Dental caries continues to be the most common chronic disease in children today. Despite the substantial involvement of genetics in the process of caries development, the specific genes contributing to dental caries remain largely unknown. We performed separate genome-wide association studies of smooth and pit-and-fissure tooth surface caries experience in the primary dentitions of self-reported white children in two samples from Iowa and rural Appalachia. In total, 1,006 children (ages 3-12 years) were included for smooth surface analysis, and 979 children (ages 4-14 years) for pit-and-fissure surface analysis. Associations were tested for more than 1.2 million single nucleotide polymorphisms, either genotyped or imputed. We detected genome-wide significant signals in KPNA4 (p value = 2.0E-9), and suggestive signals in ITGAL (p value = 2.1E-7) and PLUNC family genes (p value = 2.0E-6), thus nominating these novel loci as putative caries susceptibility genes. We also replicated associations observed in previous studies for MPPED2 (p value = 6.9E-6), AJAP1 (p value = 1.6E-6) and RPS6KA2 (p value = 7.3E-6). Replication of these associations in additional samples, as well as experimental studies to determine the biological functions of associated genetic variants, are warranted. Ultimately, efforts such as this may lead to a better understanding of caries etiology, and could eventually facilitate the development of new interventions and preventive measures.

1.
Acs G, Lodolini G, Kaminsky S, Cisneros GJ: Effect of nursing caries on body weight in a pediatric population. Pediatr Dent 1992;14:302-305.
2.
Acs G, Shulman R, Ng MW, Chussid S: The effect of dental rehabilitation on the body weight of children with early childhood caries. Pediatr Dent 1999;21:109-113.
3.
Almasy L, Blangero J: Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998;62:1198-1211.
4.
Anderson M: Risk assessment and epidemiology of dental caries: review of the literature. Pediatr Dent 2002;24:377-385.
5.
Batchelor PA, Sheiham A: Grouping of tooth surfaces by susceptibility to caries: a study in 5-16 year-old children. BMC Oral Health 2004;4:2.
6.
Beltran-Aguilar ED, Barker LK, Canto MT, Dye BA, Gooch BF, Griffin SO, Hyman J, Jaramillo F, Kingman A, Nowjack-Raymer R, Selwitz RH, Wu T: Surveillance for dental caries, dental sealants, tooth retention, edentulism, and enamel fluorosis - United States, 1988-1994 and 1999-2002. MMWR Surveill Summ 2005;54:1-43.
7.
Bingle CD, Craven CJ: Plunc: a novel family of candidate host defence proteins expressed in the upper airways and nasopharynx. Hum Mol Genet 2002;11:937-943.
8.
Bretz WA, Corby PM, Schork NJ, Robinson MT, Coelho M, Costa S, Melo Filho MR, Weyant RJ, Hart TC: Longitudinal analysis of heritability for dental caries traits. J Dent Res 2005;84:1047-1051.
9.
Browning BL, Browning SR: A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 2009;84:210-223.
10.
Conry JP, Messer LB, Boraas JC, Aeppli DP, Bouchard TJ Jr: Dental caries and treatment characteristics in human twins reared apart. Arch Oral Biol 1993;38:937-943.
11.
Divaris K, Monda KL, North KE, Olshan AF, Lange EM, Moss K, Barros SP, Beck JD, Offenbacher S: Genome-wide association study of periodontal pathogen colonization. J Dent Res 2012;91:21S-28S.
12.
Dye BA, Tan S, Smith V, Lewis BG, Barker LK, Thornton-Evans G, Eke PI, Beltran-Aguilar ED, Horowitz AM, Li CH: Trends in oral health status: United States, 1988-1994 and 1999-2004. Vital Health Stat 11 2007;1-92.
13.
Egland KA, Vincent JJ, Strausberg R, Lee B, Pastan I: Discovery of the breast cancer gene base using a molecular approach to enrich for genes encoding membrane and secreted proteins. Proc Natl Acad Sci USA 2003;100:1099-1104.
14.
Fábián TK, Hermann P, Beck A, Fejérdy P, Fábián G: Salivary defense proteins: their network and role in innate and acquired oral immunity. Int J Mol Sci 2012;13:4295-4320.
15.
Ferraro M, Vieira AR: Explaining gender differences in caries: a multifactorial approach to a multifactorial disease. Int J Dent 2010;2010:649643.
16.
Hunter PB: Risk factors in dental caries. Int Dent J 1988;38:211-217.
17.
Jiang H, Tai B, Du M, Peng B: Effect of professional application of APF foam on caries reduction in permanent first molars in 6-7-year-old children: 24-month clinical trial. J Dent 2005;33:469-473.
18.
Kumamoto H, Ooya K: Immunohistochemical detection of MT1-MMP, RECK, and EMMPRIN in ameloblastic tumors. J Oral Pathol Med 2006;35:345-351.
19.
Kumar P, Henikoff S, Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009;4:1073-1081.
20.
Levy SM, Warren JJ, Broffitt B, Hillis SL, Kanellis MJ: Fluoride, beverages and dental caries in the primary dentition. Caries Res 2003;37:157-165.
21.
Lima PM, Souza PE, Costa JE, Gomez RS, Gollob KJ, Dutra WO: Aggressive and chronic periodontitis correlate with distinct cellular sources of key immunoregulatory cytokines. J Periodontol 2011;82:86-95.
22.
Low W, Tan S, Schwartz S: The effect of severe caries on the quality of life in young children. Pediatr Dent 1999;21:325-326.
23.
Milward MR, Chapple IL, Wright HJ, Millard JL, Matthews JB, Cooper PR: Differential activation of NF-kappaB and gene expression in oral epithelial cells by periodontal pathogens. Clin Exp Immunol 2007;148:307-324.
24.
Polk DE, Weyant RJ, Crout RJ, McNeil DW, Tarter RE, Thomas JG, Marazita ML: Study protocol of the Center for Oral Health Research in Appalachia (COHRA) etiology study. BMC Oral Health 2008;8:18.
25.
Schaefer AS, Richter GM, Nothnagel M, Manke T, Dommisch H, Jacobs G, Arlt A, Rosenstiel P, Noack B, Groessner-Schreiber B, Jepsen S, Loos BG, Schreiber S: A genome-wide association study identifies GLT6D1 as a susceptibility locus for periodontitis. Hum Mol Genet 2010;19:553-562.
26.
Schreiner A, Ruonala M, Jakob V, Suthaus J, Boles E, Wouters F, Starzinski-Powitz A: Junction protein shrew-1 influences cell invasion and interacts with invasion-promoting protein CD147. Mol Biol Cell 2007;18:1272-1281.
27.
Schwab W, Harada H, Goetz W, Nowicki M, Witt M, Kasper M, Barth K: Immunocytochemical and biochemical detection of EMMPRIN in the rat tooth germ: differentiation-dependent co-expression with MMPs and co-localization with caveolin-1 in membrane rafts of dental epithelial cells. Histochem Cell Biol 2007;128:195-203.
28.
Shaffer JR, Feingold E, Wang X, Lee M, Tcuenco K, Weeks DE, Weyant RJ, Crout R, McNeil DW, Marazita ML: GWAS of dental caries patterns in the permanent dentition. J Dent Res 2013a;92:38-44.
29.
Shaffer JR, Feingold E, Wang X, Weeks DE, Weyant RJ, Crout R, McNeil DW, Marazita ML: Clustering tooth surfaces into biologically informative caries outcomes. J Dent Res 2013b;92:32-37.
30.
Shaffer JR, Wang X, Desensi RS, Wendell S, Weyant RJ, Cuenco KT, Crout R, McNeil DW, Marazita ML: Genetic susceptibility to dental caries on pit and fissure and smooth surfaces. Caries Res 2012;46:38-46.
31.
Shaffer JR, Wang X, Feingold E, Lee M, Begum F, Weeks DE, Cuenco KT, Barmada MM, Wendell SK, Crosslin DR, Laurie CC, Doheny KF, Pugh EW, Zhang Q, Feenstra B, Geller F, Boyd HA, Zhang H, Melbye M, Murray JC, Weyant RJ, Crout R, McNeil DW, Levy SM, Slayton RL, Willing MC, Broffitt B, Vieira AR, Marazita ML: Genome-wide association scan for childhood caries implicates novel genes. J Dent Res 2011;90:1457-1462.
32.
Townsend GC, Aldred MJ, Bartold PM: Genetic aspects of dental disorders. Aust Dent J 1998;43:269-286.
33.
Wang X, Shaffer JR, Weyant RJ, Cuenco KT, DeSensi RS, Crout R, McNeil DW, Marazita ML: Genes and their effects on dental caries may differ between primary and permanent dentitions. Caries Res 2010;44:277-284.
34.
Wang X, Shaffer JR, Zeng Z, Begum F, Vieira AR, Noel J, Anjomshoaa I, Cuenco KT, Lee MK, Beck J, Boerwinkle E, Cornelis MC, Hu FB, Crosslin DR, Laurie CC, Nelson SC, Doheny KF, Pugh EW, Polk DE, Weyant RJ, Crout R, McNeil DW, Weeks DE, Feingold E, Marazita ML: Genome-wide association scan of dental caries in the permanent dentition. BMC Oral Health 2012;12:57.
35.
Warren JJ, Levy SM, Broffitt B, Kanellis MJ: Longitudinal study of non-cavitated carious lesion progression in the primary dentition. J Public Health Dent 2006;66:83-87.
36.
Willer CJ, Li Y, Abecasis GR: METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 2010;26:2190-2191.
37.
Yang J, Weedon MN, Purcell S, Lettre G, Estrada K, Willer CJ, Smith AV, Ingelsson E, O'Connell JR, Mangino M, Magi R, Madden PA, Heath AC, Nyholt DR, Martin NG, Montgomery GW, Frayling TM, Hirschhorn JN, McCarthy MI, Goddard ME, Visscher PM, Consortium G: Genomic inflation factors under polygenic inheritance. Eur J Hum Genet 2011;19:807-812.
38.
Zeng Z, Shaffer JR, Wang X, Feingold E, Weeks DE, Lee M, Cuenco KT, Wendell SK, Weyant RJ, Crout R, McNeil DW, Marazita ML: Genome-wide association studies of pit-and-fissure- and smooth-surface caries in permanent dentition. J Dent Res 2013;92:432-437.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.