Abstract
Dental caries (tooth decay) is the most common chronic disease, worldwide, affecting most children and adults. Though dental caries is highly heritable, few caries-related genes have been discovered. We investigated whether 18 genetic variants in the group of non-amelogenin enamel matrix genes (AMBN, ENAM, TUFT1, and TFIP11) were associated with dental caries experience in 13 age- and race-stratified samples from six parent studies (N = 3,600). Linear regression was used to model genetic associations and test gene-by-fluoride interaction effects for two sources of fluoride: daily tooth brushing and home water fluoride concentration. Meta-analysis was used to combine results across five child and eight adult samples. We observed the statistically significant association of rs2337359 upstream of TUFT1 with dental caries experience via meta-analysis across adult samples (p < 0.002) and the suggestive association for multiple variants in TFIP11 across child samples (p < 0.05). Moreover, we discovered two genetic variants (rs2337359 upstream of TUFT1 and missense rs7439186 in AMBN) involved in gene-by-fluoride interactions. For each interaction, participants with the risk allele/genotype exhibited greater dental caries experience only if they were not exposed to the source of fluoride. Altogether, these results confirm that variation in enamel matrix genes contributes to individual differences in dental caries liability, and demonstrate that the effects of these genes may be moderated by protective fluoride exposures. In short, genes may exert greater influence on dental caries in unprotected environments, or equivalently, the protective effects of fluoride may obviate the effects of genetic risk alleles.
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Aiyer AN, Kip KE, Marroquin OC, Mulukutla SR, Edmundowicz D, Reis SE (2007a) Racial differences in coronary artery calcification are not attributed to differences in lipoprotein particle sizes: the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) Study. Am Heart J 153:328–334. doi:10.1016/j.ahj.2006.11.002
Aiyer AN, Kip KE, Mulukutla SR, Marroquin OC, Hipps L Jr, Reis SE (2007b) Predictors of significant short-term increases in blood pressure in a community-based population. Am J Med 120:960–967. doi:10.1016/j.amjmed.2007.06.021
Boraas JC, Messer LB, Till MJ (1988) A genetic contribution to dental caries, occlusion, and morphology as demonstrated by twins reared apart. J Dent Res 67:1150–1155
Bretz WA et al (2005) Longitudinal analysis of heritability for dental caries traits. J Dent Res 84:1047–1051. doi:10.1177/154405910508401115
Centers for Disease Control and Prevention Division of Oral Health (2013) Community water fluoridation, using fluoride to prevent and control tooth decay in the United States (www.cdc.gov/fluoridation/factsheets/fl_caries.htm)
Conry JP, Messer LB, Boraas JC, Aeppli DP, Bouchard TJ Jr (1993) Dental caries and treatment characteristics in human twins reared apart. Arch Oral Biol 38:937–943. doi:10.1016/0003-9969(93)90106-V
Deeley K, Letra A, Rose EK, Brandon CA, Resick JM, Marazita ML, Vieira AR (2008) Possible association of amelogenin to high caries experience in a Guatemalan-Mayan population. Caries Res 42:8–13. doi:10.1159/000111744
Gasse B et al (2013) Common SNPs of AmelogeninX (AMELX) and dental caries susceptibility. J Dent Res 92:418–424. doi:10.1177/0022034513482941
Jeremias F et al (2013) Genes expressed in dental enamel development are associated with molar-incisor hypomineralization. Arch Oral Biol 58:1434–1442. doi:10.1016/j.archoralbio.2013.05.005
Kang SW, Yoon I, Lee HW, Cho J (2011) Association between AMELX polymorphisms and dental caries in Koreans. Oral Dis 17:399–406. doi:10.1111/j.1601-0825.2010.01766.x
Olszowski T, Adler G, Janiszewska-Olszowska J, Safranow K, Kaczmarczyk M (2012) MBL2, MASP2 AMELX, and ENAM gene polymorphisms and dental caries in Polish children. Oral Dis 18:389–395. doi:10.1111/j.1601-0825.2011.01887.x
Patir A, Seymen F, Yildirim M, Deeley K, Cooper ME, Marazita ML, Vieira AR (2008) Enamel formation genes are associated with high caries experience in Turkish children. Caries Res 42:394–400. doi:10.1159/000154785
Polk DE, Weyant RJ, Crout RJ, McNeil DW, Tarter RE, Thomas JG, Marazita ML (2008) Study protocol of the Center for Oral Health Research in Appalachia (COHRA) etiology study. BMC Oral Health 8:18. doi:10.1186/1472-6831-8-18
Purcell S et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. doi:10.1086/519795
Shaffer JR et al (2011) Genome-wide association scan for childhood caries implicates novel genes. J Dent Res 90:1457–1462. doi:10.1177/0022034511422910
Shaffer JR et al (2012a) Heritable patterns of tooth decay in the permanent dentition: principal components and factor analyses. BMC Oral Health 12:7. doi:10.1186/1472-6831-12-7
Shaffer JR et al (2012b) Genetic susceptibility to dental caries on pit and fissure and smooth surfaces. Caries Res 46:38–46. doi:10.1159/000335099
Shaffer JR et al (2013) Clustering tooth surfaces into biologically informative caries outcomes. J Dent Res 92:32–37. doi:10.1177/0022034512463241
Shimizu T et al (2012) Enamel formation genes influence enamel microhardness before and after cariogenic challenge. PloS One 7:e45022. doi:10.1371/journal.pone.0045022
Slayton RL, Cooper ME, Marazita ML (2005) Tuftelin, mutans streptococci, and dental caries susceptibility. J Dent Res 84:711–714. doi:10.1177/154405910508400805
Stanley BO et al (2014) Genetic association of MPPED2 and ACTN2 with dental caries. J Dent Res. doi:10.1177/0022034514534688
Vanyukov MM, Maher BS, Devlin B, Tarter RE, Kirillova GP, Yu LM, Ferrell RE (2004) Haplotypes of the monoamine oxidase genes and the risk for substance use disorders. Am J Med Genet Part B Neuropsychiatr Genet Off Publ Int Soc Psychiatr Genet 125B:120–125. doi:10.1002/ajmg.b.20105
Wang X et al (2010) Genes and their effects on dental caries may differ between primary and permanent dentitions. Caries Res 44:277–284. doi:10.1159/000314676
Wang X et al (2012a) Genome-wide association scan of dental caries in the permanent dentition. BMC Oral Health 12:57. doi:10.1186/1472-6831-12-57
Wang X et al (2012b) Genetic and environmental factors associated with dental caries in children: the Iowa Fluoride Study. Caries Res 46:177–184. doi:10.1159/000337282
Wendell S et al (2010) Taste genes associated with dental caries. J Dent Res 89:1198–1202. doi:10.1177/0022034510381502
Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191. doi:10.1093/bioinformatics/btq340
Acknowledgments
We would like to express our deep gratitude to the participants and research teams of the six parent studies whose contributions made this work possible. This work was supported by the following National Institutes of Health grants: U01-DE018903, R01-DE014899, R01-DE009551, R01-DE012101, R01-DE018914, P50-DA005605, and R01-DA019157, as well as the National Science Foundation/Department of Defense grant DBI-1263020. The Dental Registry and DNA Repository is supported by the University of Pittsburgh School of Dental Medicine. The Dental SCORE sample is partially supported by Commonwealth of Pennsylvania Department of Health grant ME-02-384.
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Shaffer, J.R., Carlson, J.C., Stanley, B.O.C. et al. Effects of enamel matrix genes on dental caries are moderated by fluoride exposures. Hum Genet 134, 159–167 (2015). https://doi.org/10.1007/s00439-014-1504-7
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DOI: https://doi.org/10.1007/s00439-014-1504-7