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),³ 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.^{2, 3} 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.³ If the defective gene is transmitted to a daughter, she will be a carrier for the disease and may display a mild phenotype.² Disorders with X-linked inheritance include X-linked hypohydrotic ectodermal dysplasia, fragile X syndrome, and factor VIII deficiency (hemophilia).^{2, 3, 6}

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.^{2, 6} 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.² Individuals with chromosomal anomalies may have dental and/or craniofacial anomalies related to the genetic modification.

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, 2} 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, 2, 7-10}  Epigenetics refers to the mediation of gene expression without changes to the DNA sequence,¹¹ and may account for phenotypic variation between monozygotic twins.^{2, 6, 7, 9}  Epigenetic changes include DNA methylation, post-translational histone modification and non-coding RNA-associated gene silencing,^{11, 12} and may be the result of age, stress, nutrition, or environmental factors that occur during developmental stages.^{2, 7}

Genotype vs. Phenotype

Traits can be discrete or continuous, and expression can be controlled by environmental exposures or modifier genes.^{2, 6, 13}  Dominant genes (discrete) may have variable expressivity creating a range of phenotypes,² 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, 6}

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.^{2, 6}  Further, a gene may be pleiotropic, leading to several phenotypic outcomes;^{2, 6} a single gene variant, for example, may affect incidence of both caries and periodontitis.¹⁴

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, 2, 6, 12} 

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, 3} 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, 6}  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.^{6, 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.^{2, 6, 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).^{2, 3} 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, 8, 15}  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, 6, 8} 

Dental caries is caused by the acidic environment that results from carbohydrate metabolism when sugars are introduced to the oral microbiome.^20-22  Enamel and dentin structure, immune response, salivary content and volume, and oral microbiota contribute to the multifactorial and complex etiology of dental caries,^{21, 23-27} 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%^{28, 29} to as high as 85%.^29-31  The wide range of heritability may partially be due to etiological variation of caries experience, including population or race-level genetic or environmental differences.^{26, 27, 32}  Despite potential genetic control of caries susceptibility, early childhood caries experience may be strongly influenced by maternal health or obesity,³³ 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.”³⁴  Importantly, heritability of caries experience may be mediated by oral health awareness and hygiene practices,^{26, 32, 35, 36} particularly fluoride exposure.³⁷

Genes most commonly associated with caries are typically involved with enamel formation and tooth mineralization,^{14, 25, 38-42} immune response,^{14, 27, 43} salivary characteristics,^{14, 25, 39, 44} and taste,^45-47 among others.^{25, 48, 49}  Amelogenin (AMELX) and enamelin (ENAM) are responsible for tooth mineralization and have been shown frequently to be associated with caries experience,³⁸ as have the enamel matrix genes ameloblastin (AMBN), tuftelin 1 (TUFT1) and tuftelin-interacting protein 11 (TFIP11).^{37-39, 41, 42}  Other genes may affect caries experience indirectly by modulating behavioral or metabolic factors, including taste-receptor genes^{50, 51} and the starch enzyme salivary amylase (AMY1), which has also been associated with obesity.^{44, 52, 53}  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

Genetic Control of the Plaque Microbiome

Twin studies indicate that the plaque microbiome is largely hereditary and under significant genetic control in early life,^{20, 80} or in emerging (primary and secondary) dentitions,²⁰ but environmental exposures throughout life increasingly affect the taxa present.^{20, 80, 81}  Acidogenic Streptococci species are the most abundant pathogens in the oral environment, but the proliferation of cariogenic bacteria such as Streptococci spp. is primarily a result of environmental exposure, that is, the introduction of carbohydrate-rich foods.⁸⁰  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.⁸⁰  Predominant cariogenic taxa are Streptococcus mutans, S. sobrinus, and Lactobacillus spp;^{43, 58, 82, 83} and abundance of Corynebacterium matruchotii has been found to be  correlated with high caries activity.^{83, 84}  Recent studies have suggested that Scardovia wiggsiae may also be associated with caries,^{43, 85, 86} particularly early childhood caries,^{85, 87} as have Actinomyces and Candida albicans.⁸³ S. mutans has been traditionally regarded to be the most cariogenic bacterial species.^{17, 88}

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;^{89, 90} both periods were marked by a shift towards carbohydrate-rich foods.⁸⁹  These studies suggest that the genetically controlled oral environment is gradually undermined by continual exposure to the modern diet.^{20, 80, 89}  See our Oral Health Topic on Forensic Dentistry and Anthropology for more detailed information.

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.^91-96  A number of monogenic congenital syndromes can result in aggressive periodontitis, such as Papillon-Lefèvre and Chediak-Higashi syndromes,^{97, 98} 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.^{43, 95, 99, 100}  It has been suggested that periodontal disease is a two-step process, requiring both genetic susceptibility followed by a “bacterial challenge,”¹⁰¹ and most studies support the idea that periodontal disease occurs as a result of the interaction of the host immune response and environmental factors, i.e., pathogens.^{96, 102}  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.^{14, 43, 100, 101, 103}  Heritability of the genetic control of periodontal disease has been estimated at around 30%^{103, 104} to as much as 50%,^105-107 although gene variants appear to vary according to population.¹⁰⁸  A 2019 systematic review found that heritability of periodontal disease increases with disease severity, even with confounding factors such as smoking.¹⁰⁴

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.¹⁴ Other systematic reviews have found more consistent evidence for IL-1β and IL-6.^109-112  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.

The Periodontal Microbiome

Porphyromonas gingivalis has been called a necessary, but not a sufficient, cause of periodontitis,⁹⁰ although the relative abundance of oral pathogens may be influenced by geographic or ethnic origin.¹²²  Aggregatibacter (Actinobacillus) actinomycetemcomitans, Tannerella forsthia, and Treponema denticola are also believed to be periodontal pathogens.^{43, 83, 90, 122-124}  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,^{83, 125, 126} with immune response cytokines (such as interleukins) driving inflammation,¹²⁵ and the activity of matrix metalloproteinases (MMPs) that are responsible for the resulting tissue destruction.^{118, 119, 123}  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 sequence variation or chromosomal anomalies.   Most genetic tests are not regulated. The U.S. Food and Drug Administration has regulatory authority over genetic tests sold as test kits.¹²⁷  The Centers for Medicare & Medicaid Services (CMS) has regulatory authority over those clinical laboratories with certification under the Clinical Laboratory Improvement Amendments (CLIA).¹²⁸ 

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.¹²⁹ 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.¹³⁰ 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.¹³¹ 

Both caries and periodontal diseases are complex diseases with multiple genetic, behavioral and environmental risk factors, and quantifying risk requires multifaceted assessment.  Similar to risk factors for cardiovascular disease, environmental factors affect one’s risk, regardless of genetic profile.¹³²  Noninvasive salivary tests are available, but as with any genetic testing, clinical utility is limited because of the multifactorial etiology of these diseases.  For more information, see our Oral Health Topics page on Salivary Diagnostics.

Caries

Risk Profile. Candidate gene and GWAS studies have identified a number of potential susceptibility loci. These include enamel-formation genes, AMBN,^{38, 55} ENAM,^{39, 59, 66, 67} and TUFT1; the tooth development enzymes MMP16,^{59, 72} and MMP20;  among others (see Table 1, above, for more details).  As discussed above, studies suggest that oral microbiota profiles may predict caries risk.¹³³

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.  Some studies have found 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.¹⁴  SNPs in interleukin genes IL-1β and IL-6 seem to be the most consistently associated with elevated risk of periodontitis^{109, 110, 125, 134, 135} (see Table 2, above, for more details). 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.¹³⁶  Several studies suggest that the combination of biomarkers are more diagnostically accurate,^{125, 135} particularly the combination of IL-6 and MMP-8.¹³⁵

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.¹³⁷

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

1. Hernandez LM, Blazer DG. Genes, Behavior, and the Social Environment: Moving Beyond the Nature/Nurture Debate. Washington (DC); 2006.
2. Cohn R, Hamosh A, Scherer S. Thompson & Thompson Genetics and Genomics in Medicine: Elsevier; 2023.
3. Lakhani N, Kulkarni K, Barwell J, Vasudevan P, Dorkins H. Clinical Genetics and Genomics at a Glance: Wiley; 2023.
4. Cabay RJ. An overview of molecular and genetic alterations in selected benign odontogenic disorders. Arch Pathol Lab Med 2014;138(6):754-8.
5. Lazarin GA, Haque IS, Nazareth S, et al. An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet Med 2013;15(3):178-86.
6. Jobling M, Hollox E, Hurles M, Kivisild T, Tyler-Smith C. Human Evolutionary Genetics, 2nd ed. New York, NY: Garland Science; 2014.
7. Seo JY, Park YJ, Yi YA, et al. Epigenetics: general characteristics and implications for oral health. Restor Dent Endod 2015;40(1):14-22.
8. Townsend G, Hughes T, Luciano M, Bockmann M, Brook A. Genetic and environmental influences on human dental variation: a critical evaluation of studies involving twins. Arch Oral Biol 2009;54 Suppl 1:S45-51.
9. Townsend GC, Richards L, Hughes T, Pinkerton S, Schwerdt W. Epigenetic influences may explain dental differences in monozygotic twin pairs. Aust Dent J 2005;50(2):95-100.
10. Yildiz G, Ermis RB, Calapoglu NS, Celik EU, Turel GY. Gene-environment Interactions in the Etiology of Dental Caries. J Dent Res 2016;95(1):74-9.
11. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes Dev 2009;23(7):781-3.
12. Alade A, Awotoye W, Butali A. Genetic and epigenetic studies in non-syndromic oral clefts. Oral Diseases 2022;28(5):1339-50.
13. Mossey PA. The heritability of malocclusion: Part 1--Genetics, principles and terminology. Br J Orthod 1999;26(2):103-13.
14. 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-S78.
15. Visscher PM, Hill WG, Wray NR. Heritability in the genomics era--concepts and misconceptions. Nat Rev Genet 2008;9(4):255-66.
16. Nascimento MM, Zaura E, Mira A, Takahashi N, Ten Cate JM. Second Era of OMICS in Caries Research: Moving Past the Phase of Disillusionment. J Dent Res 2017;96(7):733-40.
17. Baker JL, Morton JT, Dinis M, et al. Deep metagenomics examines the oral microbiome during dental caries, revealing novel taxa and co-occurrences with host molecules. Genome research 2021;31(1):64-74.
18. Wong DT. Salivaomics. J Am Dent Assoc 2012;143(10 Suppl):19s-24s.
19. Nonaka T, Wong DTW. Saliva diagnostics: Salivaomics, saliva exosomics, and saliva liquid biopsy. The Journal of the American Dental Association 2023;154(8):696-704.
20. Bretz WA, Corby PM, Hart TC, et al. Dental caries and microbial acid production in twins. Caries Res 2005;39(3):168-72.
21. Selwitz RH, Ismail AI, Pitts NB. Dental caries. The Lancet 2007;369(9555):51-59.
22. Sharifi R, Shayan A, Jamshidy L, et al. A systematic review and meta-analysis of CA VI, AMBN, and TUFT1 polymorphisms and dental caries risk. Meta Gene 2021;28:100866.
23. Struzycka I. The oral microbiome in dental caries. Pol J Microbiol 2014;63(2):127-35.
24. Vieira AR, Modesto A, Marazita ML. Caries: review of human genetics research. Caries Res 2014;48(5):491-506.
25. Tong X, Hou S, Ma M, et al. The integration of transcriptome-wide association study and mRNA expression profiling data to identify candidate genes and gene sets associated with dental caries. Arch Oral Biol 2020;118:104863.
26. 26.Zou T, Foxman B, McNeil DW, et al. Genome-Wide Analysis of Dental Caries Variability Reveals Genotype-by-Environment Interactions. Genes (Basel) 2023;14(3).
27. Chisini LA, Cademartori MG, Conde MCM, et al. Genes and SNPs in the pathway of immune response and caries risk: a systematic review and meta-analysis. Biofouling 2020;36(9):1100-16.
28. Teixeira R, Andrade NS, Queiroz LCC, et al. Exploring the association between genetic and environmental factors and molar incisor hypomineralization: evidence from a twin study. Int J Paediatr Dent 2017.
29. Vieira AR. Genetics and caries: prospects. Braz Oral Res 2012;26 Suppl 1:7-9.
30. Wang X, Willing MC, Marazita ML, et al. Genetic and environmental factors associated with dental caries in children: the Iowa Fluoride Study. Caries Res 2012;46(3):177-84.
31. Opal S, Garg S, Jain J, Walia I. Genetic factors affecting dental caries risk. Aust Dent J 2015;60(1):2-11.
32. Olatosi OO, Li M, Alade AA, et al. Replication of GWAS significant loci in a sub-Saharan African Cohort with early childhood caries: a pilot study. BMC Oral Health 2021;21(1):274.
33. Silva MJ, Kilpatrick NM, Craig JM, et al. Genetic and Early-Life Environmental Influences on Dental Caries Risk: A Twin Study. Pediatrics 2019;143(5).
34. Oscarson N, Espelid I, Jonsson B. Is caries equally distributed in adults? A population-based cross-sectional study in Norway - the TOHNN-study. Acta Odontol Scand 2017;75(8):557-63.
35. dos Anjos AMC, Moura de Lima MdD, Muniz FWMG, et al. Is there an association between dental caries and genetics? Systematic review and meta-analysis of studies with twins. Journal of Dentistry 2023;135:104586.
36. Sharma D, Bhandary S. Role of Genetic Markers in Dental Caries: A Literature Review. Journal of Health and Allied Sciences NU 2023(EFirst).
37. Shaffer JR, Carlson JC, Stanley BO, et al. Effects of enamel matrix genes on dental caries are moderated by fluoride exposures. Hum Genet 2015;134(2):159-67.
38. Chisini LA, Cademartori MG, Conde MCM, Tovo-Rodrigues L, Correa MB. Genes in the pathway of tooth mineral tissues and dental caries risk: a systematic review and meta-analysis. Clin Oral Investig 2020;24(11):3723-38.
39. Sharifi R, Jahedi S, Mozaffari HR, et al. Association of LTF, ENAM, and AMELX polymorphisms with dental caries susceptibility: a meta-analysis. BMC Oral Health 2020;20(1):132.
40. Gachova D, Lipovy B, Deissova T, et al. Polymorphisms in genes expressed during amelogenesis and their association with dental caries: a case–control study. Clinical Oral Investigations 2023;27(4):1681-95.
41. Chisini LA, Santos Fdc, de Carvalho RV, et al. Impact of tooth mineral tissues genes on dental caries: A birth-cohort study. Journal of Dentistry 2023;133:104505.
42. Sharma A, Patil SS, Muthu MS, et al. Single nucleotide polymorphisms of enamel formation genes and early childhood caries - systematic review, gene-based, gene cluster and meta-analysis. Journal of Indian Society of Pedodontics and Preventive Dentistry 2023;41(1):3-15.
43. Esberg A, Haworth S, Kuja-Halkola R, Magnusson PKE, Johansson I. Heritability of Oral Microbiota and Immune Responses to Oral Bacteria. Microorganisms 2020;8(8).
44. Stangvaltaite-Mouhat L, Puriene A, Aleksejuniene J, et al. Amylase Alpha 1 Gene (AMY1) Copy Number Variation and Dental Caries Experience: A Pilot Study among Adults in Lithuania. Caries Res 2021;55(3):174-82.
45. de Jesus VC, Mittermuller B-A, Hu P, Schroth RJ, Chelikani P. Genetic variants in taste genes play a role in oral microbial composition and severe early childhood caries. iScience 2022;25(12):105489.
46. Alotaibi RN, Howe BJ, Chernus JM, et al. Genome-Wide Association Study (GWAS) of dental caries in diverse populations. BMC Oral Health 2021;21(1):377.
47. Chisini LA, Cademartori MG, Conde Marcus CM, et al. Single nucleotide polymorphisms of taste genes and caries: a systematic review and meta-analysis. Acta Odontologica Scandinavica 2021;79(2):147-55.
48. Haworth S, Esberg A, Lif Holgerson P, et al. Heritability of Caries Scores, Trajectories, and Disease Subtypes. J Dent Res 2020;99(3):264-70.
49. Duran-Merino D, Molina-Frechero N, Sanchez-Perez L, et al. ENAM Gene Variation in Students Exposed to Different Fluoride Concentrations. Int J Environ Res Public Health 2020;17(6).
50. Haznedaroglu E, Koldemir-Gunduz M, Bakir-Coskun N, et al. Association of sweet taste receptor gene polymorphisms with dental caries experience in school children. Caries Res 2015;49(3):275-81.
51. Wendell S, Wang X, Brown M, et al. Taste Genes Associated with Dental Caries. Journal of Dental Research 2010;89(11):1198-202.
52. Mejia-Benitez MA, Bonnefond A, Yengo L, et al. Beneficial effect of a high number of copies of salivary amylase AMY1 gene on obesity risk in Mexican children. Diabetologia 2015;58(2):290-4.
53. Kor M, Pouramir M, Khafri S, Ebadollahi S, Gharekhani S. Association between Dental Caries, Obesity and Salivary Alpha Amylase in Adolescent Girls of Babol City, Iran-2017. J Dent (Shiraz) 2021;22(1):27-32.
54. Kuchler EC, Pecharki GD, Castro ML, et al. Genes Involved in the Enamel Development Are Associated with Calcium and Phosphorus Level in Saliva. Caries Res 2017;51(3):225-30.
55. Kuchler EC, Dea Bruzamolin C, Ayumi Omori M, et al. Polymorphisms in Nonamelogenin Enamel Matrix Genes Are Associated with Dental Fluorosis. Caries Res 2017;52(1-2):1-6.
56. Americano GC, Jacobsen PE, Soviero VM, Haubek D. A systematic review on the association between molar incisor hypomineralization and dental caries. Int J Paediatr Dent 2017;27(1):11-21.
57. Negre-Barber A, Montiel-Company JM, Catala-Pizarro M, Almerich-Silla JM. Degree of severity of molar incisor hypomineralization and its relation to dental caries. Sci Rep 2018;8(1):1248.
58. Werneck RI, Mira MT, Trevilatto PC. A critical review: an overview of genetic influence on dental caries. Oral Dis 2010;16(7):613-23.
59. Zaorska K, Szczapa T, Borysewicz-Lewicka M, Nowicki M, Gerreth K. Prediction of Early Childhood Caries Based on Single Nucleotide Polymorphisms Using Neural Networks. Genes (Basel) 2021;12(4).
60. Jeremias F, Koruyucu M, Kuchler EC, et al. Genes expressed in dental enamel development are associated with molar-incisor hypomineralization. Arch Oral Biol 2013;58(10):1434-42.
61. Jeremias F, Pierri RA, Souza JF, et al. Family-Based Genetic Association for Molar-Incisor Hypomineralization. Caries Res 2016;50(3):310-8.
62. Piekoszewska-Zietek P, Turska-Szybka A, Olczak-Kowalczyk D. Single Nucleotide Polymorphism in the Aetiology of Caries: Systematic Literature Review. Caries Res 2017;51(4):425-35.
63. Esberg A, Haworth S, Brunius C, Lif Holgerson P, Johansson I. Carbonic Anhydrase 6 Gene Variation influences Oral Microbiota Composition and Caries Risk in Swedish adolescents. Sci Rep 2019;9(1):452.
64. Chaussain C, Bouazza N, Gasse B, et al. Dental caries and enamelin haplotype. J Dent Res 2014;93(4):360-5.
65. Daubert DM, Kelley JL, Udod YG, et al. Human enamel thickness and ENAM polymorphism. Int J Oral Sci 2016;8(2):93-7.
66. Devang Divakar D, Alanazi SAS, Assiri MYA, et al. Association between ENAM polymorphisms and dental caries in children. Saudi Journal of Biological Sciences 2018(In Press, Corrected Proof).
67. Gerreth K, Zaorska K, Zabel M, Borysewicz-Lewicka M, Nowicki M. Association of ENAM gene single nucleotide polymorphisms with dental caries in Polish children. Clin Oral Investig 2016;20(3):631-6.
68. Zanolli C, Hourset M, Esclassan R, Mollereau C. Neanderthal and Denisova tooth protein variants in present-day humans. PLoS One 2017;12(9):e0183802.
69. Weber ML, Hsin HY, Kalay E, et al. Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay. BMC Med Genet 2014;15:81.
70. Bartlett JD. Dental enamel development: proteinases and their enamel matrix substrates. ISRN Dent 2013;2013:684607.
71. Smith CEL, Kirkham J, Day PF, et al. A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities. Front Physiol 2017;8:333.
72. Lewis DD, Shaffer JR, Feingold E, et al. Genetic Association of MMP10, MMP14, and MMP16 with Dental Caries. Int J Dent 2017;2017:8465125.
73. Antunes LA, Antunes LS, Kuchler EC, et al. Analysis of the association between polymorphisms in MMP2, MMP3, MMP9, MMP20, TIMP1, and TIMP2 genes with white spot lesions and early childhood caries. Int J Paediatr Dent 2016;26(4):310-9.
74. Tannure PN, Kuchler EC, Lips A, et al. Genetic variation in MMP20 contributes to higher caries experience. J Dent 2012;40(5):381-6.
75. Filho AV, Calixto MS, Deeley K, et al. MMP20 rs1784418 Protects Certain Populations against Caries. Caries Res 2017;51(1):46-51.
76. Cavallari T, Salomao H, Moyses ST, Moyses SJ, Werneck RI. The impact of MUC5B gene on dental caries. Oral Dis 2018;24(3):372-76.
77. Eckert S, Feingold E, Cooper M, et al. Variants on chromosome 4q21 near PKD2 and SIBLINGs are associated with dental caries. J Hum Genet 2017;62(4):491-96.
78. Shaffer JR, Feingold E, Wang X, et al. GWAS of dental caries patterns in the permanent dentition. J Dent Res 2013;92(1):38-44.
79. Slayton RL, Cooper ME, Marazita ML. Tuftelin, mutans streptococci, and dental caries susceptibility. J Dent Res 2005;84(8):711-4.
80. Gomez A, Espinoza JL, Harkins DM, et al. Host Genetic Control of the Oral Microbiome in Health and Disease. Cell Host Microbe 2017;22(3):269-78.e3.
81. Bretz WA, Corby PM, Schork NJ, et al. Longitudinal analysis of heritability for dental caries traits. J Dent Res 2005;84(11):1047-51.
82. Featherstone JD. The continuum of dental caries--evidence for a dynamic disease process. J Dent Res 2004;83 Spec No C:C39-42.
83. Duran-Pinedo AE. Metatranscriptomic analyses of the oral microbiome. Periodontol 2000 2021;85(1):28-45.
84. Peterson SN, Snesrud E, Liu J, et al. The dental plaque microbiome in health and disease. PLoS One 2013;8(3):e58487.
85. Tanner AC, Mathney JM, Kent RL, et al. Cultivable anaerobic microbiota of severe early childhood caries. J Clin Microbiol 2011;49(4):1464-74.
86. Kressirer CA, Smith DJ, King WF, et al. Scardovia wiggsiae and its potential role as a caries pathogen. J Oral Biosci 2017;59(3):135-41.
87. Vacharaksa A, Suvansopee P, Opaswanich N, Sukarawan W. PCR detection of Scardovia wiggsiae in combination with Streptococcus mutans for early childhood caries-risk prediction. Eur J Oral Sci 2015;123(5):312-18.
88. Banas JA, Drake DR. Are the mutans streptococci still considered relevant to understanding the microbial etiology of dental caries? BMC Oral Health 2018;18(1):129.
89. Adler CJ, Dobney K, Weyrich LS, et al. Sequencing ancient calcified dental plaque shows changes in oral microbiota with dietary shifts of the Neolithic and Industrial revolutions. Nat Genet 2013;45(4):450-5, 55e1.
90. Costalonga M, Herzberg MC. The oral microbiome and the immunobiology of periodontal disease and caries. Immunol Lett 2014;162(2 Pt A):22-38.
91. Ganesan SM, Joshi V, Fellows M, et al. A tale of two risks: smoking, diabetes and the subgingival microbiome. ISME J 2017;11(9):2075-89.
92. Batty GD, Jung KJ, Mok Y, et al. Oral health and later coronary heart disease: Cohort study of one million people. Eur J Prev Cardiol 2018;25(6):598-605.
93. Miranda TS, Napimoga MH, Feres M, et al. Antagonists of Wnt/beta-catenin signalling in the periodontitis associated with type 2 diabetes and smoking. J Clin Periodontol 2017.
94. Joaquim CR, Miranda TS, Marins LM, et al. The combined and individual impact of diabetes and smoking on key subgingival periodontal pathogens in patients with chronic periodontitis. J Periodontal Res 2017.
95. 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.
96. Brodzikowska A, Górski B. Polymorphisms in Genes Involved in Inflammation and Periodontitis: A Narrative Review. Biomolecules 2022;12(4).
97. Vieira AR, Albandar JM. Role of genetic factors in the pathogenesis of aggressive periodontitis. Periodontol 2000 2014;65(1):92-106.
98. Hart TC, Kornman KS. Genetic factors in the pathogenesis of periodontitis. Periodontol 2000 1997;14:202-15.
99. Gu Y, Ryan ME, Loos BG. Periodontal Diseases: Classification, Epidemiology, Pathogenesis, and Management. Periodontal Disease and Overall Health: A Clinician’s Guide Second Edition; 2014. p. 6.
100. Loos BG, Van Dyke TE. The role of inflammation and genetics in periodontal disease. Periodontol 2000 2020;83(1):26-39.
101. de Vries TJ, Andreotta S, Loos BG, Nicu EA. Genes Critical for Developing Periodontitis: Lessons from Mouse Models. Front Immunol 2017;8:1395.
102. Zhang S, Yu N, Arce RM. Periodontal inflammation: Integrating genes and dysbiosis. Periodontol 2000 2020;82(1):129-42.
103. Shaddox LM, Morford LA, Nibali L. Periodontal health and disease: The contribution of genetics. Periodontol 2000 2021;85(1):161-81.
104. Nibali L, Bayliss-Chapman J, Almofareh SA, et al. What Is the Heritability of Periodontitis? A Systematic Review. J Dent Res 2019;98(6):632-41.
105. Michalowicz BS, Diehl SR, Gunsolley JC, et al. Evidence of a substantial genetic basis for risk of adult periodontitis. J Periodontol 2000;71(11):1699-707.
106. Nibali L, Di Iorio A, Onabolu O, Lin GH. Periodontal infectogenomics: systematic review of associations between host genetic variants and subgingival microbial detection. J Clin Periodontol 2016;43(11):889-900.
107. Razzouk S. Regulatory elements and genetic variations in periodontal diseases. Arch Oral Biol 2016;72:106-15.
108. Wu X, Offenbacher S, Lomicronpez NJ, et al. Association of interleukin-1 gene variations with moderate to severe chronic periodontitis in multiple ethnicities. J Periodontal Res 2015;50(1):52-61.
109. da Silva MK, de Carvalho ACG, Alves EHP, et al. Genetic Factors and the Risk of Periodontitis Development: Findings from a Systematic Review Composed of 13 Studies of Meta-Analysis with 71,531 Participants. Int J Dent 2017;2017:1914073.
110. Salles AG, Antunes LAA, Kuchler EC, Antunes LS. Association between Apical Periodontitis and Interleukin Gene Polymorphisms: A Systematic Review and Meta-analysis. J Endod 2018;44(3):355-62.
111. Reis CLB, Barbosa MCF, Machado B, et al. Genetic polymorphisms in interleukin-6 and interleukin-1-beta were associated with dental caries and gingivitis. Acta Odontol Scand 2021;79(2):96-102.
112. de Alencar JB, Zacarias JMV, Tsuneto PY, et al. Influence of inflammasome NLRP3, and IL1B and IL2 gene polymorphisms in periodontitis susceptibility. PLoS One 2020;15(1):e0227905.
113. Offenbacher S, Divaris K, Barros SP, et al. Genome-wide association study of biologically informed periodontal complex traits offers novel insights into the genetic basis of periodontal disease. Hum Mol Genet 2016;25(10):2113-29.
114. Liu X, Li H. A Systematic Review and Meta-Analysis on Multiple Cytokine Gene Polymorphisms in the Pathogenesis of Periodontitis. Frontiers in Immunology 2022;12.
115. Scapoli L, Girardi A, Palmieri A, et al. Interleukin-6 gene polymorphism modulates the risk of periodontal diseases. Journal of Biological Regulators & Homeostatic Agents 2015;29(3):111-16.
116. Finoti LS, Nepomuceno R, Pigossi SC, et al. Association between interleukin-8 levels and chronic periodontal disease: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore) 2017;96(22):e6932.
117. Andia DC, de Oliveira NF, Letra AM, et al. Interleukin-8 gene promoter polymorphism (rs4073) may contribute to chronic periodontitis. J Periodontol 2011;82(6):893-9.
118. Weng H, Yan Y, Jin YH, et al. Matrix metalloproteinase gene polymorphisms and periodontitis susceptibility: a meta-analysis involving 6,162 individuals. Sci Rep 2016;6:24812.
119. de Morais EF, Pinheiro JC, Leite RB, et al. Matrix metalloproteinase-8 levels in periodontal disease patients: A systematic review. J Periodontal Res 2018;53(2):156-63.
120. Deng K, Pelekos G, Jin L, Tonetti MS. Diagnostic accuracy of a point-of-care aMMP-8 test in the discrimination of periodontal health and disease. J Clin Periodontol 2021.
121. Yang S, Gu B, Zhao L, et al. Meta-analysis of the association between serum and gingival crevicular fluid matrix metalloproteinase-9 and periodontitis. J Am Dent Assoc 2019;150(1):34-41.
122. Arredondo A, Àlvarez G, Isabal S, et al. Comparative 16S rRNA gene sequencing study of subgingival microbiota of healthy subjects and patients with periodontitis from four different countries. Journal of Clinical Periodontology 2023;50(9):1176-87.
123. Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol 2015;15(1):30-44.
124. Bartold PM, Van Dyke TE. An appraisal of the role of specific bacteria in the initial pathogenesis of periodontitis. J Clin Periodontol 2019;46(1):6-11.
125. Cafiero C, Spagnuolo G, Marenzi G, et al. Predictive Periodontitis: The Most Promising Salivary Biomarkers for Early Diagnosis of Periodontitis. J Clin Med 2021;10(7).
126. Buduneli N. Environmental factors and periodontal microbiome. Periodontol 2000 2021;85(1):112-25.
127. U.S. Food and Drug Administration. Direct-to-Consumer Tests. Silver Spring, MD.: 2019. "https://www.fda.gov/medical-devices/in-vitro-diagnostics/direct-consumer-tests". Accessed October 2, 2023.
128. U.S. Centers for Medicare and Medicaid Services. Clinical Laboratory Improvement Amendments (CLIA). Baltimore, MD. "https://www.cms.gov/medicare/quality/clinical-laboratory-improvement-amendments?redirect=/CLIA". Accessed October 2, 2023.
129. National Human Genome Research Institute. Genetic Testing FAQ. NIH. "https://www.genome.gov/FAQ/Genetic-Testing". Accessed October 2, 2023.
130. National Institutes of Health. The NIH Undiagnosed Diseases Network expands. Bathesda, Maryland; 2018.
131. Undiagnosed Diseases Network. Frequently Asked Questions About the Undiagnosed Diseases Network. Cambridge, MA. "https://undiagnosed.hms.harvard.edu/about-us/faqs/". Accessed October 2, 2023.
132. Khera AV, Kathiresan S. Is Coronary Atherosclerosis One Disease or Many? Setting Realistic Expectations for Precision Medicine. Circulation 2017;135(11):1005-07.
133. Grier A, Myers JA, O'Connor TG, et al. Oral Microbiota Composition Predicts Early Childhood Caries Onset. J Dent Res 2021;100(6):599-607.
134. Arias-Bujanda N, Regueira-Iglesias A, Blanco-Pintos T, et al. Diagnostic accuracy of IL1beta in saliva: The development of predictive models for estimating the probability of the occurrence of periodontitis in non-smokers and smokers. J Clin Periodontol 2020;47(6):702-14.
135. Kc S, Wang XZ, Gallagher JE. Diagnostic sensitivity and specificity of host-derived salivary biomarkers in periodontal disease amongst adults: Systematic review. J Clin Periodontol 2020;47(3):289-308.
136. 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 e4.
137. Greenstein G, Hart TC. Clinical utility of a genetic susceptibility test for severe chronic periodontitis: a critical evaluation. J Am Dent Assoc 2002;133(4):452-9; quiz 92-3.

Oral Health Topics

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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