss. This is a relevant problem due to the fact that the absolute number of dental implants being placed is growing and consequently, the number of failures is growing as well. The motivation exists to prevent those instances, and even vaccine development is being considered (Guo et al. 2014) due to dental implant popularity. For that, strategies testing the injection of genetically engineered DNA to stimulate direct production of antigens and consequent immune response are being tested. Initial findings show generation of immunoglobulins G and A and slow progressing bone loss in experimental peri-implantitis in dogs (Chuanhua et al. 2018).

© Springer Nature Switzerland AG 2019 A. R. Vieira, Genetic Basis of Oral Health Conditions, https://doi.org/10.1007/978-3-030-14485-2_6

6.2

 isk Factors for Dental R Implant Failure

A multitude of factors have been studied aiming to explain dental implant failure (Chrcanovic et al. 2014). Didactically, these factors can be divided into categories: surgical, locational, extraneous patient conditions, implant properties, prosthetic properties, and miscellaneous conditions (Table 6.1). Genetic variation has also been studied as a potential risk factor for dental implant failure, however, the studies have relatively small sample sizes and apparently are underpowered to detect associations with genes that may, in reality, have small effects (Doetzer et al. 2015; Cosyn et al. 2016; Ribeiro et al. 2017). There are two main approaches that may be used to overcome these shortcomings. To obtain enough power in a given study, one must consider studying a large enough pool of samples (Fig. 6.1). This is especially challenging to handle in relatively smaller settings, so one alternative is using more sophisticated clinical descriptions that would increase homogeneity among study groups. It has been previously shown that associations between BRINP3 and dental implant failure were driven by cases with single dental implant losses rather than cases with multiple implant losses (Casado et al. 2015). Finally, it is ideal for the original reports to include a replication sample so that the association results can be confirmed in the same report. 51

52

6  Genetic Basis of Dental Implant Failure and Alveolar Ridge Resorption

Table 6.1  Risk factor studied for dental implant failure (Chrcanovic et al. 2014; Santiago et al. 2018) Risk factor category Surgical conditions

Location conditions Patient conditions

Implant conditions

Prosthetic conditions

Miscellaneous conditions

Risk factor –  Prophylactic antibiotics –  Different types/regimen of antibiotic therapy –  Submerged versus non-submerged implants –  Flapless versus conventionally flapped surgery –  Various insertion torques –  Bone condensing versus bone drilling –  Implant inserted with versus without piezoelectric surgery split crest –  Intra- or post-operative complications –  Two surgical guide systems –  Fresh extraction sockets versus healed sites –  Immediate placement in sockets with versus without periapical pathology –  Socket depth –  Surgeon’s level of experience –  Maxilla versus mandible –  Region of the jaws –  Male versus female –  Age of the patient –  Smokers versus nonsmokers –  Periodontally compromised versus noncompromised situations –  Bone quality –  Jaw bone volume/jaw bone resorption – Bruxism –  Number of present teeth/edentulism status – Ethnicity –  Oral hygiene –  Patients with versus without oral lichen planus – Compromised medical status/systemic conditions (diabetes, estrogen replacement, corticosteroid therapy, antidepressants intake, metabolic diseases, hypertension, cardiac problems, gastric problems, osteoporosis, hypo- or hyperthyroid, hypercholesterolemia, asthma, Crohn’s disease rheumatoid arthritis, chemotherapy, head and neck radiotherapy, hysterectomy) –  Genetic variation –  Implant length –  Implant width/diameter/taper –  Initial stability –  Threaded versus cylindrical implants –  Implant thread type/design –  Number of implants placed per patient –  Implant surface –  Tilted versus axially placed implants –  One-piece versus two-piece implants –  Wide versus double implants –  Time since implant placement –  Occlusal versus non-occlusal loading –  Cemented versus screw-retained implant –  Type of prosthesis –  All-on-2 versus all-on-4 implants mandibular cross-arch fixed prosthesis –  Splinted versus unsplinted implants –  Number of implants for overdentures –  Type of overdenture attachment –  Morse taper connection versus conventional abutments –  Immediate/early/delayed/late loading – Computer numeric controlled (or laser-welded) titanium frameworks versus cast gold-allow frameworks –  Contamination with prefabricated stainless steel guide versus no guide –  Immediate orthodontic loading –  Internal sinus lift without material versus implants in the native posterior maxilla – Reason for tooth extraction (periodontitis, trauma, root fracture, periapical inflammation, dental caries) –  Narrow versus wide edentulous maxilla crest

6.3  BRINP3 (Bone Morphogenetic Protein/Retinoic Acid Inducible Neural Specific 3)

53

Statistical power

80%

Minor Allele Frequency

60%

0.2 0.1 0.05 0.01

40% 20%

1000

1500 Sample Size

2000

Fig. 6.1  Statistical power for an odds ratio of 1.3 in relation to sample size and allele frequency. A genetic marker with a minor allele frequency of 20% in the general population would require 1500 cases and 1500 controls to

achieve a power of 80% with an alpha value of 0.05. Studying rarer alleles with a frequency of 1% would require more than 20,000 cases and 20,000 controls (Schaefer 2018)

6.3

2010), was also associated with norepinephrine change during physical exercise (Karoli et  al. 2012), which suggests this gene influences neurological functions as well. This same BRINP3 marker we found associated with dental implant failure (Casado et  al. 2015). Expression levels of BRINP3 in healthy peri-­implant tissues were lower than those found in corresponding diseased tissues. When diseased tissues were divided depending on the cases of origin (individuals with both periodontitis and periimplantitis versus individuals with just peri-­ implantitis), expression was lower in individuals with just peri-implantitis. These data suggest that periodontitis and peri-implantitis may be unrelated conditions. Diseased peri-implant tissues harbor distinct microbiological ecosystems in comparison to healthy periodontal tissues, which are less diverse and include putative periodontal pathogens (Apatzidou et  al. 2017). However, it appears that dental implant placement in patients with a history of periodontitis is

 RINP3 (Bone Morphogenetic B Protein/Retinoic Acid Inducible Neural Specific 3)

It has been shown that periodontitis with an earlier disease onset is associated with markers in BRINP3 (Carvalho et al. 2010). BRINP3 is related to proliferation, migration, and programmed cell death, and is also related to several diseases, including invasion of pituitary tumors, atherosclerosis (Shorts-Cary et  al. 2007), myocardial infarction (Connelly et  al. 2008), and cerebral infarction in diabetics (Long et al. 2017). BRINP3 expression in response to ischemia in the left ventricular myocardium is more accentuated in females than in males, which may explain the higher risk of heart failure post-myocardial infarction seen in females (Stone et  al. 2019). Interestingly, the BRINP3 single nucleotide polymorphism rs1935881, the same polymorphism, the same one found to be associated with periodontitis (Carvalho et  al.

54

6  Genetic Basis of Dental Implant Failure and Alveolar Ridge Resorption

a viable option that may be used to restore oral function with survival outcomes similar to those found in patients without a history of periodontitis (Monje et al. 2014).

(Beyer et  al. 2005) and suggests that dental implant failure is also at least in part influenced by more than one gene and thus fits a multifactorial framework.

6.4

6.5

A Changing Paradigm

Dental implants are highly predictable and work well 97% of the time. This fact has motivated the suggestion that placing a dental implant is a more attractive option than the effort of saving a tooth, which may require periodontal surgery, endodontic intervention, and restorative treatment, all of which may have a higher chance of failure than dental implants. Therefore, extraction of teeth and their replacement with dental implants are becoming increasingly popular in the management of periodontally compromised patients (Lundgren et al. 2008). Patients, however, tend to prefer a conservative approach for the treatment of a tooth with poor prognosis and are willing to pay for those services (Re et al. 2017). At this point, there is no evidence to support that the placement of a dental implant is a better alternative to the conservative treatment used to prolong the life span of natural tooth structure (Telles et  al. 2019). Clinical and demographic data on dental implant failures consistently show a lack of consistency, and it is not possible to establish definitive predictive factors to allow for the design of preventive strategies. Further, when data on dental implant failure was analyzed by age, there is an apparently higher risk of dental implant loss in younger patients (30–39  years of age) was found when compared to older patients (older than 79 years) (Jemt 2019). This difference of frequency depending on age is seen in other complex traits such as Alzheimer’s disease

Alveolar Ridge Resorption

After tooth loss, the alveolar socket is remodeled leading to further bone loss. This typically generates aesthetic problems as well as limits the feasibility of dental implants, fixed partial dentures, or removable partial and complete dentures. Most of the horizontal and vertical dimensional alterations of the alveolar ridge happen during the first 3  months of healing (Johnson 1969; Schropp et al. 2003). After this pronounced initial phase of reduction in the period of wound healing, further reductions appear to be less pronounced during the later stage of healing. According to the published literature, the mean clinical reduction in alveolar ridge width is 3.87  mm, the mean clinical mid-buccal height loss is 1.67 mm, the mean crestal height change as assessed on mid-buccal height loss is 1.53  mm, and the socket fill in height as measured relative to the original socket floor is on average 2.57 mm (Van der Weijden et al. 2009). However, what is interesting about these figures is the variation that exists among people (Fig.  6.2). The reason why certain individuals have a quicker or more dramatic reduction can be explained by referring to the multifactorial inheritance framework, likely with genes involved in the osteoclastic activity as part of the ones contributing to such reduction. Clinically, the dentist sees certain individuals with more dramatically resorption than others (Fig.  6.3) and in general terms, it is likely that the rate of resorption between individuals is different as well (Fig. 6.4).

6.5 Alveolar Ridge Resorption Fig. 6.2  Alveolar width change post-extraction varies greatly among people (Bars indicate means and lines standard deviations. (1) Barone et al. 2008; (2) Camargo et al. 2000; (3) Iasella et al. 2003; (4) Lekovic et al. 1997; (5) Lekovic et al. 1998; (6) Serino et al. 2003)

55

0 -0.5

1

2

3

4

-1 -1.5 -2 -2.5 -3 -3.5 -4 -4.5 -5

Fig. 6.3  Range of levels of mandibular alveolar bone resorption in edentulous specimens

5

6

6  Genetic Basis of Dental Implant Failure and Alveolar Ridge Resorption

56 Fig. 6.4 Panoramic radiographs with 8 years of span of edentulous patients showing relatively slow (a) and more rapid (b) mandibular alveolar bone resorption (courtesy of Aaema Athar)

a

b

References

References

57

integrated oral implants. (I). Success criteria and epidemiology. Eur J Oral Sci. 1998;106:527–51. Guo M, Wang Z, Fan X, Bian Y, Wang T, Zhu L, Lan Apatzidou D, Lappin DF, Hamilton G, Papadopoulos CA, J. kgp, rpgA, and rpgB DNA vaccines induce antiKonstantinidis A, Riggio MP. Microbiome associated body responses in experimental peri-implantitis. J with peri-implantitis versus periodontal health in indiPeriodontol. 2014;85:1575–81. viduals with a history of periodontal disease. J Oral Hickin MP, Shariff JA, Jennette PJ, Finkelstein J, Microbiol. 2017;9(Suppl 1):1325218. Papapanou PN.  Incidence and determinants of denBarone A, Aldini NN, Fini M, Giardino R, Calvo tal implant failure: a review of electronic health Guirado JL, Covani U.  Xenograft versus extraction records in a U.S. dental school. J Dent Educ. alone for ridge preservation after tooth removal: a 2017;81(10):1233–42. clinical and histomorphometric study. J Periodontol. Iasella JM, Greenwell H, Miller RL, Hill M, Drisko 2008;79:1370–7. C, Bohra AA, Scheetz JP.  Ridge preservation with Beyer K, Lao JI, Latorre P, Ariza A.  Age at onset: an freeze-dried bone allograft and a collagen membrane essential variable for the definition of genetic risk faccompared to extraction alone for implant site develtors for sporadic Alzheimer’s disease. Ann N Y Acad opment: a clinical and histologic study in humans. J Sci. 2005;1057:260–78. Periodontol. 2003;74:900–99. Camargo PM, Lekovic V, Weinlaender M, Klokkevold Jemt T.  Implant failures and age at the time of surPR, Kenney EB, Dimitrijevic B, Nedic M, Jancovic gery: a retrospective study on implant treatments in S, Orsini M. Influence of bioactive glass on changes 4585 edentulous jaws. Clin Implant Dent Relat Res. in alveolar process dimensions after exodontia. Oral 2019;21(4):514–20. Surg Oral Med Oral Pathol Oral Radiol Endod. Johnson K. A study of the dimensional changes occurring 2000;90:581–6. in the maxilla following tooth extraction. Aust Dent J. Carvalho FM, Tinoco EMB, Deeley K, Duarte PM, 1969;14:241–4. Faveri M, Marques MR, Mendonça AC, Wang X, Karoli HC, Stevens CJ, Magnan RE, Harlaar N, Hutchison Cuenco K, Menezes R, Garlet GP, Vieira AR. FAM5C KE, Bryan AD.  Genetic influences on physiological contributes to aggressive periodontits. PLoS One. and subjective responses to an aerobic exercise ses2010;5(4):310053. sion among sedentary adults. J Cancer Epidemiol. Casado PL, Aguiar DP, Costa LC, Fonseca MA, Vieira 2012;2012:540563. TCS, Alvim-Pereira CCK, Alvim-Pereira F, Deeley Lekovic V, Keeney EB, Weinlaender M, Han T, K, Granjeiro JM, Trevilatto PC, Vieira AR. Different Klokkevold PR, Dimitrijevic B, Nedic M, Orsini M. A contribution on BRINP3 gene in chronic periodontibone regenerative approach to alveolar ridge maintetis and peri-implantitis: a cross-sectional study. BMC nance following tooth extraction. Report of 10 cases. J Oral Health. 2015;15:33. Periodontol. 1997;68:563–70. Chrcanovic BR, Albrektsoon T, Wennerberg A.  Reasons Lekovic V, Camargo PM, Klokkevold PR, Weinlaender for failures of oral implants. J Oral Rehabil. M, Keeney EB, Dimitrijevic B, Nedic M. Preservation 2014;41:443–76. of alveolar bone in extraction sockets using bioabsorbChuanhua L, Zhifeng W, Lina Z, Xin F, Jing able membranes. J Periodontol. 1998;69:1044–9. L. Experimental research on arginine-gingipain a gene Long Y, Zhan Q, Yuan M, Duan X, Zhou J, Lu J, Li Z, vaccine for porphyromonas gingivalis that prevents Yu F, Zhou X, Yang Q, Xia J.  The expression of peri-implantitis in beagle dogs. Hua Xi Kou Qiang Yi microRNA-223 and FAM5C in cerebral infarction Xue Za Zhi. 2018;32(1):76–81. patients with diabetes mellitus. Cardiovasc Toxicol. Connelly JJ, Shah SH, Doss JF, Gadson S, Nelson S, 2017;17(1):42–8. Crosslin DR, Hale AB, Lou X, Wang T, Haynes C, Lundgren D, Rylander H, Laurell L.  To save or to Seo D, Crossman DC, Mooser V, Granger CB, Jones extract, that is the question. Natural teeth or dental CJ, Kraus WE, Hauser ER, Gregory SG. Genetic and implants in periodontitis-susceptible patients: clinifunctional association of FAM5C with myocardial cal decision-making and treatment strategies exeminfarction. BMC Med Genet. 2008;9:33. plified with patient case presentations. Periodontol. Cosyn J, Christiaens V, Koningsveld V, Coucke PJ, De 2008;47:27–50. Coster P, De Paepe A, De Bruyn H.  An exploratory Monje A, Alcoforado G, Padial-Molina M, Suarez F, Lin case-control study on the impact of IL-1 gene polyGH, Wang HL.  Generalized aggressive periodontimorphisms on early implant failure. Clin Implant Dent tis as a risk factor for dental implant failure: a sysRelat Res. 2016;18(2):234–40. tematic review and meta-analysis. J Periodontol. Doetzer AD, Schlipf N, Alvim-Pereira F, Alvim-­ 2014;85(10):1398–407. Pereira CC, Werneck R, Riess O, Bauer P, Trevilatto Re D, Ceci C, Cerutti F, Del Fabbro M, Corbella S, PC.  Lactotransferrin gene (LTF) polymorphisms and Taschieri S. Natural tooth preservation versus extracdental implant loss: a case-control association study. Clin tion and implant placement: patient preferences Implant Dent Relat Res. 2015;17(Suppl 2):e550–61. and analysis of the willingness to pay. Br Dent J. Esposito M, Hirsch JM, Lekholm U, Thomsen 2017;222:467–71. P. Biological factors contributing to failures of osseo-

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Ribeiro R, Melo R, Tortamano Neto P, Vajgel A, Souza PR, Cimões R.  Polymorphisms of Il-10 (−1082) and RANKL (−438) genes and the failure of dental implants. Int J Dent. 2017;2017:3901368. Santiago JF Jr, Biguetti CC, Matsumoto MA, Kudo GAH, Silva RBP, Saraiva PP, Fakhouri WD. Can genetic factors compromise the success of dental implants? A systematic review and meta-analysis. Genes (Basel). 2018;9(9):444. Schaefer AS. Genetics of periodontitis: discovery, biology, and clinical impact. Periodontol. 2018;78:162–73. Schropp L, Wenzel A, Kostopoulos L, Karring T.  Bone healing and soft tissue contour changes following single-tooth extraction: a clinical and radiographic 12-month prospective study. Int J Periodontics Restorative Dent. 2003;23:313–23. Serino G, Biancu S, Iezzi G, Piattelli A. Ridge preservation following tooth extraction using a polylactide and polyglycolide sponge as space filler: a clinical and histological study in humans. Clin Oral Implants Res. 2003;14:651–8.

Shorts-Cary L, Xu M, Ertel J, Kleinschmidt-Demasters BK, Lillehei K, Matsuoka I, Nielsen-Preiss S, Wierman ME.  Bone morphogenetic protein and retinoic acid-inducible neural specific protein-3 is expressed in gonadotrope cell pituitary adenomas and induces proliferation, migration, and invasion. Endocrinology. 2007;148(3):967–75. Stone G, Choi A, Meritxell O, Gorham J, Heydarpour M, Seidman CE, Seidman JG, Aranki SF, Body SC, Carey VJ, Raby BA, Stanger BE, Muehlschlegel JD. Sex differences in gene expression in response to ischemia in human left ventricular myocardium. Hum Mol Genet. 2019;28(10):1682–93. Telles V, Bezamat M, Vieira AR.  An argument against extraction as a treatment alternative for restorable teeth. Compend Contin Educ Dent. 2019;40(6):342–5. Van der Weijden F, Dell’Acqua F, Slot DE.  Alveolar bone dimensional changes of post-extraction sockets in humans: a systematic review. J Clin Periodontol. 2009;36:1048–58.

7

Genetic Basis of Craniofacial Deformities and Malocclusion, Oral Clefts, and Craniosynostosis

7.1

Craniofacial Deformities and Malocclusions

Estimations of the frequency of craniofacial deformities and malocclusions (hereinafter collectively referred to as malocclusions) exist for many countries, and are generally high, with approximately one-third of the population requiring treatment (Bilgic et al. 2015). Malocclusion is not a disease but rather a condition defined as a series of deviations away from normally described occlusion that may impact quality of life. There is no evidence that orthodontic treatment improves oral health or function, but the treatment is justified by the potential social and psychological improvement a change in appearance can bring (Shaw 2002). The suggestion that malocclusion has a genetics component comes from observations of mandibular prognathism (frequently associated with Angle’s class III malocclusion) segregating in families. A well-known example is the House of Habsburg, which produced emperors and kings of Bohemia (current Czech Republic), England, Germany, Hungary, Croatia, Illyria (a region of Austria), the Mexican second empire, Ireland, Portugal, Spain, and several administrators and principalities of Denmark and Italy (Fig.  7.1) (Wolff et al. 1993). Since many cases of mandibular prognathism aggregate in families, there is the perception that it follows an autosomal dominant Mendelian mode of inheritance (monogenic © Springer Nature Switzerland AG 2019 A. R. Vieira, Genetic Basis of Oral Health Conditions, https://doi.org/10.1007/978-3-030-14485-2_7

or single gene). The perception that one gene with a main effect leads to mandibular prognathism (Cruz et  al. 2008) motivated linkage (Yamaguchi et  al. 2005; Li et  al. 2010, 2011; Cruz et  al. 2011) and association (Rodrigues et al. 2013; Xue et al. 2014; Signer-Hasler et al. 2014; Bayram et  al. 2014; Ikuno et  al. 2014; Perillo et al. 2015; Guan et al. 2015; Xiong et al. 2017; Saito et al. 2017) studies, which fall under the hypothesis that a strong genetic effect can be identified despite sample sizes that are relatively small (definitions of linkage and association are given in the box below).

Glossary

• Association: Observational study that tests in individuals if a particular genetic variant is more frequent than another one depending on the person being affected by a disease or being a carrier of a trait of interest. • Linkage: The tendency for genes and other genetic markers to be inherited together since they are physically close on the same chromosome.

The results of these studies are inconsistent, suggesting that monogenic inheritance and a gene with a major effect are not the best explana59

60

7  Genetic Basis of Craniofacial Deformities and Malocclusion, Oral Clefts, and Craniosynostosis

Fig. 7.1  Silhouette of Carlos V of Spain and Germany at 17 years of age. His family included 13 lineages of European royalty and 409 documented individuals (Wolff et al. 1993), where 321 diagnosed with mandibular prognathism varying from mild to severe. Analyses of this family suggested that mandibular prognathism has an autosomal dominant mode of inheritance, and cases that did not fit well may be due to consanguinity. In some cases, the prognathism escaped a generation and penetrance was estimated at 0.88

tions for the majority of cases of malocclusion. Currently, it is understood that inheritance of mandibular prognathism and malocclusions in general is multifactorial or complex, which means that more than one gene (instead of just one) contribute to the establishment of malocclusion, and these genes can be influenced by the environment, though as seen in other conditions, there are exceptions, and a major gene effect with autosomal dominant inheritance may be possible.

7.1.1 An Unconventional Myosin Knowing that malocclusion is influenced by more than one gene and that clinically these cases are heterogeneous, it was first proposed to approach the question by studying cases that were clinically well-characterized (Tassopoulou-­ Fishell et al. 2012). Profile photos were obtained from all study participants showing soft tissue relationships (concave or convex) and cephalometric measurements to classify individuals as

orthognathic versus prognathic. More specifically, measurements of Steiner, ANB, Wits, and the Downs A-B plane were focused upon. According to the Steiner analysis, an ANB angle smaller than 2° indicates that the mandible is positioned ahead of the maxilla. The individuals with ANB values smaller than 2° were evaluated further to determine if the discrepancy was due to the maxilla being smaller than average rather than the inverse. Such cases were not considered true prognathic individuals, but cases with a normal size mandible apparently protruded due to anteroposterior maxillary deficiency. Wits, which indicates anteroposterior relationships according to intracranial references, was also an included metric. A negative Wits value indicates a skeletal Class III relationship, and the lower the Wits value, the more severe the Class III case. A Downs A-B plane with an angle of 4.6 or higher also indicates a skeletal Class III, although this measurement is more severe when the individual has a more accentuated pogonium. Additional clinical criteria for a Class III diagnosis were included, such as Class III rela-

7.1 Craniofacial Deformities and Malocclusions

61

tionships of molars and canines, and instances of negative overjet. In a study with North American families of Hispanic origin that showed an autosomal dominant pattern of mandibular prognathism, five loci (chromosomal regions) were identified as being linked to mandibular prognathism due to maxillary deficiency: 1p22.1, 3q26.2, 11q22, 12q13.13, and 3 12q23 (Frazier-Bowers et  al. 2009) [each chromosome has a short (“p” for “petit”) and a long arm (“q” for “queue”), with each arm is divided into cytogenetic bands, which are called p1, p2, p3, q1, q2, q3, etc., counted from the centromere to the telomere]. When those five regions were studied, an association was found with MYO1H in 12q23  in North Americans (Tassopoulou-Fishell et  al. 2012). MYO1H is an unconventional myosin and this result was independently replicated in a group of patients from Brazil with prognathisms without maxillary discrepancy (Cruz et  al. 2017) and in prognathic individuals from midwestern regions in the USA (Fontoura et al. 2015). The mutation of a proline to a leucine in the position 1001 of the MYOH protein can be a functional variant in humans, and orthologs (similar DNA sequence in distinct spe-

RR 60 50 40

cies, suggesting they had a common ancestor) of myo1h in zebrafish (Danio rerio) are expressed in the mandible (Sun et al. 2018) as well, suggesting its function during craniofacial development. This accumulated evidence suggests that MYO1H could be a predictor for the establishment of prognathism, and may help in determining which patients will respond better to treatment.

7.1.2 Sprinters Versus Marathon Runners The idea that craniofacial deformities and malocclusions can be influenced by factors not directly related to the skeletal basis is intriguing. Motivated by the results found with MYO1H, genes that code for skeletal muscle alpha-actin were tested: ACTN2, which is expressed in all muscle fibers, and ACTN3, which is expressed in only fast-twitch muscle fibers (type 2). The frequency of a particular genetic variant, the mutation R577X, is increased in people who run longer distances, and decreased in sprinters (Fig.  7.2) (Yang et  al. 2003). When this was tested for association of genetic variation in the

RX

XX

[VALUE] % [VALUE] %

47%

[VALUE] % [VALUE] %

30

[VALUE] %

20 10 [VALUE] 0

SPRINTERS

LONG DISTANCE RUNNERS

Fig. 7.2  Frequency of ACTN3 R577X genotypes in track more common in long-distance runners. The frequency of X and field Olympic athletes who are sprinters versus long-­ is also more common in Class II individuals and less comdistance runners (Yang et  al. 2003). The XX genotype is mon in individuals with a deep bite (Zebrick et al. 2014)

62

7  Genetic Basis of Craniofacial Deformities and Malocclusion, Oral Clefts, and Craniosynostosis

genes that code for alpha-actin, as well as sagittal and vertical definitions of malocclusion, we found skeletal Class II individuals more frequently had two copies of 577X and less type 2 fast-twitch muscle fibers in the masseter (Zebrick et al. 2014). This evidence suggests that the function of the connective tissue, in particular muscle, has a role in the establishment and severity of skeletal deformities.

7.1.3 Facial Asymmetry A perception of symmetry between the two sides of the face defines attractiveness. Deviations of this harmony, which are referred to asymmetry, bring discomfort and low self-esteem. In general, the right and left of the face mirror each other, and keeping symmetry is apparently important for midline definition. The lefty proteins are responsible for interrupting body symmetry to allow the normal positioning of the heart, lungs, and stomach (Chen and Shen 2004). In the face, a similar event of expression of lefty occurs on the left side only, which has not been identified on the right side (Boorman and Shimeld 2002), and this difference may explain, at least in part, why clefts affect the lip twice as frequently on exclusively the left side of the face (Vieira 2012a). Similarly, facial asymmetry is typically found on the left side (Hafezi et al. 2017).

a

b

By studying individuals who had undergone orthognathic surgery to correct craniofacial deformities, four types of asymmetry were detected: asymmetry of the body of the mandible, asymmetry of the ramus of the mandible, atypical asymmetry, and “C” shaped asymmetry (Fig. 7.3) (Chung et al. 2017). Genetic variation in ESR1 and ENPP1, which are genes involved in bone mineralization found to be associated with Class II and Class III malocclusions, respectively (Nicot et al. 2016), and may influence facial formation in cases of asymmetry (Chung et  al. 2017). ENPP1 is also associated with mandibular condyle shape variation (Constant et  al. 2017). Individuals with asymmetry of the body of the mandible more often showed genetic variation in ENPP1, when compared to other types of asymmetry (Fig.  7.3). People with atypical a­ symmetries or “C” shaped asymmetry, more often had variation in ESR1. Of interest is that only 3% of the cases considered symmetrical were diagnosed with temporomandibular joint disorder, in comparison to 78% of people with asymmetries described in Fig.  7.3. The challenge then continues to be identifying which individuals benefit from orthognathic surgery—about 7% of patients end with their temporomandibular joint dysfunction worsening after orthognathic surgery, even when most of them were individuals without asymmetry to begin with.

c

d

Fig. 7.3  Studied asymmetries in Chung et al. (2017): (a) asymmetry of the body of the mandible, (b) asymmetry of the ramus of the mandible, (c) atypical asymmetry, and (d) “C” shaped asymmetry

7.2 Oral Clefts

7.1.4 Orthodontic Tooth Movement The initial response to the compressive forces of orthodontics involves the activation of genes that control angiogenesis, inflammation, osteoblast formation, and extracellular matrix remodeling (Schröder et al. 2018). The protein osteopontin is thought to be a potential biomarker able to predict the result of orthodontic treatment due to its role in bone and periodontal remodeling (Wolff et  al. 1993). External root resorption secondary to orthodontic tooth movement and variation in the speed each patient supports orthodontic tooth movement without negative consequences are modulated by genes under a multifactorial or complex inheritance mode. The implication is that the instances where robust external root resorption occurs may not be the fault of the orthodontist. Similar implications of genetic influence were noted in cases of dental implant failure (Esposito et al. 1998; Hickin et al. 2017), or as in failure of extensive composite resin restorations (Vieira et  al. 2017), which occur due to individual susceptibility for those failures and that are also determined by a multifactorial or complex mode of inheritance.

63

still may be due to teratogenic influences. The most interesting and salient aspects related to oral clefts are their frequency worldwide, the effect of maternal cigarette smoking, the lip being affected on the left side, more often the disturbances on dental development, and the occurrence of cancer in the families of affected individuals.

7.2.1 O  ral Clefts Frequency Worldwide

Geographic origin is the only demographic variable consistently associated with oral clefts, with frequencies being higher in Asians and American Indians, intermediate in Whites, and lower incidences in Africans and African Americans (Vanderas 1987), a pattern consistent with a multifactorial or complex mode of inheritance for oral clefts, where many genes with small effects contribute to the defect, and these gene contributions vary depending on the geographic area due to populations accumulating independently distinct frequencies of hypomorphic alleles that have small additive effects in the development of clefts. Another geographic pattern of note in Europe is the higher frequencies of clefts in the north that get 7.2 Oral Clefts lower as one travels southward to the Mediterranean Sea (Vieira 2006). In North America, it should be Fifty years ago, Dr. Fraser predicted that identi- expected to find significantly higher Amerindian fying genes for isolated forms of cleft lip and pal- ancestry and lower African ancestry in patients ate would be difficult and that we would likely born with cleft lip with or without cleft palate than not identify a biochemical defect (Fraser 1970). in unaffected individuals, and significantly lower Since first suggestion of a gene (TGFA) was asso- African ancestry in patients born with cleft palate ciated with isolated cases of cleft lip and palate only than in unaffected individuals. In South from Iowa by Dr. Murray (Ardinger et al. 1989), America, however, although the same higher frethe field has moved from targeted hypothesis-­ quency of cleft lip with or without cleft palate risk driven gene discovery work to hypothesis-free in Native Americans, intermediate frequency in genome-wide scans and back, and genes have European American, and lower frequencies in been consistently added to a list of genetic etio- African Americans can be seen, this does not look logic factors, but there still exists very little like the case for cleft palate only, due to their mechanistic understanding (Vieira 2018). Most apparently higher European genetic ancestry cases of oral clefts are defined by the contribu- (Vieira-­Machado et al. 2016). Knowing these pattions of multiple genes and neatly fit a multifac- terns, populations that have admixture may protorial or complex mode of inheritance, where vide opportunities for identifying genes if analyses although some cases are monogenic forms, oth- take into consideration population-specific molecers are chromosomal abnormalities, and others ular markers. South Americans born with isolated

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7  Genetic Basis of Craniofacial Deformities and Malocclusion, Oral Clefts, and Craniosynostosis

cleft lip with or without cleft palate compared to matched individuals born without clefts have a higher frequency of the specific Native American mitochondrial haplogroup D, a lower frequency of the African-specific Y-chromosome marker YAP, and a higher frequency of the Native American Y-chromosome marker DYS199 (Vieira et  al. 2002). Taking into consideration the maternal lineage containing the mitochondrial DNA haplotype D, an association was shown between IRF6 (interferon regulatory factor 6) and cleft lip with or without cleft palate (Vieira et al. 2007). This could not be detected in South Americans in the original report that found an association between IRF6 and isolated cleft lip with or without cleft palate (Zucchero et  al. 2004). This is relevant because IRF6 is one of the few genes that has been consistently associated with oral clefts, independent of the study design (linkage, targeted association, genome-wide association, reviewed in Vieira (2012b)), and any report suggesting the association does not exist probably lacks statistical power or includes a very heterogeneous sample. Reduced folate carrier 1 (RFC1) was also shown to be associated with cleft lip only when affected children carried Native American mitochondrial-specific markers A, B, or C (Vieira et al. 2008). When a similar design was implemented in another cohort from a very distinct part of the world, still similar patterns were found. Individuals born with oral clefts in Latvia, a country with one of the highest prevalences of cleft lip with or without cleft palate in Europe, were more likely to carry European-specific mitochondrial haplotypes U4 and U5 (Vieira et al. 2011). When those haplotypes were considered in the analyses, distinct associations were found depending on individuals carrying non-U or U4/U5 mitochondrial haplotypes (Lace et al. 2011) showing that increasing homogeneity of the sample can be accomplished. Studying more homogeneous groups allows in theory for identifying associations with smaller sample sizes.

7.2.2 Left Versus Right One of the most intriguing observations regarding oral clefts is that when clefting is unilateral,

the upper lip is affected on the left side in two-­ thirds of the cases that are not bilateral. For practical reasons, the distinction between left and right in genetic studies of clefts has not been made. For one, it would result in a reduction in sample size for analysis. Secondly, there is a general sense that there is no difference in main genetic influences for oral clefts, independent of whether it affects one or both sides of the lip, if it unilaterally affects the left or right lip, or if it is complete or incomplete. Since the work done by Poul Fog-Anderson (Fogh-Anderson 1942) it has been known that cleft palate only is a distinct entity from the cleft lip with or without cleft palate and these two have been studied separately ever since. In the cases of cleft lip with or without cleft palate, it appears that it is justified that cases are studied separately depending on the lip being affected on the left, right, or both sides. Assuming a difference in genetic control depending on the side, there is evidence from many vertebrates that a gene pathway including nodal, lefty (left–right determination factor), and Pitx2 (paired-like homeodomain transcription factor 2) is functional on the left side of the jaws, and has not been identified on the right side (Boorman and Shimeld 2002). Assuming that this difference implies different genetic control depending on the side, associations between AXIN2 (Axin-­ related protein 2) and CDH1 (E-cadherin) were found when isolated unilateral right cleft lip with or without cleft palate (not left) was considered in our studies (Letra et al. 2009).

7.2.3 Maternal Cigarette Smoking Smoking while pregnant increases both the risk for a baby born with cleft lip with or without cleft palate (odds ratio 1.4, 95% confidence intervals 1.3–1.47) and cleft palate only (odds ratio 1.24, 95% confidence interval 1.12–1.38) (Xuan et al. 2016). This effect appears to be enhanced by interaction with TGFA (Vieira 2006; Ebadifar et al. 2016). Nicotine is the likely chemical culprit for increasing the risk of oral clefts when smoking while pregnant, as it may modify gene expression and lead to the persistence of epithelial cells in areas where connective tissue should

7.2 Oral Clefts

level and fuse (Vieira and Dattilo 2018). The other effect is probably related to the increase in embryonic hypoxia (Vieira 2012a). Two distinct models support the idea that maternal cigarette smoking increases susceptibility to be born with oral clefting: acardiac twins and living in high altitudes. Artery-to-artery and vein-to-vein anastomosis in the monochorial placenta of twins leads to the return of blood of one twin directly to the umbilical artery of the acardiac twin, and the blood reaching the head of the embryo is thus poorly oxygenated. In these instances, the chances of showing oral clefting appear to grow from 1 in 700 among live births, to 1 in 2 among acardiac twins (Jones et  al. 2008), which provides strong evidence that hypoxia is a mechanism that can lead to oral clefts. Another scenario that supports this hypoxic mechanism is living in high altitudes. Children born in La Paz, Bogota, and Quito (Bolivia, Colombia, and Ecuador, respectively), metropolitan areas higher than 2000 m above the sea level, are more likely than children born at the sea level to be born with cleft lip, microtia, preauricular tag, branchial arch anomaly complex, constriction band complex, and anal atresia, whereas they are less likely to be born with neural tube defects, hydrocephaly, and pes equinovarus (Castilla et al. 1999). The coincidental finding in these areas of high altitude of four types of craniofacial defects with higher frequency among live borns, and neural tube defects with lower frequency in areas of high altitude suggests a real biological cause for such conditions. When we provoked hypoxia during the development of the Danio rerio (zebrafish), we noticed clefting of the ethmoid plate, the structure corresponding to the palate in mammals (Fig. 7.4).

7.2.4 Dental Development Oral clefts are referred to as isolated (or nonsyndromic) and syndromic. This distinction aims to separate the typical case in which the cleft appears to be the only structural abnormality the person has (about 70% of all clefts) from the cases in which other structural defects are visible

65

(30% of cases and more than 400 entities described as including oral clefts as part of the phenotype). This isolated versus syndromic classification has been used for the gene discovery work, both in hypothesis-driven and hypothesis-­ free approaches. Genome-wide genetic variation data have been analyzed by different approaches, each time providing a unique result. As the list of suggested genes contributing to oral clefts increases, so does the perception that this line of work will not provide conclusive answers on the specific gene variants that may help define individual risks for having a child being born with oral clefting. In this matter, after a series of association studies utilizing genome-wide genotypes, the field is no further along today than when the initial insights gained by direct sequencing of specific genes (Vieira et  al. 2005; Vieira 2008) were obtained (Fig. 7.5). Individuals born with oral clefts are at least four times more likely to have dental anomalies (Letra et al. 2007). These dental anomalies can be classified based on alterations in the structure of the teeth or their number, and they appear to associate as well (Fig. 7.6). It appears that oral clefting is, in fact, a syndrome of alterations of the dentition (Koruyucu et  al. 2018). The problem for many study cohorts is that individuals born with clefts are identified at birth and information about their dentitions cannot be collected. When the dentition is considered, specific associations can be found since this more sophisticated clinical description likely increases the homogeneity of the sample. As an example, the PVR/CD155 (poliovirus receptor/cluster of differentiation 155) Ala67Thr mutation is associated with individuals born with oral clefts who do not have dental anomalies (Vieira et al. 2018). A pattern that was noticed is the presence of alterations in the maxillary lateral incisor opposite to the side where the lip is clefted ­ (Fig. 7.7). It was first suggested that this clinical presentation was a form of a bilateral cleft of the lip, in which one side has overt clefting and the other side an anomalous maxillary lateral incisor (Letra et al. 2007). The frequency of these cases varies from 12.5 to 39% depending on the specific population studied (Vieira 2012b).

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7  Genetic Basis of Craniofacial Deformities and Malocclusion, Oral Clefts, and Craniosynostosis

a

c

b

d

e

Fig. 7.4  The dissolved oxygen level of the system water under ambient conditions of approximately 6.5 ± 0.5 mg/L (normoxia) was reduced by 30%, 50%, and 80% via bubbling nitrogen gas into the water. The oxygen levels were monitored by a dissolved oxygen meter (SonTek/YSI model 58, Fisher Scientific) (Kajimura et  al. 2005). Embryos were exposed at 14 h postfertilization and after 24  h of exposure, embryos were transferred back to the normal oxygen conditions. By postfertilization day 7, zebrafish craniofacial cartilage was stained by Alcian blue to reveal the effects of low oxygen. Individual fish were

visualized under a microscope after the subsequent removal of the mandible. Tissue hypoplasia in the median aspect of the ethmoid plate: (a) control, (b) 30% hypoxia, (c) 50% hypoxia, and (d) 80% hypoxia. A lack of Alcian blue staining can be seen in the middle aspect of the ethmoid plate for the specimens exposed to hypoxia. (e) Zebrafish staining of the head, where the ethmoid plate can be seen above the jaws (arrows). This analysis was approved by the University of Pittsburgh Institutional Animal Care and Use Committee

7.2 Oral Clefts

67 Contributions to Multifactorial Clefts

Maternal cigarette smoking

Private mutations in genes with major effects

MSX1

FGF signaling pathway

IRF6

Yet to be determined

Fig. 7.5  Estimated contributions to oral clefts (modified from Vieira (2008)). Refer also to Zucchero et al. (2004), Xuan et al. (2016), Jezewski et al. (2003), Vieira et al. (2005), Riley et al. (2007) Fig. 7.6  Oral and craniofacial phenotypes that occur in association (modified from Koruyucu et al. (2018))

Cleft Lip and Palate

Dental Caries

Tooth Agenesis

Microdontia Enamel Hypoplasia/ Hypomineralization

Supernumerary Teeth

7.2.5 Severity of Oral Clefts There are several hints that suggest oral clefts has a multifactorial or complex inheritance and they are noticed when recurrence risks are measured (Fraser 1970):

–– The risk of recurrence is increased in relatives of individuals born with oral clefts. Conversely, more distant relatives have lower risks than closer relatives. –– Women are less likely than men to be affected by cleft lip with or without cleft palate, but

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7  Genetic Basis of Craniofacial Deformities and Malocclusion, Oral Clefts, and Craniosynostosis

Fig. 7.7  Eight-year-old male child that was born with unilateral left cleft lip with cleft palate and has a clefted right lateral incisor tooth limited to enamel. If the contra-

lateral side of the overt cleft lip is considered affected it would characterize this case as bilaterally affected (image courtesy of Rosa Helena Wanderley Lacerda)

recurrence risks are higher of relatives of an affected woman in comparison to an affected man. This is also true for cleft palate only, where females are slightly more likely to be affected. Recurrence risks of relatives of a male born with cleft palate only are higher than of relatives of a female born with cleft palate only. –– The more severe the oral clefts, the higher the recurrence risks of relatives of the affected individual. Relatives of someone born with bilateral cleft lip with cleft palate have a higher recurrence risk in comparison to relatives of someone born with unilateral cleft lip with cleft palate.

family, in an attempt to allow for more conclusive discoveries has been proposed (Vieira 2012b).

The variation of severity of oral clefts, considering unilateral or bilateral involvement and differences in palatal involvement, suggest different genes are contributing to the formation of the clefts. This heterogeneity has been largely ignored by studies published thus far, greatly in part to the challenge of gathering large sample sizes for the studies. This trade of heterogeneity for larger sample sizes, however, may hinder discovery and ideally, studies would take into consideration those distinctions and try to analyze more homogeneous groups. Even definitions such as complete versus incomplete clefts are an oversimplifications of the complexity of the clinical presentations of the defect (Fig.  7.8). Providing a more complete description of the oral clefts, including concomitant minor defects, such as alterations in the dentition or concomitant occurrence of cancer in the

7.2.6 Cancer Perhaps the most intriguing fact related to oral clefts is that families with babies born with oral clefts report cancer more often than families who did not have a history of children being born with oral clefts (Menezes et al. 2009). The most likely explanation is that the genetic variation that predisposes someone to oral clefts probably disrupts cell proliferation and differentiation during the developing face, and thus later in life, this disruption may lead to cancer. Since cancer is a disease that originates from a single cell, the likelihood of a disruption to occur is unfortunately higher. It is interesting that a number of genes considered to play a role in oral clefts also appear to play a role in cancer. The data from a cohort of families from Latvia (Vieira et al. 2012) suggest that pediatric cancer is increased six times amongst children born with oral clefts, three times among first- and second-­ degree relatives of children born with clefts, and 1.5  times amongst third-degree relatives of children born with clefts. Children being treated for leukemia are also more likely to have a family history of oral clefts when compared to children being treated for asthma and upper respiratory issues (Jindal and Vieira 2012). There are even instances in which oral clefts and cancer appear to segregate

7.3 Craniosynostosis

69

Fig. 7.8  Three cases of complete cleft palate without cleft lip that have clearly very distinct severities of the defect (image courtesy of Rosa Helena Wanderley Lacerda) Fig. 7.9  The causation of craniosynostosis (and oral clefts) likely follows a distribution where most of the cases are due to the effects of multiple genes that are influenced by the environment, instead of direct teratogenic effects or major gene effects (modified from Durham et al. (2017))

Most cases are caus ed by multiple genes that may be influenced by the environment

[Text]

e due Few cases ar ne ge e gl to sin or major effects teratogens

in an autosomal dominant fashion as part of a midline defect syndrome (Vieira and Dattilo 2018). This relationship between oral clefts and cancer in families deserves more investigation and may explain, at least in part, the reason why individuals born with clefts appear to have about 10 less years in their life span (Christensen et al. 2004).

7.3

Craniosynostosis

Similar to oral clefts, craniosynostosis also fits a multifactorial inheritance framework. The bony infiltration of the cranial sutures prior to completion of brain growth is a relevant issue and one of the hopes of research surrounding this issue is generating knowledge to allow for treatments to be developed for bone regeneration purposes. Craniosynostosis is less frequent than oral clefting (around 1  in every 2000 live births) and

affects twice as many males as females, which is a similar pattern seen for cleft lip with or without cleft palate. Many cases of craniosynostosis are associated with syndromes (approximately 200 have been described as including craniosynostosis as one of the features) and some of these are the result of mutations in fibroblast growth factor receptors and TWIST (Twist-related protein). Also similar to oral clefts, the majority of cases (85%) are isolated forms of craniosynostosis (Durham et  al. 2017). When considering how genes and environment influence craniosynostosis (and the same applies to oral clefts), it is likely that the majority of cases are due to interactions between genes and the environment. There are exceptions that are due to teratogenic agents or strong gene effects, including monogenic forms of inheritance and chromosomal abnormalities (Fig. 7.9), but a multifactorial inheritance pattern is responsible for the majority of cases.

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7  Genetic Basis of Craniofacial Deformities and Malocclusion, Oral Clefts, and Craniosynostosis

Xiong X, Li S, Cai Y, Chen F.  Targeted sequencing in FGF/FGFR genes and association analysis of variants for mandibular prognathism. Medicine (Baltimore). 2017;96(25):e7240. Xuan Z, Zhongpeng Y, Yanjun G, Jiaqi D, Yachi Z, Bing S, Chenghao L. Maternal active smoking and risk of oral clefts: a meta-analysis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;122(6):680–90. Xue F, Rabie AB, Luo G. Analysis of the association of COL2A1 and IGF-1 with mandibular prognathism in a Chinese population. Orthod Craniofac Res. 2014;17(3):144–9. Yamaguchi T, Park SB, Narita A, Maki K, Inoue I. Genome-wide linkage analysis of mandibular prognathism in Korean and Japanese patients. J Dent Res. 2005;84(3):255–9. Yang N, MacArthur DG, Gulbin JP, Hahn AG, Beggs AH, Easteal S, North K.  ACTN3 genotype is associated

with human elite athletic performance. Am J Hum Genet. 2003;73(3):627–31. Zebrick B, Teeramongkolgul T, Nicot R, Horton MJ, Raoul G, Ferri J, Vieira AR, Sciote JJ.  ACTN3 R577X genotypes associate with Class II and deepbite malocclusions. Am J Orthod Dentofacial Orthop. 2014;146(5):603–11. Zucchero TM, Cooper ME, Maher BS, Daack-Hirsch S, Nepomuceno B, Ribeiro L, Caprau D, Christensen K, Suzuki Y, Machida J, Natsume N, Yoshiura KI, Vieira AR, Orioli IM, Castilla EE, Moreno L, Arcos-Burgos M, Lidral AC, Field LL, Liu Y, Ray R, Goldstein T, Schultz RE, Shi M, Johnson MK, Kondo S, Schutte BC, Marazita ML, Murray JC.  Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med. 2004;351:769–80.

8

Genetic Basis of Lichen Planus and Oral Cancer

8.1

Lichen Planus

Oral lichen planus manifest as chronic lesions that are inflammatory in nature. Lichen planus has been associated with certain medications, dental materials, the hepatitis C virus, and genetic variants. It is a condition that fits the multifactorial inheritance mode well, with multiple genes likely with small individual effects as well as environmental factors playing a role (Zhou and Vieira 2018). Oral lichen planus assumes multiple forms (reticular, popular, plaque type, atrophic, erosive, and bullous), and may manifest as pain or a burning sensation. It appears to be more frequent in females than males (Modesto and Vieira 1994), which is a feature seen in conditions with multifactorial or complex inheritance. The main interest in oral lichen planus revolves around its potential to transform into oral squamous cell carcinoma. Approximately 1% of lichen planus progress into oral squamous cell carcinoma, most typically the ones with erosive lesions located on the tongue. Smokers, alcohol users, and those infected with the hepatitis C virus are also at higher risk (Mignogna et al. 2001; Bombeccari et al. 2011; Aghbari et al. 2017). Oral squamous cell carcinoma that developed from a preexisting oral lichen planus lesion has a higher rate of recurrence (Muñoz et al. 2016). The chronic inflammatory state is what leads to the malignant transformation of oral lichen planus. Inflammatory responses are common fea© Springer Nature Switzerland AG 2019 A. R. Vieira, Genetic Basis of Oral Health Conditions, https://doi.org/10.1007/978-3-030-14485-2_8

tures of a number of conditions, and they can be said as having a multifactorial or complex mode of inheritance. It appears that minimizing inflammation in the absence of injury or infection is beneficial. Since the suggestion of anti-metastatic effects of aspirin (Wood Jr. and Hilgard 1972), it appears that taking aspirin to reduce risks of heart attack and stroke also decreases the risk of developing or dying from some types of cancer. It is possible that this effect is through hypoxia. Hypoxia induces cell proliferation and migration, and angiogenesis and aspirin can weaken this promotion (Chen et  al. 2019). Carbonic anhydrase IX is upregulated by hypoxia and its expression is not seen in normal mucosa but found in oral lichen planus (Pérez et  al. 2018). The combination of hypoxia and inflammation predisposes an individual to ultimately develop cancer and thus at the microenvironment level (Fig.  8.1), the malignant transformation of oral lichen planus to oral squamous cell carcinoma is the result of these two conditions.

8.2

Oral Cancer

Head and neck squamous cell carcinoma is the sixth most common form of cancer worldwide. Head and neck cancer affects more males than females, and this is an indication that head and neck cancer has a complex or multifactorial mode of inheritance (see comment in box). Oral 73

8  Genetic Basis of Lichen Planus and Oral Cancer

74 Apoptosis Angiogenesis

Hypoxia

Cytokines Metalloproteinases

HIF-1α NF-κB

Inflammation

HIF-2α

Cytokines Inflammation

Fig. 8.1  Hypoxia leads to the activation of hypoxia-­ inducible factors (HIF1A and HIF2A). HIF1A is involved in several cellular processes, such as apoptosis and angiogenesis. HIF2A is involved in activation of pro-­

cancer-­associated behaviors such as alcohol consumption, tobacco smoking, betel quid chewing, and using smokeless tobacco impact individual risks, which are consequent of changes in tumor suppressor genes and proto-oncogenes, among other genetically controlled cellular processes (Ali et  al. 2017). Genes that regulate craniofacial development and appear to be associated with oral clefts, in particular GSK3B (glycogen synthase kinase 3 beta), contribute to individual susceptibility to oral squamous cell carcinoma (Andrade Filho et al. 2011). Human papillomavirus (HPV) infection also increases the frequency of oral cancer, particularly in the presence of the p53 Arg72Pro variant (Hou et al. 2015). Oral cavity and oropharyngeal cancers have a high mortality due to delay in the diagnosis, with a mean time of 270 days (up to 2520 days) between the time a patient is first aware of the problem to the time he/she visits a primary care clinician. The mean of the time from when the patient visited a primary care clinician to the starting time of definitive treatment is 90  days (up to 270 days) (Jafari et al. 2013). But similarly to other types of cancer, the survival chances of patients are improving, and that means a growing need for care after cancer treatment.

inflammatory cytokines. Inflammation activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which activates more inflammation (Biddlestone et al. 2015)

Females and males differ across a broad spectrum of morphological, physiological, and behavioral characters and there are differences in gene expression not only in gonadal tissue but also in non-gonadal tissues, including the liver, heart, kidney, and brain. Multiple genes show sexually dimorphic expressions and these include a number of molecular functions, such as lipid metabolism, and differences in cognitive function, attention, and memory (Rigby and Kulathinal 2015).

8.3

Oral Mucositis

Oral mucositis can cause pain, restrict oral intake, increase chance of infection, cause the interruption of cancer therapy, require prolonged use of antibiotics and narcotics, increase the length of hospitalization, and increase the overall financial burden of cancer treatment. Hence, patients being treated for cancer who developed oral mucositis have potentially lower survival rates when treatments need to be interrupted. In cases

8.3 Oral Mucositis

75

where patients have concomitant neutropenia (white blood cell deficiency), having oral mucositis will increase the patient’s risk for septicemia four times (septicemia is a systemic, toxic illness caused by the invasion of the bloodstream by virulent bacteria entering through the site of the mucositis). Prolonged use of antibiotics may lead to drug resistance and extended use of narcotics may lead to drug dependence. Nausea and vomiting often occur during cancer treatment and they further complicate oral mucositis. Chemotherapy and radiation therapies themselves affect the ability of cells to reproduce, slowing healing of the oral mucosa, and often extending the duration of present mucositis. The inability to eat and have proper nutrition further debilitates the immune system and slows the healing process. The combination of a damaged oral mucosa and a debilitated immune system makes patients under cancer therapy more prone to oral infections. Oral mucositis generally begins 5–10  days fol-

lowing the initiation of chemotherapy and lasts anywhere from 1 to 6 weeks or more (The Oral Cancer Foundation, http://www.oralcancerfoundation.org/complications/mucositis.php). Virtually 100% of the patients being treated for head and neck cancer develop oral mucositis (Mallick et  al. 2016), however, there is variation reported in the literature (Table 8.1). This variation can be understood as the result of the role of multiple genes with small effects each, and therefore response to treatment can be understood as having a multifactorial or complex mode of inheritance. Treatment of oral mucositis includes oral hygiene, topical anesthetics, antimicrobial agents, and other drugs that aim to protect the oral mucosa. Oral mucositis responds well to low-level laser therapy and this response vary among individuals supporting the idea that response to treatment can be defined as a complex or multifactorial trait (Table 8.1, Fig. 8.2).

Table 8.1  Oral mucositis and low-level laser therapy Type of laser and study Sample Effectiveness of 15 patients undergoing laser therapy: A chemotherapy pilot study

Grading scale Intraoral perfusion was measured by laser Doppler technology; the visual analogue score was used to evaluate the impact of laser therapy on pain control Wilcoxon test

13 adult patients receiving oncology treatment were treated with LLLT therapy during a 5-day period; no control group was possible due to low number of patients 12 patients aged 34–42 Daily mucositis Phototherapy with noncoherent years were treated three index (DMI) times a day for 1 week: light Non-randomized control group of 12 patients with comparable stomatitis Low-level laser therapy: A clinical test

Results 11 out of 15 patients experienced no mucositis; less discomfort experienced among patients

Reference Wong and Wilder-­ Smith (2002)

Location California, USA

A significant 67% decrease in the daily average experience of pain felt before and after each treatment

Nes and Posso (2005)

Norway

Median healing time as detected by the DMI was 1.7 in 7 light-emitting diode treated patients, shorter than in the control group

Corti et al. (2006)

Italy

(continued)

8  Genetic Basis of Lichen Planus and Oral Cancer

76 Table 8.1 (continued) Type of laser and study Low-level laser therapy: A pilot clinical study

Low-level infrared laser therapy: A randomized placebo-­ controlled trial in children Low-level laser: A pilot study

Sample Patients undergoing chemotherapy without mucositis were randomized in either a laser or placebo group

Grading scale Oral mucositis grading assessment

Oral mucositis 21 patients; nine grading assessment patients were randomized in the laser group and 12 were placebo controlled

Patients showed improvement with a reduction in pain sensation – Low-level laser Low-level laser: 24 adult patients who decreased the intensity had undergone Double-blind of chemotherapy-­ chemotherapy during randomized induced oral mucositis controlled study 2009–2010 18 onco-hematological WHO oral mucositis All mucositis was Class IV laser cleared at the 11-day grading objective pediatric patients therapy: A follow-up visit with no scale prospective study treated for 4 apparent side effects consecutive days Patients who received WHO scoring 40 patients were Effect of light-emitting diode system and visual divided into two light-emitting therapy responded analog scale groups: Each group diode and laser with improvement in were treated with either phototherapy contrast with those light-emitting diode or treatment treated with laser laser phototherapy protocols phototherapy

8.4

16 children suffering from COM

Results 73% of patients who received low-level laser therapy in the intervention group had no mucositis in comparison with 27% in the placebo group 1/9 of patients remained with lesions in the laser group and 9/12 of patients in the placebo control group by day 7

WHO scoring system

Radiation Caries

Another common consequence of head and neck cancer treatment is the development of caries. Salivation is impaired after irradiation of the salivary glands but susceptibility to caries will depend on the individual who shows variation in clinical presentations (Fig.  8.3). These different responses can be interpreted as the consequence of the effect of multiple genes and can be classified as a complex or multifactorial mode of inheritance. One underlying mechanism is how individuals modulate their bacterial colonization, and differences can be seen in microbiomes, with certain species present or absent in cases

Reference Abramoff et al. (2008)

Location Brazil

Kuhn et al. Brazil (2009)

Cauwels and Martens (2011) Arbabi-­ Kalati et al. (2013) Chermetz et al. (2014) Freitas et al. (2014)

Belgium

Iran

Italy

Brazil

that develop dental caries (Mougeot et al. 2019). Shared living conditions affect microbial community composition (Shaw et al. 2017) and this system should be understood as depending on the individual host (their genes) and the living situation (environment).

8.5

Precision

Personalization of therapy according to the risks and molecular features of a given disease is something that is now under consideration for the treatment of oral cancer. Individuals can be defined as having low, intermediate, or high risk

8.5 Precision

77

Fig. 8.2  Painful ulcers on both lips before low-level laser therapy treatment (top) and 24 h after treatment, where cicatrization can be seen and pain was gone (bottom) (photos courtesy of Thais Maeta)

Fig. 8.3  Radiation caries is a common consequence of head and neck radiation therapy and despite similar radiation regimens, individual salivation is affected differently and oral microbiomes are likely distinct along with the ability to disturb the oral biofilm. The result is distinct

clinical presentations, with some cases more severe than others, demonstrating a complex interplay between multiple genetic pathways and the environment (photos courtesy of Evelise Machado de Souza and Bruna Nascimento)

8  Genetic Basis of Lichen Planus and Oral Cancer

78

Programmed death ligand Cytotoxic T lymphocytes antigen-4

Cancer Cell

T-cell

Fig. 8.4  Upregulation of inhibitory ligands by cancer cells inhibits anti-cancer lymphocyte activity (modified from Kaidar-Person et al. (2018))

of death on the basis of HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage (Ang et  al. 2010). Individuals at low risk (nonsmokers, nonalcohol drinkers, and non-HPV positive) could be considered for reduced radiotherapy dose, no chemotherapy, or radiotherapy solely to the involved neck. There is, however, complexity related to p16 (a tumor suppressor gene) and this heterogeneity remains to be better understood. Oral cancer is an immunosuppressive disease and the expression of immune checkpoint ligands suppresses the host immune response. Initial evidence suggests that Cetuximab, 5-Fluorouracil, and cis-platinum shows better results in patients with recurrent or metastatic head and neck squamous cell carcinoma whose tumor expresses PDL1 (programmed death ligand 1) (Kaidar-­ Person et al. 2018). The evaluation of checkpoint inhibitors such as anti-PDL1 and anti-PDL2 antibodies is a strategy that takes advantage of the understanding that oral cancer is an immune-­ related disease (Fig. 8.4).

References Abramoff MM, Lopes NN, Lopes LA, Dib LL, Guilherme A, Caran EM, Barreto AD, Lee ML, Petrilli AS. Low-­ level laser therapy in the prevention and treatment of chemotherapy-induced oral mucositis in young patients. Photomed Laser Surg. 2008;26:393–400. Aghbari SMH, Abushouk AI, Attia A, Elmaraezy A, Menshawy A, Ahmed MS, Elsaadany BA. Malignant transformation of oral lichen planus and oral lichenoid lesions: a meta-analysis of 20095 patient data. Oral Oncol. 2017;68:92–102. Ali J, Sabiha B, Jan HU, Haider SA, Khan AA, Ali SS.  Genetic etiology of oral cancer. Oral Oncol. 2017;70:23–8. Andrade Filho PA, Letra A, Cramer A, Prasad JL, Garlet GP, Vieira AR, Ferris RL, Menezes R. Insights from studies with oral clefts suggest associations between WNT-pathway genes and risk of oral cancer. J Dent Res. 2011;90:740–6. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35. Arbabi-Kalati F, Arbabi-Kalati F, Moridi T.  Evaluation of the effect of low level laser on prevention of

References chemotherapy-induced mucositis. Acta Med Iran. 2013;51:157–62. Biddlestone J, Bandarra D, Rocha S. The role of hypoxia in inflammatory disease (review). Int J Mol Med. 2015;35(4):859–69. Bombeccari GP, Guzzi G, Tettamanti M, Gianni AB, Baj A, Pallotti F, Spadari F.  Oral lichen planus and malignant transformation: a longitudinal cohort study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112(3):328–34. Cauwels RG, Martens LC.  Low level laser therapy in oral mucositis: a pilot study. Eur Arch Paediatr Dent. 2011;12:118–23. Chen J, Xu R, Xia J, Huang J, Su B, Wang S.  Aspirin inhibits hypoxia-mediated lung cancer cell stemness and exosome function. Pathol Res Pract. ­ 2019;215(6):152379. Chermetz M, Gobbo M, Ronfani L, Ottaviani G, Zanazzo GA, Verzegnassi F, Treister NS, Di Lenarda R, Biasotto M, Zacchigna S.  Class IV laser therapy as treatment for chemotherapy-induced oral mucositis in onco-haematological paediatric patients: a prospective study. Int J Paediatr Dent. 2014;24:441–9. Corti L, Chiarion-Sileni V, Aversa S, Ponzoni A, D’Arcais R, Paonutti S, Fiori D, Scotti G.  Treatment of chemotherapy-­ induced oral mucositis with light-­ emitting diode. Photomed Laser Surg. 2006;24:207–13. Freitas AC, Campos L, Brandão TB, Cristófaro M, Eduardo FP, Luiz AC, Marques MM, Eduardo CP, Simões A.  Chemotherapy-induced oral mucositis: effect of LED and laser phototherapy treatment protocols. Photomed Laser Surg. 2014;32:81–7. Hou J, Gu Y, Hou W, Wu S, Lou Y, Yang W, Zhu L, Hu Y, Sun M, Xue H. p53 codon 72 polymorphism, human papillomavirus infection, and their interaction to oral carcinoma susceptibility. BMC Genet. 2015;16:72. Jafari A, Najafi SH, Moradi F, Kharazifard MJ, Khami MR. Delay in the diagnosis and treatment of oral cancer. J Dent (Shiraz). 2013;14(3):146–50. Kaidar-Person O, Gil Z, Billan S.  Precision medicine in head and neck cancer. Drug Resist Updat. 2018;40:13–6. Kuhn A, Porto FA, Miraglia P, Brunetto AL.  Low-level infrared laser therapy in chemotherapy-induced oral mucositis: a randomized placebo-controlled trial in children. J Pediatri Hematol Oncol. 2009;31:33–7.

79 Mallick S, Benson R, Rath GK.  Radiation induced oral mucositis: a review of current literature on prevention and management. Eur Arch Otorhinolaryngol. 2016;273(9):2285–93. Mignogna MD, Lo Muzio L, Lo Russo L, Fedele S, Ruoppo E, Bucci E.  Clinical guidelines in early detection of oral squamous cell carcinoma arising in oral lichen planus: a 5-year experience. Oral Oncol. 2001;37(3):262–7. Modesto A, Vieira AR.  Oral soft tissue alterations. Part 1. Vesicle-bubble diseases, ulcerative conditions, and papilloma-verrucous lesions. J Bras Med. 1994;67:101–6. Mougeot JC, Stevens CB, Almon KG, Paster BJ, Lalla RV, Brennan MT, Mougeot FB.  Caries-associated oral microbiome in head and neck câncer radiation patients: a longitudinal study. J Oral Microbiol. 2019;11(1):1586421. Muñoz AA, Haddad RI, Woo SB, Bhattacharyya N. Behavior of oral squamous cell carcinoma in subjects with prior lichen planus. Otolaryngol Head Neck Surg. 2016;136(3):401–4. Nes AG, Posso MB.  Patients with moderate chemotherapy-­induced mucositis: pain therapy using low intensity lasers. Int Nurs Rev. 2005;52:68–72. Pérez MÁ, Gandolfo MS, Masquijo Bisio P, Paparella ML, Itoiz ME.  Different expression. Patterns of carbonic anhydrase IX in oral lichen planus and leukoplakia. Acta Odontol Latinoam. 2018;31(2):77–81. Rigby N, Kulathinal RJ.  Genetic architecture of sexual dimorphism in humans. J Cell Physiol. 2015;230(10):2304–10. Shaw L, Ribeiro AL, Levine AP, Pontikos N, Balloux F, Segal AS, Roberts AP, Smith AM. The human salivar microbiome is shaped by shared environment rather than genetics: evidence from a large family of closely related individuals. MBio. 2017;8(5):e011237–17. Wong SF, Wilder-Smith P. Pilot study of laser effects on oral mucositis in patients receiving chemotherapy. Cancer J. 2002;8:247–54. Wood S Jr, Hilgard P.  Aspirin and tumor metastasis. Lancet. 1972;3(7783):932–3. Zhou Y, Vieira AR. Association between TNFα −308 G/A polymorphism and oral lichen planus (OLP): a meta-­ analysis. J Appl Oral Sci. 2018;26:e20170184.

9

Genetic Basis of Orofacial Pain and Temporomandibular Joint Dysfunction

9.1

Orofacial Pain

Orofacial pain has not only deleterious effects on the affected individual but also leads to considerable economic impact upon society at large through an increased loss of productivity and the utilization of health care systems (Lipton et  al. 1993). Most cases are odontogenic in nature, but a subset of orofacial pain cases suffer from trigeminal neuralgia (an anecdote exemplifying the magnitude of the effect of orofacial pain has on the individual is given in the box below). Trigeminal neuralgia corresponds to a clinical manifestation of paroxysmal attacks of sudden, unilateral, and lancinating facial pain with characteristic triggers (e.g., light touch, cold air), lasting a few seconds to a few minutes, and most often involving the mandibular and maxillary branches of the trigeminal nerve. These attacks are often associated with vascular compression and demyelination of the trigeminal nerve near its entry into the brainstem (Lipton et al. 1993; Zakrzewska and Linskey 2014; Barker et al. 1996). Vascular compression may be part of the etiopathogenesis of trigeminal neuralgia, but occurs in a minority of patients with facial pain (Frederickson et al. 2016).

© Springer Nature Switzerland AG 2019 A. R. Vieira, Genetic Basis of Oral Health Conditions, https://doi.org/10.1007/978-3-030-14485-2_9

A Typical Case of Trigeminal Neuralgia

A microvascular decompression was planned and executed for a 65-year-old woman with classical trigeminal neuralgia. Although the patient’s left-sided facial pain was immediately relieved by the procedure, she suffered a complication: a small embolic stroke of the midbrain as a result of manipulation of the superior cerebellar artery. Although it was expected that the patient would make a full recovery, the surgeon was nevertheless dejected and could not understand why the patient and her husband were so pleased when she/he came to examine her in her hospital room. The surgeon soon understood however, when the patient’s husband said, “Doctor, we’ll deal with her recovery. I have my wife back… for the past year, she has asked me to take her life on multiple occasions.” The patient smiled and said, “I can live again!”

Orofacial pain affects the lives of both underserved and affluent populations. Chronic pain patients spend countless hours suffering while seeking advice from one practitioner after

81

9  Genetic Basis of Orofacial Pain and Temporomandibular Joint Dysfunction

82

another and experimenting with various possible therapies (Verhaak et  al. 1998; Pereira Jr. et  al. 2004). These are compelling reasons why the management and relief of suffering should be the primary focus of the healthcare professional. It is accepted that unresolved acute pain can cause delayed healing, undue stress, and potentially can lead to autoimmune disorders. Patients have reported countless psychosocial symptoms leading to real life disruptions when experiencing various levels of pain. These symptoms include but are not limited to: loss of self-esteem, sleep disturbances, loss of libido, loss of appetite, fatigue, and depression. In short, pain can govern one’s life (Williamson 1996). It is accepted that there are two different kinds of chronic pain: nociceptive/inflammatory pain and neuropathic/genic pain. The first, associated with inflammation, is caused by tissue damage, while neurogenic pain syndromes arise as a consequence of central and peripheral nerve damage (Woolf and Salter 2000). Both inflammation-­associated and neurogenic pain are likely influenced by multiple pathways and can be said to have a complex or multifactorial mode of inheritance with more than one gene involved (Fig.  9.1). Environmental Fig. 9.1  Distribution of a summary of pain sensitivity derived from 16 individual pain measures (modified from Mao and Nah (2004)). The distribution fits a complex or multifactorial mode of inheritance. Y axis corresponds to the number of individuals tested

influences can also be thought of as part of the origin of some cases of pain, which may be due to physical injury. Pain overall is said to be a complex multidimensional experience resultant of a noxious stimulus which travels along nociceptive nerve pathways to the central nervous system. Pain perception is a multifaceted physio-anatomical process. Defined are multiple components of pain perception, including the sensory-discriminative, affective-motivational, and autonomic. A patient may report sensory-discriminative properties of their pain when describing a severe dull ache in their right maxillary first molar over the past 24 h. They may include affective-motivational aspects of their pain perception by stating that due to this pain, sleep was not possible until a conventional therapeutic was administered. In the autonomic phase, this patient may also report being upset to the level that they felt “out-of-­breath” during the entire encounter until the pain was relieved (Lund et al. 2001). In 1959, Beecher (1959) described a state of pain known as the pain threshold. The pain threshold can be defined as the first perceptible pain produced by a noxious stimulation in the conscious subject. The variability of a thresh-

50 45 40 35 30 25 20 15 10 5 0

Integral Z-score of 16 pain measures

9.2 Variation in the Ability to Respond to Pain Relief Strategies

old from person to person in this area can be attributed to factors such as, but not limited to: age, sex, poor stimulus control, education, cultural background, fatigue, attention, suggestion, previous pain exposure and interpretation, genetics, etc. As a result, pain is an example of a highly complex biobehavioral health outcome that exhibits unpredictability among individuals; that is, individuals differ in how they respond to painful and/or anxiety-provoking stimuli. Therefore, it is fundamentally established that the perception of pain is a combined multidimensional sensory and emotional experience. This leads us to ask as did Mogil (2005) based on observations of his pain model in mice, “Of the genes relevant to pain, which ones when inherited in different forms (i.e., with different DNA sequences or ‘alleles’) are responsible for inherited variability?” Pain in the facial region, including orofacial pain and craniofacial pain (excluding the traditional headache), accounts for a significant proportion of the population that suffer from chronic pain conditions, such as those caused by dental caries, periodontal diseases, and neuropathic OR musculoskeletal conditions (Hart et  al. 2004). Orofacial pain is a major symptom of temporomandibular disorders (Roda et  al. 2007) (TMD) and among the orofacial pain disorders, TMD comprises a significant proportion of the total cases. Persistent pain among patients constitute a public health concern that primarily inflicts women between 20 and 40  years of age (Shah 2003; Uyanik and Murphy 2003; Fricton 2004; Gesch et  al. 2004; Pereira Jr. et  al. 2004; Tuerlings and Limme 2004; Schmitter et al. 2005; Abou-Atme et al. 2006; Dodić et al. 2006; Vieira and Gamboa 2006), and while the current treatments for these conditions could benefit from new approaches (Hart et al. 2004; Roda et al. 2007), studies concerning TMD have been limited because of the heterogeneous nature of symptoms leading to difficulties in diagnosis (Nilsson 2007; John et al. 2005; Manfredini et al. 2006).

9.2

83

Variation in the Ability to Respond to Pain Relief Strategies

Perhaps the most important aspect of pain is how to manage it. The individual response to treatment is another aspect of pain disorders that can be described as influenced by multiple genes, therefore can be described as having a multifactorial or complex mode of inheritance. As with all multifactorial conditions multiple genes with small effects influence the ability to control pain. Upon analysis of the records of 5025 subjects participating in the University of Pittsburgh School of Dental Medicine Dental Registry and DNA Repository (Vieira et  al. 2015), 865 individuals were identified as requiring more than one anesthetic carpule to allow for a single tooth posterior restoration to be performed. The patients were compared to 365 individuals that required only one anesthetic carpule to perform similar work. It was found that individuals requiring more than one carpule of anesthetic solution were approximately 20% more likely to carry a certain allele in the catechol-O-methyltransferase (COMT) gene. These results are consistent with postoperative studies in adults with lumbar degenerative disc disease (Dai et  al. 2010) and in pediatric patients that had tonsillectomy (Sadhasivam et  al. 2014) and required lesser analgesic interventions depending on the COMT genotypes they carried. COMT produces a protein that allows for a chemical reaction in the neurotransmitters dopamine, epinephrine, and norepinephrine. When an electrical signal reaches the end of a neuron, it triggers the release of neurotransmitters. These neurotransmitters bind to receptors of nearby cells, either exciting or inhibiting the receiving neuron. The result of this experiment is a clear indication that in the future, dentists will be able to use genomics testing to predict the likelihood of patient responses to certain treatments (Table 9.1).

9  Genetic Basis of Orofacial Pain and Temporomandibular Joint Dysfunction

84

Table 9.1  Genotyping frequencies of COMT markers between individuals that required more than one anesthetic carpule to allow for a single tooth posterior restoration to be performed in comparison to individuals that did not need more than one tube to perform similar work COMT marker rs6269 AA AG GG A G rs4818 CC CG GG C G

Individuals that required more than one anesthetic tube

Individuals that required one anesthetic tube

304 393 136 P = 0.068 1001 665 P = 0.63

117 183 41

276 489 120 P = 0.03 1045 729 P = 0.02

142 181 42

417 265

465 265

These data were generated with partial support from the American Association of Orofacial Pain (AAOP) given to support a research experience of the student Arielle Forbes

9.3

Congenital Insensitivity to Pain

Pain is a protective mechanism that decreases the chance of serious harm to our bodily tissues and alerts us to potential deviations of health. The inhibition of the ability to perceive physical pain (Fig. 9.2) is an autosomal recessive trait and is a model for the determination of genetic contributors to pain. This is an example of why it is important to study single gene inheritance patterns in order to better understand complex (multifactorial) conditions.

9.4

Temporomandibular Joint Dysfunction (TMD)

TMD is a collection of symptoms related to the muscles and joints of the masticatory system. TMD likely comprises a number of etiologically

Fig. 9.2  Congenital insensitivity to pain is rare and the person cannot feel pain. Identification of genes for the monogenic condition is useful and helps define targets for study for the understanding of complex or multifactorial pain

distinct conditions with similar symptoms. For this reason, it is not surprising genetics has not been considered as a main etiologic factor until more recently. For many years, a combination of stressors (environmental and/or nutritional) was believed to be the underlying cause of TMD, not genetics (Eggleston 1980). In support to this theory, studies that have attempted to find a segregation pattern in families of cases with TMD (Raphael et al. 1999) or through the use of twin models (Heiberg et  al. 1980) have suggested that TMD is not in fact a genetic disorder with a major gene contributor. However, TMD fits well on the framework we have described in which multiple genes with small effects each contribute to the condition with additional influence from the environment, and therefore it can be defined as having a complex or multifactorial mode of inheritance.

9.5 Stress and Inflammation

Individuals are not equally susceptible to TMD. Women in their reproductive years represent the majority of those seeking care (Oakley and Vieira 2008). The fact that women are more likely to seek care than men does not explain this difference, which suggests there is a real biological explanation for this disparity. As such, the resulting symptoms of TMD can be understood as the person’s complex response trait with specific complaints being either amplified or attenuated by their unique genetic makeup and/or prior experience (Stohler 2004). Hormonal milieus are believed to augment the inherent genetic vulnerability to TMD, explaining the greater likelihood of the condition among women of childbearing age (Woda and Pionchon 2000; Mao and Nah 2004). There are also a number of detectable differences in anatomical measurements of the skull between sexes and individuals of different geographic origins (Fig. 9.3). The identification of genetic contributors to TMD has included both hypothesis-free (genome-­wide association studies or GWAS) and hypothesis-­driven approaches but this work did not unveil variants that can be used for predicting TMD or TMD treatment outcomes (Scariot et al. 2018). The evidence that particular COMT haplotypes decrease 2.3 times the risk of women developing TMD (Fig.  9.4) continues to be of particular interest in this discussion (Diatchenko et al. 2005).

9.4.1 Mitochondria and Temporomandibular Joint Dysfunction (TMD) TMD conditions are typically myofascial in origin, due to an internal derangement, or osteoarthrosis and may be thought of as primarily a muscle disorder. A small subset of those cases is likely to have an underlying systemic myopathy (Van Sickels et  al. 1987). Collectively, myopathy disorders are common genetic diseases. Duchenne muscular dystrophy has an incidence of 1  in 2500 males and spinal muscular atrophy occurs at a frequency of about 1  in 5000. Mitochondrial myopathy disorders, although

85

less common, have an incidence of about 1  in 7600–10,000 (Chinnery et al. 2000; Darin et al. 2001; Skladal et  al. 2003). It is not inconceivable that a number of patients with facial pain, whether or not they respond to traditional therapeutic modalities, have an underlying mitochondrial myopathy. When articular chondrocytes in the temporomandibular joint of rats with partial resection of the articular disc were sequenced, 42 novel mitochondrial DNA mutations were found in the tRNA and D-loop regions of the mitochondrial genome, suggesting the mutations occurred in the mitochondrial DNA of the temporomandibular joint osteoarthrosis articular chondrocytes (Fang and Ma 2006).

9.5

Stress and Inflammation

Stress will modify the pain threshold and worsen or create the conditions for the onset of TMD. Humans have an inherent difficulty dealing with death and the motivation to live longer drives many. There are three things that can be done to improve one’s chance to live longer: move more, eat less, and sleep better. “Moving more” and “eating well” address cardiovascular and cancer risks. “Sleeping better” is a surrogate for less stress and has the potential to impact nearly all facets of the human health. In extreme conditions of stress, such as those seen in sleep deprivation (Wu et  al. 2004), individuals deteriorate to a poor mental and physical state. Serum levels of estradiol (a naturally occurring hormone) increase markedly within days but return to initial levels in a week, which suggests how quickly we can adapt to stressful conditions, allowing for improved basic functionality in the short term, but also negatively impacting longevity overall. Risk areas such as the temporomandibular joint, have enhanced expression of pain-related factors and inflammatory markers such as the ones found in the synovial membrane of the joint, become activated in response to high levels of stress. Reducing the body’s inflammatory responses may then be more beneficial than ever anticipated, where the chronic use of low doses of acetylsalicylic acid, also known as aspirin, a medication

86 Fig. 9.3 The temporomandibular joint is a hinge that connects the jaw bone to the temporal bones of the skull. Temporomandibular joint disorders (TMD) arise because of dysfunction within the muscles of mastication and the temporomandibular joints. Anatomical differences probably underlie some of cases with temporomandibular joint symptoms. We performed the measurements below (Gill et al. 2015) in 61 adult skulls from the University of Pittsburgh, School of Dental Medicine collection (Rose and Vieira 2008): (1) Each skull was documented whether it was male or female, and categorized by geographic origin. (2) Various measurements were conducted in coronal and lateral view for both sides. (3) Specific areas of measurement include lines of the condyle; left and right line of the condyle to coronoid process, and left and right condyle to the base of the mandible. (4) Differences in the measurements were then assessed between sex and geographic origin, and values were computed, with 95% confidence

9  Genetic Basis of Orofacial Pain and Temporomandibular Joint Dysfunction Images of the Measurements of the Skulls Condyle to Coronoid Process

Width of Condyle

Length of Foramen

Condyle to Mandible

Length of Condyle

Bottom of Foramen to Bone

9.5 Stress and Inflammation Top of Foramen to Bottom of Eye

Width of Foramen

Foramen to Top

Fig. 9.3 (continued)

87 Foramen to Outer Mandible

Foramen to Inner Mandible

Tunnel

9  Genetic Basis of Orofacial Pain and Temporomandibular Joint Dysfunction

88

Foramen to Bottom

Length of Inside Foramen

•

Width of Inside Foramen

In comparing measurements between sexes, the male skulls tended to have greater measurements in all the different variables measured.

•

In comparing average measurements between geographic origins, despite not statistically significant, Blacks had the greatest measurements in lateral right side and left condyle to coronoid process.

•

The smallest measurements were most observed in Whites, in the coronal right side, lateral right side, lateral left side, and left condyle to coronoid process variables.

•

Blacks had the smallest measurements in the coronal right side, right condyle to mandible, and left condyle to mandible variables. Asians had the smallest measurements for the right condyle to coronoid process.

•

Even though the average values are distributed among different geographic origins, Whites have the greatest maximum value and the smallest minimum value among all of the variables.

Fig. 9.3 (continued)

9.5 Stress and Inflammation Measurement (in millimeters) Coronal right side Coronal left side Lateral right side Lateral left side Right condyle to coronoid process Left condyle to coronoid process Right condyle to mandible Left condyle to mandible

89

Sex

N

Mean

Median

Minimum

Maximum

Male

45

20.5

20.5

11.5

29

Percent deviation 2.6

Female Male

21 45

16.4 20.2

17 20.5

9.5 11.5

21 24

3.2 2.1

0.00001

Female Male

21 45

16.6 8.6

17 8.5

9.5 6

21 10.5

3.2 1.2

0.047

Female Male Female Male

21 44 21 45

8 8.9 8.2 39.6

7.5 9 8 40

6.5 6 6 30

10.5 14 12 47.5

1.2 1.6 1.6 4

0.28

Female Male

21 45

38.5 40.9

39 41

29 30

46 48.5

4.1 4.1

0.09

Female Male

21 45

39 65.7

40 65

29.5 56.5

47.5 82.5

4.5 6.4

0.001

Female Male

21 45

59.6 65

60 64

48.5 53.5

70 82.5

6.5 6.5

0.00001

Female

21

57.5

60

42.5

66

6.2

Fig. 9.3 (continued)

p-value 0.00001

0.1

9  Genetic Basis of Orofacial Pain and Temporomandibular Joint Dysfunction

90 Measurement (in millimeters) Coronal right side

18.7

Standard Deviation 3.3

0.36

7 6 3 42

19 19.7 21 18.8

3.5 4.5 0.5 3.2

0.09

Black Asian Others White

7 6 3 42

17.9 18.8 21.5 8.2

2.8 3 0.5 1.1

0.1

Black Asian Others Lateral left side White Black Asian Others Right condyle White to coronoid process Black Asian Others Left condyle to White coronoid process Black Asian Others Right condyle White to mandible Black Asian Others Left condyle to White mandible Black Asian Others

7 6 3 41 7 6 3 42

9.4 8.5 9 8.5 8.8 8.8 9.5 38.7

1.2 1.1 1 1.6 1.3 1.7 0.9 4.3

7 6 3 42

40.5 36.9 40.7 39.4

3 2.8 1.2 4.7

0.36

7 6 3 42

40.7 40.2 43.3 63.9

2.3 0.8 2.1 7.4

0.1

7 6 3 42

59.2 61.8 68.7 62.4

5.7 4.3 1.8 7.8

0.11

7 6 3

58.8 60.8 68.5

6.8 3.7 3.2

Coronal left side

Lateral right side

Geographic origin White

N

Mean

42

Black Asian Others White

p-value

0.42

0.24

These data illustrate that there are differences in mandible bone measurements among humans, both based on sex and likely on ethnicity (geographic origin). As expected, males had larger overall measurements compared to females. When observing geographic origin, there is a trend for a different distribution of measurements among them. Variation based on sex and ethnic background suggests a polygenic nature that likely underlies temporomandibular joint dysfunction (TMD).

Fig. 9.3 (continued)

References Fig. 9.4  COMT single nucleotide polymorphisms rs6269 G/A, rs4633 T/C, rs4818 G/C, and rs4680 (Val158Met) A/G for haplotypes that define low (1), intermediate (2), and high (3) sensitivity to pain in women with TMD. Bars are pain responsiveness represented by the mean z-score with associated error

91

more pain 10 8 6 4 2 0

1

2

3

-2 -4 -6

less pain

Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius

formulated to treat pain, fever, or inflammation, M. The incidence of mitochondrial encephalomyopais now regularly recommended for the primary thies in childhood: clinical features and morphological, biochemical and DNA abnormalities. Ann Neurol. prevention of cardiovascular disease and colorec2001;49:377–83. tal cancer in individuals, 50  years of age and Diatchenko L, Slade GD, Nackley AG, Bhalang K, older (Thun et  al. 1991). It is likely in the near Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner future that evidence will soon demonstrate the W. Genetic basis for individual variation in pain pereffect of lowering inflammation in the incidence ception and the development of a chronic pain condiof other cancers, as well as other inflammatory-­ tion. Hum Mol Genet. 2005;14(1):135–43. based conditions such as TMD and periodontitis. Dodić S, Stanisić-Sinobad D, Vukadinović M, Milić A,

References Abou-Atme YS, Zawaki KH, Melis M. Prevalence, intensity, and correlation of different TMJ symptoms in Lebanese and Italian subpopulations. J Contemp Dent Pract. 2006;7:71–8. Barker FG, Jannetta PJ, Bissonette DJ, Larkins MV, Jho HD. The long-term outcome of microvascular decompression for trigeminal neuralgia. N Engl J Med. 1996;334:1077–83. Beecher HK.  Measurement of subjective responses. 1st ed. New York: Oxford University Press; 1959. Chinnery PF, Johnson MA, Wardell TM, Singh-Kler R, Hayes C, Brown DT, Taylor RW, Bindoff LA, Turnbull DM.  The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol. 2000;48:188–93. Dai F, Belfer I, Schwartz CE, Banco R, Martha JF, Tighioughart H, Tromanhauser SG, Jenis LG, Kim DH.  Association of cathecol-O-methyltransferase genetic variants with outcome in patients undergoing surgical treatment for lumbar degenerative disc disease. Spine J. 2010;10(11):949–57.

Sinobad V. The prevalence of craniofacial disorders in the military population of the Republic of Serbia. Med Pregl. 2006;59:259–64. Eggleston DW. The interrelationship of stress and degenerative diseases. J Prosthet Dent. 1980;44:541–4. Fang ZQ, Ma XC.  Analysis of the mitochondrial mutations of articular chondrocyte in temporomandibular joint osteoarthrosis. Beijing Da Xue Xue Bao. 2006;38:293–7. Frederickson AM, Gold MS, Sekula RF Jr. Pathogenesis of trigeminal neuralgia. In: Microvascular decompression surgery. 1st ed. Dordrecht: Springer; 2016. Fricton JR. The relationship of temporomandibular disorders and fibromyalgia: implications for diagnosis and treatment. Curr Pain Headache Rep. 2004;8:355–63. Gesch D, Bernhardt O, Mack F, John U, Kocher T, Alte D.  Dental occlusion and subjective temporomandibular joint symptoms in men and women. Results of the Study of Health in Pomerania (SHIP). Schweiz Monatsschr Zahnmed. 2004;114:573–80. Gill N, Gonsar B, Deeley K, Potluri A, Scariot R, Vieira AR.  Differences in mandibular bone measurements in comparing race and sex using human skulls. In: Abstracts of the 93rd general session of the interna-

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tional association of dental research, Boston; 2015. p. 3605. Hart TC, Pihlstrom BL, Tabak LA. Oral health research at the crossroads: translate we must. J Endod. 2004;30:684–8. Heiberg A, Heloe B, Heiberg AN, Heloe LA, Magnus P, Berg K, et  al. Myofascial pain dysfunction (MPD) syndrome in twins. Community Dent Oral Epidemiol. 1980;8:434–6. John MT, Dworkin SF, Mancl LA.  Reliability of clinical temporomandibular disorder diagnosis. Pain. 2005;118:61–9. Lipton JA, Ship JA, Larach-Robinson D. Estimated prevalence and distribution of reported orofacial pain in the United States. J Am Dent Assoc. 1993;124:115–21. Lund JP, Lavigne GJ, Dubner R, Sessle BJ.  Orofacial pain. From basic science to clinical management. 1st ed. Carol Stream: Quintessence Publishing; 2001. Manfredini D, Chiappe G, Bosco M. Research diagnostic criteria for temporomandibular disorders (RDC/TMD) axis I diagnosis in an Italian patient population. J Oral Rehabil. 2006;33:551–8. Mao JJ, Nah HD.  Growth and development: hereditary and mechanical modulations. Am J Orthod Dentofac Orthop. 2004;125:676–89. Mogil JS. Genetic linkage mapping and association studies of pain-related traits. In: Justins DM, editor. Pain 2005 – an updated review. Seattle: IASP Press; 2005. p. 209–15. Nilsson IM.  Reliability, validity, incidence and impact of temporomandibular pain disorders in adolescents. Swed Dent J Suppl. 2007;(183):7–86. Oakley M, Vieira AR. The many faces of the genetics contribution to temporomandibular joint disorder. Orthod Craniofac Res. 2008;11:125–35. Pereira FJ Jr, Vieira AR, Prado R, Miasato JM. Epidemiology and etiology of TMD. Rev Gaúcha Odontologia. 2004;52:117–21. Raphael KG, Marbach JJ, Gallagher RM, Dohrenwend BP.  Myofascial TMD does not run in families. Pain. 1999;80:15–22. Roda PP, Bagan JV, Fernandez JMD, Bazan SH, Soriano YJ.  Review of temporomandibular joint pathology. Part I: classification, epidemiology and risk factors. Med Oral Patol Oral Cir Bucal. 2007;12:E292–8. Rose EK, Vieira AR.  Caries and periodontal disease: insights from two US populations living a century apart. Oral Health Prev Dent. 2008;6(1):23–8. Sadhasivam S, Chidambaran V, Olbrechy VA, Esslinger HR, Zhang K, Zhang X, Martin LJ.  Genetics of pain perception, COMT and postoperative pain

management in children. Pharmacogenomics. 2014;15(3):277–84. Scariot R, Corso PFCL, Sebastiani AM, Vieira AR. The many faces of genetic contributions to temporomandibular joint disorder: an updated review. Orthod Craniofac Res. 2018;21:186–201. Schmitter M, Rammelsberg P, Hassel A. The prevalence of signs and symptoms of temporomandibular disorders in very old subjects. J Oral Rehabil. 2005;32:467–73. Shah N. Gender issues and oral health in elderly Indians. Int Dent J. 2003;53:475–84. Skladal D, Halliday J, Thornburn DR.  Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain. 2003;126:1905–12. Stohler CS.  Taking stock: from chasing occlusal contacts to vulnerability alleles. Orthod Craniofacial Res. 2004;7:157–61. Thun MJ, Naboodiri MM, Heath CW Jr. Aspirin use and reduced risk of fatal colon cancer. N Engl J Med. 1991;325:1593–6. Tuerlings V, Limme M. The prevalence of temporomandibular joint dysfunction in the mixed dentition. Eur J Orthod. 2004;26:311–20. Uyanik JM, Murphy E.  Evaluation and management of TMDs, part 1. History, epidemiology, classification, anatomy, and patient evaluation. Dent Today. 2003;22:140–5. Van Sickels JE, Gruber AB, Kagan-Hallet KS, Dowd DC.  Mitochondrial myopathy presenting as temporomandibular dysfunction. J Oral Maxillofac Surg. 1987;63:168–72. Verhaak PF, Kerssens JJ, Dekker J, Sorbi MJ, Bensing JM. Prevalence of chronic benign pain disorder among adults: a review of the literature. Pain. 1998;2:49–53. Vieira AR, Gamboa GR. Dental characteristics of a cohort from the Cebu province. Sun Star Cebu. 2006;24:203. Vieira AR, Hilands KM, Braun TW. Saving more teeth – a case for personalized care. J Pers Med. 2015;5(1):30–5. Williamson M. Fibromyalgia: a comprehensive approach. New York: Walker and Company; 1996. Woda A, Pionchon P. A unified concept of idiopathic orofacial pain: pathophysiologic features. J Orofac Pain. 2000;14:196–212. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–8. Wu G, Chen L, Wei G, Li Y, Zhu G, Zhao Z, Huang F.  Effects of sleep deprivation on pain-related factors in the temporomandibular joint. J Surg Res. 2004;192:103–11. Zakrzewska JM, Linskey ME.  Trigeminal neuralgia. Br Med J. 2014;348:g474.

Genetic Influence on Behavior and the Impact on Oral Health Conditions

10

10.1 Introduction

10.2 T  he Interplay of Genes and Environment: Measuring The two most common oral diseases (dental carIntelligence ies and periodontitis) are bacteria mediated and can be prevented by satisfactory dental biofilm control. Control implies a daily struggle, since the formation of dental biofilm begins again quickly after its removal, is a daily struggle. Dentists typically intervene by requesting their patients to routinely disturb the biofilm (i.e., brush their teeth and floss), and experience shows that the response from patients greatly varies (AmooAchampong et al. 2018). Verbal and written advices are the two simplest and most widely used methods of promoting oral health. These two approaches are effective by increasing patient knowledge regarding oral health (reviewed in Kay et al. 2016) but data suggest that this does not have an impact on oral disease presentation. Here we discuss behavior from a standpoint of host biology, which cannot be modulated by direct intervention (i.e., gene modification) but can be impacted by interventions that modify external factors (the environment). In this framework, behavior can be defined as having a complex or multifactorial mode of inheritance.

© Springer Nature Switzerland AG 2019 A. R. Vieira, Genetic Basis of Oral Health Conditions, https://doi.org/10.1007/978-3-030-14485-2_10

Imagine a classroom full of students (Fig. 10.1). The order in which each individual is sitting represents the results of an intelligence quotient test.

Intelligent quotient (IQ) was proposed as a measure of intelligence (Terman 1916) and was widely used at one time, but the general consensus today is that society gains very little by testing the IQ of its members. Although higher IQs are correlated to persons securing “better jobs” later in life, this correlation is not perfect (a large number of Lewis Terman’s “Gifted” subjects, who were selected for having very high IQs, pursued more humble occupations such as policeman, fisherman, typewriter, or filling clerk, suggesting that intelligence and societal job achievement do not perfectly correlate) (Terman and Oden 1947).

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10  Genetic Influence on Behavior and the Impact on Oral Health Conditions

Fig. 10.1 Absolute values of performance are higher from baseline to after an intervention but the individual performance relative to one another does not change dramatically. Genetics explains the relative stable order of each person’s performance in regard to one another, but the environment explains how the performance of everyone for the most part improved

The person sitting in one of the extremes at one the far ends obtained the worst score. For each individual sitting next, the scores steadily go up until reaching the last person sitting in the classroom, who got the highest score. To improve the scores, this group practices the test for the next 6 months and retake the test. The results will show that everyone’s scores are better than those at which they were initially tested, but the order in which they are sitting in the auditorium is the

same with a few exceptions of some individuals switching places throughout the room. The genes are the same, so in general the performance of each individual in the room relative to the others is the same, but the environment changed the final score of the test. This same framework can be applied for any phenotype that has a complex or multifactorial mode of inheritance including fluoride exposure and dental caries risk. Once I was asked

10.3 Sexual Orientation: A Behavioral Genetics Case Study

about fluoridating flour that is used for making bread or fluoridating any food for that matter. To answer the question, I posed the following scenario: In the auditorium, individuals are sitting based on their dental caries risk. Exposure to fluorides will decrease their risk, but the order in which they are sitting will likely stay the same. The highest risk person with be sitting in the first row in the seat on the far right, and the person with the lowest risk will be sitting in the last row. Thus, although individual risk may have decreased, persons with the highest relative risk of caries will remain at the highest relative risk, and persons with the lowest relative risk of caries will remain at the lowest relative risk, due to their individual genetic backgrounds.

10.3 Sexual Orientation: A Behavioral Genetics Case Study For centuries, society has imposed that if you are born a man, you are to be attracted to women; if you are born a woman, you are to be attracted to men. In other words, one’s biological sex is to match the person’s sexual orientation toward the opposite sex. The evidence shows that some individuals are oriented toward the same sex. An additional number of people are oriented to both sexes. Finally, it is likely that a smaller number may not be oriented toward either sex, falling into the category of an “asexual state.” In addition, an individual’s gender identity may differ from their biological sex. Existing figures on sexual orientation show a prevalence of a little more than 80% of individuals defining themselves as heterosexuals (Sell et al. 1995). Having 10–20% of the population whose biological sex does not match their sexual orientation and/or sexual identity (Laumann et al. 1994; Dunne et  al. 2000; Savin-Williams and Ream 2003; Wichstrøm and Hegna 2003; Eskin et  al. 2005; Mosher et  al. 2005) has created an intellectual revolution that is pressing for changes in policy in many corners of the world. At the same time, this movement has been the target of

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a backlash of oppressive rhetorical speech that is in many ways divisive. A number of documented cases clearly show that signs of sexual orientation diverging from a heterosexual status can be seen as early as childhood (the case of Jonas and Wyatt/Nicole Maines is an excellent example. Born identical twin males, Wyatt since age 2 displayed a female identity; http://www.people.com/article/meetidentical-twins-jonas-nicole-maines-familytransgender-story). The evidence from child and adolescent twin samples suggest that homosexualism and gender identity questioning are heritable, traits, with as much as 60% of the variance seen in the populations studied due to genetics. These findings imply that sexual orientation and gender identity are much less a matter of choice and much more a matter of biology (Kirk et al. 2000; Coolidge et  al. 2002). Furthermore, heritability is used to imply the amount of environmental influence in a particular trait or clinical presentation. However, environment needs to be interpreted in a broader sense. Epigenetic gene control and cellular microenvironment changes will not necessarily display familial aggregation to contribute to heritability but also cannot be easily tied to typical environmental factors, such as dietary habits or use of medications, recreational drugs, tobacco, or alcohol, or other household and parental influences. Social pressures to be cis-gendered have historically forced people to hide their sexual orientation. More recently, individuals have felt that acting on their sexual orientation was permissible, which created the perception that individuals “choose to be gay.” That perception typically follows a conservative view of sexuality that is commonly motivated by religious beliefs and is often associated with intolerant or demeaning discourse.

10.3.1 Measuring Heterosexual– Homosexual Orientation The idea of creating a scale to translate individual sexual orientation is not new. With the argument that “The living world is a continuum in

10  Genetic Influence on Behavior and the Impact on Oral Health Conditions

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each and every one of its aspects,” Kinsey et al. (1948) introduced the Heterosexual–Homosexual Rating Scale (The Kinsey Scale). The reports on the matter in 1948 and 1953 (Kinsey et al. 1948, 1953) helped to start a change in public perception of sexuality as they addressed male (1948) and female (1953) orientations. Since the Kinsey Scale does not address all possible sexual identities, others were developed to further define sexual expression [Sex Orientation Scale (Benjamin 1966), The Klein Orientation Grid (Klein et  al. 1985), the Storms Scale (Storms 1980), and the Multidimensional Scale of Sexuality (Berkey et  al. 1990)]. Despite these efforts, research on the assessment of sexual orientation has been limited, and descriptions tend to be conflicting and confusing.

10.3.2 Height as a Model

10.3.3 Sexual Orientation Distribution in a Population There is good evidence that a strong biological component modulates sexual orientation. Homosexual males and heterosexual females have similar brain structures, such as having thinner brain cortices, primarily in the visual areas, and smaller thalamus volumes than their heterosexual male counterparts (Abé et al. 2014). Compared with heterosexual women, homosexual women display less grey matter bilaterally in the temporo-basal cortex, ventral cerebellum, and left ventral premotor cortex (Ponseti et  al. 2007). There are also metabolic serotonergic system differences depending on the sexual orientation (Kinnunen et al. 2004). Family, twin, and adoptee studies indicate that sexual orientation

0.2

0.3

0.4

Sexual orientation is a complex or multifactorial trait (Rodríguez-Larralde and Paradisi 2009), very similar to height, intelligence, weight, blood pressure, levels of sugar in the blood, etc. In the case of height, some of the many genes in play have been identified (Wood et  al. 2014). One can argue that some genes will predispose you to be taller at the same time that others will pre-

vent you from being tall (or make you shorter). Furthermore, nutrition, in particular, may boost or hinder individual potential growth. When you assess height in the population, you see a distribution with the parameters shown in Fig.  10.2. There are also obvious differences in absolute height when the data of females and males are plotted separately (females are statistically smaller and shorter than males).

34.1%

0.1

34.1%

2.1%

2.1%

13.6%

13.6%

0.1%

0.0

0.1%

–3σ

–2σ

–1σ

µ

1σ

2σ

3σ

Fig. 10.2  Parameters of a normal distribution in a population. Human height, body mass index (BMI), blood pressure, and other population traits fit this distribution

10.3 Sexual Orientation: A Behavioral Genetics Case Study

run in families (Pillard and Bailey 1998). In the case of male sexual orientation, linkage to genes on pericentromeric chromosome 8 and chromosome Xq28 which influence development of male sexual orientation has been described (Sanders et al. 2015). Since sexual orientation is a complex trait that is defined by variation in more than one gene, it cannot be easily explained nor properly and fully assessed by a dichotomous state (i.e., biological sex, female, and male). Like other complex traits, it is best assessed by a continuous variable (i.e., height according to the metric system, weight in kilograms, measuring the pressure of the blood in the circulatory system, measuring blood sugar levels, measuring intelligence quotient from standardized tests designed to compare one’s score to others of her/his own age). Continuous variables provide a more discreet profile of the population. One can be either tall or short, but a height of 1 m 70 cm (5 ft 7 in.) provides an additional level of sophistication; one can place that height in regard to the rest of a group. Depending on the group, one can be tall (a 5 ft 7 in. 11-year-old female is tall for her age) or short (a 5 ft 7 in. 19-year-old male professional basketball player is likely to be considered short). What about sexual orientation? Kinsey et al. (1953) pointed out that “Many persons do not want to believe that there are gradations in these matters from one to the other extreme.” Indeed, we believe sexual orientation could also be measured by a continuous variable, but that this measurement needs to be further developed. The ideal measurement would provide a composite score for an orientation toward the opposite sex and orientation toward the same sex. The assessment of blood pressure is such a composite score, where each value (diastolic versus systolic) has a distinct clinical significance. In humans, sexual orientation is defined during childhood (Tyson 1982). Children show interest in physical differences as early as 3 or 4 years of age, and most will eventually define themselves in a male or female role. This coincides with the number of brain cells rapidly increasing in boys and girls at the same rate until 2–4 years of age. After that

97

time, a decrease in brain cell number takes place in girls, but not in boys (Swaab et  al. 1995). Romantic interest will display around the time as the first signs of puberty arrive. Therefore, assessing sexual identity during childhood should show the same results when determined at a later age, even if assessments will likely need to be customized for each age group. An assessment of sexual orientation would give us a degree of interest for the same and opposite biological sex. A defined threshold would indicate that the interest includes sexual attractiveness (Fig. 10.3). Absolute scores of 0 or 100% would probably be less frequent and may have clinical relevance, indicating asexuality or tendencies for displaying sexist or misogynist behavior that is biologically influenced.

10.3.4 Lack of Evolutionary Pressure A common reaction to the description of sexual orientation as a complex trait is “if sexual orientation is determined by genes, orientation for the same sex would not favor perpetuation of the species and would be selected against.” However, homosexual orientation in the population is close to 20% in frequency. How could that be possible? Through human evolution, variation is seen. Some grow to be a bit taller, others a bit shorter than the average height of a group. Taller individuals no longer have the disadvantage of being easier to spot by predators and these negative pressures have stopped. At the same time, more caloric and protein-rich diets have favored growth. Due to the nature of height being determined by multiple genes, there is also the possibility that some individuals will be shorter than the average of the group. When it comes to sexual orientation, male individuals with homosexual orientation would likely have been in disadvantage and their frequency in the group would have been low. They may have had offspring but were less likely to have them in comparison to individuals with a heterosexual orientation. Females with a homosexual orientation, based on what

10  Genetic Influence on Behavior and the Impact on Oral Health Conditions

98 1 0.9 0.8

Sexual attraction threshold

Probability

0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

Male

Female Orientation

Fig. 10.3  In a composite assessment of female and male orientation, an individual will have a probability for being oriented toward a female and a male. The “line trajectory” in regard to an arbitrary threshold of sexual attractiveness would indicate an orientation for one biological sex, both, or neither. This “trajectory” in the plot is just a visual aid created by connecting the two points, one measuring orientation toward males and the other orientation toward females. The determination of this threshold is another aspect that needs definition. It could vary person-to-­ person based on their individual thoughts on sexuality or be a predetermined value based on existing population

data. The example assumes values of 20% of probability of interest toward a male on the left and 80% toward a female on the right (the point on the left indicates an orientation to the same sex and the point on the right, orientation toward the opposite sex. The “trajectory” is the line connecting these two points). The number of individuals in a population that fit each specific possible trajectory (from zero probability to be orientated to males and females to be oriented to both biological sexes on a 100% probability and all other possible combinations) would possibly fit or approximate to a normal distribution

we know from humans, would probably not be at a disadvantage for having offspring, since the submissive role of females in groups would have overcome their original sexual nature. Therefore, the frequency of homosexualism, if it has not been increasing over the centuries (likely at a rate much slower than height) has at the very least not been decreasing. However, when more recently societies (particularly in Europe, the Middle East, and the Indian subcontinent) established social norms such that sexual orientation should match biological sex, it precipitated a sharper increase in the frequency of homosexualism. Facing persecution individuals will tend to ­conform with the rules, and despite homosexual or bisexual orientation, they would have offspring to keep up the image found acceptable

for their given society, but most importantly as a safeguard of their own lives. Another aspect of this discussion is that humans are a highly successful species and any possible evolutionary pressure against genes that influence sexual orientation toward the same sex has long ceased, likely when humans started numbering in the thousands to the millions.

10.4 Decision-Making Genes The interplay between behaviors that dictate risk for disease and the underlying genetic factors contributing to those behaviors is one that has been often ignored in regard to oral health, despite behaviors having a very important role

10.4 Decision-Making Genes U-Curve

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Inverted U-Curve

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in dental disease. Genes coding for the recognition of bitter, sweet, and umami tastes have been defined (Bachmanov and Beauchamp 2007). As expected, evidence exists suggesting that associations between these genes and dental caries exist (reviewed in Vieira et al. 2014). For example, an individual genetically predisposed to have more sweet taste perceptions may be more inclined to seek out sugary foods. It is unlikely, however, that these data will provide new tools for managing dental caries, since it is well established that a diet rich in sugars that goes without proper oral hygiene will increase individual risks for the disease. In this case, behavioral modification is the key to decrease risk for caries and oral disease, and genes involved in our decision-making are promising targets for oral health research. Decision-making is a complex executive function, and choices are often made in dynamic situations that require evaluation of potential risk and reward. Decisions related to what and when to eat, perform oral hygiene activities, and seek oral health care impact not only individual oral health, but also the oral health of children within a family unit. An inverted U-shaped relationship between dopaminergic function and cognitive performance exists, perhaps depending on the variation in optimal dopamine levels in relevant brain regions. This relationship is likely impacted by sex and genetic variation as well (Kohno et al. 2016). Understanding the biological process that leads to an individual decision for delaying oral hygiene, eating certain foods, or avoiding professional oral health care, and how that interacts with socioeconomic status, cultural beliefs, sex, age, and geographic origin will provide a roadmap for dissecting the complexity of dental caries or periodontitis etiology. A simple intervention such as providing oral hygiene instructions (Fig.  10.4) has distinct responses depending on the patient. It is reasonable to believe that more effective approaches could be tailored for certain groups, such as more frequent professional plaque removal rather than relying solely on the patient’s self-care at home. These responses are possibly influenced by sev-

99

40 20 0

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3

4

5

6

Visits

Fig. 10.4  Longitudinal data on periodontal patients and their plaque and bleeding indexes as surrogates of oral hygiene practices at home. Some individuals start with measurable plaque accumulation that reduces overtime only to return to original levels (U-curve), whereas some individuals have their plaque accumulation get worse after starting treatment but return to the better original values (U-inverted curve), while a third group fluctuates overtime (modified from Amoo-Achampong et al. (2018))

eral distinct pathways from the biological (being more prone to plaque accumulation) to the behavioral (electing to not buy dental floss or electing not to use it).

100

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10.5 Risk-Taking Genes Risk-taking behaviors are part of several psychiatric conditions, such as attention-deficit hyperactivity disorder, schizophrenia, and bipolar disorder. Genes contributing specifically to the definition of risk-taking behavior, which are independent from sex-specific effects (males tend to take more risks than females), ethnic differences, and psychiatric conditions have been identified (Strawbridge et al. 2018). Risk taking and impulsivity associated with reduced grey matter volume and thickness, and reduced white matter integrity (Peper et al. 2013; Lin et al. 2016; Fradkin et al. 2017). Similar to as described above for sexual orientation, those ­anatomical distinctions suggest a strong biological (and not environmental) component influencing risk taking and impulsivity. In general terms, genetics can be thought to influence 50% of the variation seen in traits like behavior and personality. The other portion can be thought to be influenced by the environment. The aggregate data show that despite the environment, genes will largely shape one’s personality, and even if the environment takes you away from your trajectory, sudden changes such as severe illness, the person will tend to return to their trajectory and be the person “they are meant to be.” Understanding these genetic influences allows for a better appreciation of people’s limits and potential. The notion that someone can become anything they want is likely, not true and probably not helpful. Someone should not insist on a path they clearly are not shaped for and ideally individuals will have the resources to identify the ideal path for themselves. Not everyone can be president. The two most common dental diseases, dental caries and periodontitis, are bacteria mediated and the dentist typically relies on long-term treatment by requesting modifications to oral hygiene and diet. The response to these requests varies immensely because of the range of behaviors in the population. What may be effective for a dentist is approaching their patients with a range of interventions, including more frequent dental visits, rather than requests for behavioral changes. Changing behavior is possible, but

the effective techniques (individually tailored oral health approaches, motivational interviews, autonomy-­ supportive interviews, counseling with the six-­step method, oral hygiene education based on social cognitive aid implementation theory, transtheoretical behavior change counseling) (Kay et al. 2016), are typically beyond the expertise of the dental professional.

10.6 Altruism, Cooperation, and Fear Is there a genetic basis for being afraid of the dark? Or of the dentist? The ocean? What about disinterested and selfless behavior? And why are some people nice? These behaviors do have a genetic component and they are prevalent today because they were selected over the course of human evolution. Hominids were never on the top of the food chain until very recently. They used to be the hunted, not the hunters (Fig.  10.5). To survive, humans organized themselves in groups and someone would be on the lookout for predators. This individual would draw the attention of the predator to themself and give time for the rest of the group to find refuge. By putting their life at risk, he/she would increase the chances of survival of others and specifically those individuals who had the ability to survive and procreate had their genes passed. This altruistic behavior was likely frequent enough to persist and can be found today and explain why someone would cross the line of fire to save a stranger. Cooperation probably evolved in a similar way. In humans today, there is evidence that shows that young children who have not yet been exposed to many caregivers or other adults, appear to be naturally altruistic and cooperative (Wynn 2011). For no obvious reason, children are intuitively nice to others, even if that means the inconvenience of having to stop what they are doing. Cooperation was likely beneficial for the individuals and the entire group and hominids that stayed in the group were more likely to survive and pass their genes. Conversely, the ones that tended to not cooperate would be more vulnerable to predators.

6

5

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Fig. 10.5  Time span comparison of ancient African predators and hominids (modified from Treves and Palmqvist (2007))

CARNIVORES Crocuta, Hyaena, Parahyaena Panthera Lycaon Megantereon Acinonyx Pachycrocuta Homotherium Dinofelis Machairodus Chasmaporthetes Agriotherium

Millions of Years Ago HOMINIDS Homo Paranthropus Australopithecus Ardipithecus Orrorin

2

1

10.6 Altruism, Cooperation, and Fear 101

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A similar evolutionary argument can be made for irrational fear. Why is someone afraid of going to the bathroom in the middle of the night, despite knowing that nothing and no one is there? Imagine two hominids at the edge of a forest and they hear a noise. One is curious and goes to investigate the sound whereas the other is cautious and stays away from the edge of the forest. More often than not, the curious one was eaten by a predator and the cautious one had an opportunity to survive and procreate, passing their genes. The frequency and variety of irrational fears we see today could be explained by the cumulative effect of such genes that define cautious behaviors over generations.

10.7 Belief in the Supernatural Observation of groups of humans living in isolated communities around the world offers a unique opportunity to answer the question of how supernatural beliefs came into the human psyche. Observing human groups that have remained isolated enough to preserve a lifestyle similar to that of 11,000  years ago, one can extrapolate and conclude that humans are prone to assume supernatural explanations for questions as a consequence of how our brains evolved (Diamond 2012). When answering a question about a phenomenon, our brain requires understanding the function and why. Function is typically less complex, but why requires elaborating the origins and reasons for the natural phenomenon in question. The reasons why are not always obvious, but the need for explanations, particularly if this need relates to acceptance of a great loss, opens the door for accepting anything that can be intelligently articulated. Traditional societies of today living in New Guinea today have very similar tales comparable to current religions, despite being isolated from modern civilization for centuries (Diamond 2012). Computer simulations also show that the belief in the supernatural brings benefits for the members of the group by enforcing commitment within the group, increasing the chances of their genes to be passed (Dow 2008). From an evolu-

tionary standpoint, believing in the supernatural provided another chance for survival, hence it is a behavior prevalent today, that translated into the perception of a need for religion.

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