Genetics and Oral Health

Every cell in the human body contains 23 pairs of chromosomes with one chromosome in the pair inherited from each parent. Each chromosome, in turn, contains thousands of DNA gene sequences, some of which are active or expressed, and others that are dormant. Factors like time, the environment, and the type of cell containing the chromosome (e.g., tooth, brain, kidney, etc.), determine whether or not the gene will be expressed. The control of gene expression is essential for the proper growth, development, and functioning of an organism.

Mendelian Inheritance

Traditionally, the passing on of genetic traits and diseases is thought of in terms of Mendelian inheritance patterns. Children inherit one chromosome from each parent, and depending on the dominance of a gene in those chromosomes, a particular trait or disease may develop in the child. In Mendelian genetics, genes can be autosomal dominant or recessive or linked to one of the sex chromosomes—X or Y.

Autosomal Dominant. In autosomal dominant inheritance, only one chromosome in the pair needs to have the gene defect in question for the trait to manifest. An affected parent has a 50% chance of transmitting the mutated gene to any child.^1-3 Dentinogenesis imperfecta is an example of an autosomal dominant disorder. Other autosomal dominant disorders include achondroplasia (short-limbed dwarfism), some forms of amelogenesis imperfecta,⁴ and Marfan syndrome.³

Autosomal Recessive. By contrast, when a disorder is autosomal recessive, the child must inherit one copy of the defective gene from each parent for the disease or disorder to occur. Because each parent has one copy of the defective gene and is a carrier, there is a 25% chance that both mutant copies of the gene will be passed on to their offspring and that the child will manifest the disease. As with autosomal dominant disorders, it is equally likely that males and females will be affected. Fifty percent of the time, the offspring will get one copy of the mutant gene from one parent and will be a carrier, and 25% of the time the offspring will get two normal copies of the gene and will not develop the associated disease or disorder.^{2, 3} Although autosomal recessive disorders are relatively uncommon, the carrier status in certain populations can be significant. For example, as many as 1 in 23 people of northwestern European descent are carriers of cystic fibrosis.⁵ Some forms of ectodermal dysplasia and of amelogenesis imperfecta are inherited as autosomal recessive traits.⁴

Sex Linked. Sex-linked genes are genes that occur on either the X or Y chromosome, although only males can inherit Y-linked genes. For traits on the X chromosome, as males only have one X chromosome, a son has a 50% chance of inheriting the defective gene from his mother and manifesting the disease. If the defective gene is transmitted to a daughter, she will be a carrier for the disease and may display a mild phenotype. Disorders with X-linked inheritance include X-linked hypohydrotic ectodermal dysplasia, fragile X syndrome, and factor VIII deficiency (hemophilia).^{2, 3}

Chromosomal Anomalies

Some disorders result from defects in chromosomes that involve multiple genes. This includes duplication of all or part of a chromosome, deletion of part of a chromosome, or translocation of one chromosome onto another. Since chromosomal anomalies affect many genes, they result in multiple physical defects, as well as intellectual and developmental disturbances. Down syndrome (trisomy 21) is one example of a disorder with a chromosomal anomaly. Individuals with chromosomal anomalies may have dental and/or craniofacial anomalies related to the genetic modification.^{2, 3}

Multifactorial Inheritance/Complex Traits

Many common diseases are not inherited as a single gene defect, but instead are the result of modifications in gene expression or as gene-environment interactions. This includes diseases such as diabetes, hypertension, and bipolar disorder, nonsyndromic cleft lip and/or palate, dental caries, and periodontal disease. These diseases are considered “complex” because they involve multiple interactions between genes and environmental factors such as smoking, diet, stress, and environmental chemicals.^1-3 An individual’s response to environmental factors and his or her subsequent susceptibility to disease are related to mechanisms that modify gene expression without altering the DNA sequence.^{1-3, 6-9} Epigenetics refers to the mediation of gene expression without changes to the DNA sequence, and may account for phenotypic variation between monozygotic twins.^{2, 6, 8} Epigenetic changes include DNA methylation and histone modification non-coding RNA-associated gene silencing, and may be the result of age, stress, nutrition, or environmental factors that occur during developmental stages.^{2, 6}

Genotype vs. Phenotype

Traits can be discrete or continuous, and expression can be controlled by environmental exposures or modifier genes.^{2, 3, 10} Dominant genes (discrete) may have variable expressivity creating a range of phenotypes, while others can be threshold traits, in which there is a genotype continuum, but a ‘threshold’ determines only a limited number of phenotypes. In contrast to a phenotypic range of expressivity in individuals, penetrance refers to the likelihood of a gene variant arising in a phenotype.^{2, 3}

Environmental and other external and internal factors can affect the expression of one’s genotype, so that the presence or absence of gene variants or alleles only partially affects one’s phenotype. Further, a gene may be pleiotropic, leading to several phenotypic outcomes;^{2, 3} a single gene variant, for example, may affect incidence of both caries and periodontitis.¹¹

Estimating Genetic Control and Heritability

Mapping and Identifying Genes

Among families with consistent inheritance of a disease, linkage studies can determine the chromosomal region or genetic variant (polymorphism) responsible for the expression of the disease by following the appearance of genetic markers exclusive to the phenotype.^1-3

Within each individual’s genome are sequence variations (single nucleotide polymorphisms or SNPs) that may be associated with a complex disease, but that are not considered causative.^{1, 2} These variations often affect how genes interact with each other or how proteins interact with specific genes to regulate their activity. Association studies identify SNPs that are responsible for phenotypic traits or diseases by sequencing a specific gene in a representative sample of individuals with the phenotype.^{1, 2} Candidate gene studies look for gene variants of a suspected gene (i.e., “candidate”) found in individuals with a disease, compared to those without it.¹² Variation in the sequences (polymorphisms) of these suspected regions can be determined by sequencing and may then be identified as the gene variant associated with the disease.^{3, 12} For example, a T allele in a specific SNP may be a protective or normal factor, while an A allele may be a risk factor.

SNPs have been identified as part of the sequencing of the entire human genome and have been incorporated into studies referred to as genome-wide association studies (GWAS). In these studies, individuals with a certain disease, like dental caries, are compared to individuals without the disease by looking at the SNP sequences at millions of sites throughout the genome.^{1, 2} Using sophisticated, statistical analysis, researchers identify specific SNPs that are more frequently associated with the disease. Once a site on the genome is identified as a potential site of the disease in question, further investigation is completed to identify genes involved and understand their clinical significance.

Studies of complex disorders, by definition, include relevant environmental factors that are known to contribute to the disease. For example, a GWAS study of dental caries would need to include fluoride exposure, socioeconomic status, dietary habits, oral microflora, and oral hygiene habits to be able to assess the gene-environment interactions that contribute to disease.

Twin Studies and Heritability

Heritability is a measure of genetic control of a phenotypic trait; usually represented by h², the proportion of variance attributable to genetic variation, a continuous value in which essentially no genetic influence is 0 and full genetic influence is 1.^{2, 7, 13} Heritability estimates often rely on studies of concordance between twins. Because monozygotic (i.e., identical) twins share the same genome, and dizygotic (i.e., fraternal) twins approximately half, researchers can estimate the contributions of additive genetic variance, non-additive (essentially Mendelian) genetic variance, the shared or common environment, and the unique (individual) environment.^{2, 3, 7}

Dental caries is caused by the acidic environment that results from carbohydrate metabolism when sugars are introduced to the oral microbiome.^14-16 Enamel and dentin structure, immune response, salivary content and volume, and oral microbiota contribute to the multifactorial and complex etiology of dental caries,^16-18 but the extent to which susceptibility to caries is under genetic control, and which genes may be involved, is the subject of some debate.

Discovery of a direct role of individual gene variants in the etiology of caries has met with inconsistent results. Twin studies have suggested partial genetic control, from as low as around 20%^{19, 20} to as high as 85%.^20-22 The wide range of heritability may partially be due to etiological variation of caries experience, including population or race-level genetic or environmental differences. Despite potential genetic control of caries susceptibility, early childhood caries experience may be strongly influenced by maternal health or obesity,²³ and “[l]iving in a rural area, low socioeconomic status, less frequent tooth cleaning and sugar containing soft drinks [are] associated with a higher prevalence of dental caries.”²⁴ Genes consistently associated with caries experience in recent studies are listed in Table 1, below.

Table 1. Genes believed to be involved in caries experience

Gene	Role	Associated Disease
Ameloblastin (AMBN)	Enamel matrix	Caries,25 dental fluorosis26
Amelogenin (AMELX)	Tooth mineralization	Amelogenesis imperfecta4, caries27-29 Molar incisor hypomineralization30, 31
Aquaporin 5 (AQP5)	Saliva production	Caries32 (possibly protective)21
Carbonic Anhydrase VI (CA6)	Saliva pH regulation	Caries9, 33
Enamelin (ENAM)	Enamel matrix	Amelogenesis imperfecta4, molar incisor hypomineralization31, caries34-38
Estrogen related receptor beta (ESRRB)	Enamel hardness	Caries,11, 32, 39 hearing impairment39
Kallikrein 4 (KLK4)	Enamel matrix strengthening	Hypomaturation amelogenesis imperfecta40, 41
Matrix metalloproteinase 16 (MMP16)	Degradation of extracellular proteins	Caries42
Matrix metalloproteinase 20 (MMP20)	Early stages of tooth development	Caries43, 44 (possibly protective in some populations45)
Mucin 5 (MUC5B)	Inhibits biofilm formation	Caries susceptibility46
Polycystin-2 (PKD2)	Transient receptor potential channel	Polycystic kidney disease; caries47, 48
Tuftelin 1 (TUFT1)	Enamel matrix	Caries49, 50
Tuftelin-interacting protein 11 (TFIP11)	Enamel matrix	Caries49

Genetic Control of the Plaque Microbiome
Twin studies indicate that the plaque microbiome is largely hereditary and under significant genetic control in early life,^{14, 51} or in emerging (primary and secondary) dentitions,¹⁴ but environmental exposures throughout life increasingly affect the taxa present.^{14, 15, 51} Acidogenic Streptococci species are the most abundant pathogens in the oral environment, but a 2017 study⁵¹ of 485 dizygotic and monozygotic twins found that caries experience was not associated with heritable bacteria, and argued that proliferation of cariogenic bacteria such as Streptococci spp. is primarily a result of environmental exposure, that is, the introduction of carbohydrate-rich foods.⁵¹ Genetic control of the oral environment is likely responsible for healthy or non-cariogenic bacteria that make up plaque during development of the dentition, including the highly-heritable Prevotella pallens, Veillonella spp., Pasteurellaceae, and Croynebacterium durum, as well as potentially heritable Leptotrichia and Abiotophia.⁵¹ Predominant cariogenic taxa are Streptococcus mutans, S. sobrinus, and Lactobacillus spp;^{29, 52} and abundance of Corynebacterium matruchotii has been found to be correlated with high caries activity.⁵³ Recent studies have suggested that Scardovia wiggsiae may also be associated with caries,^{54, 55} particularly early childhood caries.^{54, 56} S. mutans is largely regarded to be the most cariogenic bacterial species.⁵⁷

Archaeological studies of ancient dental plaque show that plaque microflora had become less diverse and more dominated by cariogenic Streptococci (particularly S. mutans) following the transition to agriculture around 10,000 years ago and again, more drastically and permanently, after the Industrial Revolution;^{58, 59} both periods were marked by a shift towards carbohydrate-rich foods.⁵⁸ These studies suggest that the genetically controlled oral environment is gradually undermined by continual exposure to the modern diet.^{14, 51, 58}

Periodontal disease, like caries, is complex and multifactorial, but shares more of a direct link with overall health, so that risk factors such as smoking and diabetes can significantly contribute to its etiology.^60-64 A number of monogenic congenital syndromes can result in aggressive periodontitis, such as Papillon-Lefèvre and Chediak-Higashi syndromes,^{65, 66} but periodontal diseases are generally believed to be caused by a combination of several mechanisms, including the subgingival microbiome; genetic and epigenetic factors; behavioral and environmental factors; and systemic health.^{64, 67} Genetics plays a role in the etiology of periodontal disease by controlling periodontal structural integrity as well as affecting the host response to subgingival microbiota.^{11, 68} Heritability of the genetic control of periodontal disease has been estimated at around 50%,^69-71 although gene variants appear to vary according to population.⁷²

It has been suggested that periodontal disease is a two-step process, requiring both genetic susceptibility followed by a “bacterial challenge.”⁶⁸ A study indicated that a number of genes, including several interleukins, played in combination with specific microbiota to produce periodontal disease in mice, while variants of certain genes involved in structural integrity did not require the pathogens to initiate periodontal disease.⁶⁸

Research to determine which genes may play a role in periodontal disease has produced inconsistent results, but a 2017 systematic review identified the vitamin D receptor gene, VDR, Interleukin-10, IL-10, and the immunoglobulin platelet receptor gene Fc-γRIIA as the strongest candidates.¹¹ Other systematic reviews have found more consistent evidence for IL-1β and IL-6.^73-74 Many of the genes commonly associated with periodontal disease are listed in Table 2, below.

Table 2. Genes widely believed to play a role in development of periodontal disease.

Gene	Role	Associated Conditions
Fc-γRIIA	Platelet receptor	Chronic periodontitis11, 70
Interleukin-1 (IL-1α, IL-1β)	Proinflammatory response	Periodontitis,71, 72, 74, 75 several systemic diseases
Interleukin-6 (IL-6)	Proinflammatory response; bone resorption	Gingivitis,76 periodontitis,73, 76 acute apical periodontitis74
Interleukin-8	Immune response	Apical periodontitis,74 chronic periodontitis77, 78
Interleukin-10	Immune response	Aggressive periodontitis, inflammatory bowel disease, type 1 diabetes;64 chronic periodontitis in some populations73
Interleukin-37	Immune response	Severe periodontitis, tooth loss, stroke75
Matrix metalloproteinase 2 (MMP2)	Degradation of extracellular matrix during development, tissue repair	Periodontitis73
MMP3	Degradation of extracellular matrix during development, tissue repair	Chronic periodontitis73, 79
MMP8	Degradation of extracellular matrix during development, tissue repair	Periodontitis73, 79, 80
MMP9	Degradation of extracellular matrix during development, tissue repair	Chronic periodontitis,73, 79 periodontitis81
VDR	Tooth formation, calcium and phosphate balance	Periodontitis11

The Periodontal Microbiome
Porphyromonas gingivalis has been called a necessary, but not a sufficient, cause of periodontitis,⁵⁹ and Aggregatibacter (Actinobacillus) actinomycetemcomitans, Tannerella forsthia, and Treponema denticola are also believed to be periodontal pathogens.^{59, 82, 83} While dental caries has a more direct relationship of pathogenic activity leading to acidic destruction of tooth structure, destruction from periodontal disease is largely driven by the host response to microbiotic dysbiosis, with immune response cytokines (such as interleukins) driving inflammation, and the activity of matrix metalloproteinases (MMPs) that are responsible for the resulting tissue destruction.^{79, 80, 82} Thus, most research into the genetic control of periodontal disease has focused on these regulatory and immune response mechanisms.

Tests currently exist for genetic diseases that result from a gene mutation or chromosomal anomalies. For diseases in which the gene is known, the gene is sequenced and compared to the known, normal sequence.⁸⁴ For chromosomal anomalies, the entire karyotype is analyzed using fluorescent markers to determine if the full complement of chromosomes is present, and if there are significant duplications, deletions, or translocations.⁸⁴

Most genetic tests are not regulated. The U.S. Food and Drug Administration has regulatory authority over genetic tests sold as test kits.⁸⁵ The Centers for Medicare & Medicaid Services (CMS) has regulatory authority over those clinical laboratories with certification under the Clinical Laboratory Improvement Amendments (CLIA).⁸⁶

For complex diseases, there are many commercially marketed tests that claim to measure risk of disease or susceptibility to future disease. These tests are generally based on studies of SNPs that have been identified as part of a GWAS of a particular disease. These tests are either in the category of laboratory-developed tests or direct-to-consumer (DTC) tests.⁸⁷ While the proficiency of these tests to detect these markers is regulated through CMS in CLIA-certified laboratories, this does not substantiate claims about the relative contribution of the marker to the condition of interest. The National Institutes of Health manages an online list of self-reported genetic tests on the Genetic Testing Registry.

Patients with symptoms of unknown etiology can apply to be part of the Undiagnosed Diseases Network (UDN), funded by the National Institute of Health Common Fund. The UDN consists of a network of clinical and research facilities working using patient information, genome sequencing and other cutting-edge technology to diagnose rare or mysterious diseases.⁸⁸ Patients, with referral and information provided by their health care provider, may apply to the UDN and, if accepted, their case will be reviewed by a UDN site.⁸⁹

A predictive test for dental caries or for periodontal disease does not currently exist. Since these are both complex diseases with multiple genetic and environmental risk factors, quantifying risk will require multifaceted assessment. Similar to risk factors for cardiovascular disease, environmental factors affect one’s risk, regardless of genetic profile.⁹⁰

Caries

Risk Profile. Candidate gene and GWAS studies have identified a number of potential susceptibility loci. These include MMP10, MMP14, and MMP16;⁴² MPPED2 and ACTN2;⁹¹ Tuftelin;⁵⁰ as well as chromosomal regions with unknown function (i.e., rs7791001 in 7q22.3).¹¹ A 2017 review of 30 studies found that AMELX, AQP5, and ESRRB appear to be “a solid source of information” for genetic association with caries.³²

Potential Clinical Utility. A genetic test for caries susceptibility has the potential to identify patients at risk prior to disease occurrence; however, there are currently no genetic tests with this predictive ability. There may also be opportunity to develop genetic tests to develop more targeted therapies that precisely address the individual’s personal risk.

Significance of the Information (Effect Size). Not applicable at this time.

Does the Information Change Treatment of the Patient? Currently the most reliable predictor of caries risk is the presence of at least one caries lesion. Other clinical risk indicators include a diet with frequent (e.g., more than three) exposures per day to simple carbohydrates, poor oral hygiene, visible plaque, high levels of cariogenic bacteria, low socioeconomic status and low oral health literacy, among other things. In the future, genetic information about an individual’s risk profile may change how disease is managed.

Periodontal Disease

Risk Profile. Candidate genes and GWAS studies have identified a number of loci for study. A recent systematic review found there was a strong level of evidence that the vitamin D receptor (VDR), Fc-cRIIA and interleukin-10 (IL10) genes, and a moderate level of evidence for the IL-1α and IL-1β genes, play a role in periodontal disease etiology.¹¹ SNPs in interleukin genes IL-1β and IL-6 seem to be the most consistently associated with elevated risk of periodontitis.^{73, 74} However, a study of genetic tests to identify risk from IL1 variants in 2015 found no evidence that the tests provides any benefit outside of standard dental care.⁹²

In addition to genetic testing of the host, genetic testing for microbial identification may offer an additional avenue to explore for clinical application.

Potential Clinical Utility. Identifying a basis for severe disease in young individuals or as a means to better understand drivers of inflammation in excess of local factors; as well as monitoring treatment responses are among applications of host testing. Microbial identification may have value when coupled with antibiotic sensitivity testing for selecting antibiotics. Patients who have periodontitis that is refractory to treatment also may benefit from microbial assessments and monitoring. In addition, identification of patient genes that confer risk for microbial imbalance may be an important part of the puzzle, since gene-environment interactions are key when considering the interaction of the microbiome and the host at mucosal surfaces.

In addition, microbial testing may provide insight for patient management when treatment responses are poor—for example, under circumstances when there are low plaque scores, yet paradoxically high bleeding on probing and/or increased pocketing following exhaustive periodontal therapy and careful maintenance. Although it may be possible one day to combine insight about genetic information, comorbidities (e.g., diabetes), and environmental factors (e.g., smoking) to enhance decision making regarding treatment options and outcomes, this is not yet the state of the art.⁹³

Significance of the Information (Effect Size). Not applicable at this time.

Does the Information Change Treatment of the Patient? At this time, neither genotyping nor microbial testing are recommended as a routine dental procedure to identify the presence, absence, or severity of the disease. Clinical measurements (i.e., probing measurements and radiographic evaluations) for assessing the presence or absence of disease remain the single best method for assessing disease.

Genetic Testing for Risk Assessment (Trans.2017:266)

Resolved, that for the health and well-being of the public, the American Dental Association believes that any payer organization using a genetic test to determine eligibility for benefit coverage for specific oral healthcare services and any manufacturer of a test(s) used in such an effort must publish specific information on:

• Confirmation from an independent third party agency of test validity and reliability for the intended purpose
• Analysis on how this specific plan design will impact health outcomes and plan costs
• Disclosure of financial relationships between the manufacturer and payer
• Disclosure of bias and conflict of interest between the test manufacturer, investigators providing evidence and literature used to promote the test and plan design and with the payer organization

American Dental Association
Adopted 2017

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MouthHealthy

Genetic Testing and Your Dental Health

ADA News and Science in the News

Scientists Agree to Disagree on Genetic Testing (Berry; October 14, 2014)

JADA Resources:

Pihlstrom BL and Barnett ML. Conference summary: Navigating the Sea of Genomic Data, October 28-29, 2015. JADA 147(3): 207-213, 2016.

Genomics in Dentistry (Video)

National Academies Press:  An Evidence Framework for Genetic Testing (available for free download after registration)

National Institutes of Health Genetic Testing Registry

National Human Genome Research Institute: www.genome.gov

Regulation of Genetic Tests

Online Mendelian Inheritance in Man (OMIM): www.omim.org

Online database for SNPs SNPedia