Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Variants on chromosome 4q21 near PKD2 and SIBLINGs are associated with dental caries

Abstract

A recent genome-wide association study (GWAS) for dental caries nominated the chromosomal region 4q21 near ABCG2, PKD2 and the SIBLING (small integrin-binding ligand N-linked glycoprotein) gene family. In this investigation, we followed up and fine-mapped this region using a tag-SNP (single-nucleotide polymorphism) approach in 13 age- and race-stratified samples from 6 independent studies (N=4089). Participants were assessed for dental caries via intraoral examination and 49 tag-SNPs were genotyped capturing much of the variation in the 4q21 locus. Linear models were used to test for genetic association, while adjusting for sex, age and components of ancestry. SNPs in and near PKD2 showed significant evidence of association in individual samples of black adults (rs17013735, P-value=0.0009) and white adults (rs11938025; P-value=0.0005; rs2725270, P-value=0.003). Meta-analyses across black adult samples recapitulated the association with rs17013735 (P-value=0.003), which occurs at low frequency in non-African populations, possibly explaining the race specificity of the effect. In addition to race-specific associations, we also observed evidence of gene-by-fluoride exposure interaction effects in white adults for SNP rs2725233 upstream of PKD2 (P=0.002). Our results show evidence of regional replication, though no single variant clearly accounted for the original GWAS signal. Therefore, while we interpret our results as strengthening the hypothesis that chromosome 4q21 may impact dental caries, additional work is needed.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3

References

  1. 1

    Bretz, W. A., Corby, P. M., Melo, M. R., Coelho, M. Q., Costa, S. M., Robinson, M. et al. Heritability estimates for dental caries and sucrose sweetness preference. Arch. Oral Biol. 51, 1156–1160 (2006).

    Article  Google Scholar 

  2. 2

    Bretz, W. A., Corby, P. M., Schork, N. J., Robinson, M. T., Coelho, M., Costa, S. et al. Longitudinal analysis of heritability for dental caries traits. J. Dent. Res. 84, 1047–1051 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Wang, X., Shaffer, J. R., Weyant, R. J., Cuenco, K. T., DeSensi, R. S., Crout, R. et al. Genes and their effects on dental caries may differ between primary and permanent dentitions. Caries Res. 44, 277–284 (2010).

    CAS  Article  Google Scholar 

  4. 4

    Shaffer, J. R., Wang, X., Desensi, R. S., Wendell, S., Weyant, R. J., Cuenco, K. T. et al. Genetic susceptibility to dental caries on pit and fissure and smooth surfaces. Caries Res. 46, 38–46 (2012).

    CAS  Article  Google Scholar 

  5. 5

    Shaffer, J. R., Feingold, E., Wang, X., Tcuenco, K. T., Weeks, D. E., DeSensi, R. S. et al. Heritable patterns of tooth decay in the permanent dentition: principal components and factor analyses. BMC Oral Health 12, 7 (2012).

    Article  Google Scholar 

  6. 6

    Zeng, Z., Feingold, E., Wang, X., Weeks, D. E., Lee, M., Cuenco, D. T. et al. Genome-wide association study of primary dentition pit-and-fissure and smooth surface caries. Caries Res. 48, 330–338 (2014).

    CAS  Article  Google Scholar 

  7. 7

    Zeng, Z., Shaffer, J. R., Wang, X., Feingold, E., Weeks, D. E., Lee, M. et al. Genome-wide association studies of pit-and-fissure- and smooth-surface caries in permanent dentition. J. Dent. Res. 92, 432–437 (2013).

    CAS  Article  Google Scholar 

  8. 8

    Shaffer, J. R., Feingold, E., Wang, X., Lee, M., Tcuenco, K., Weeks, D. E. et al. GWAS of dental caries patterns in the permanent dentition. J. Dent. Res. 92, 38–44 (2013).

    CAS  Article  Google Scholar 

  9. 9

    Shaffer, J. R., Wang, X., Feingold, E., Lee, M., Begum, F., Weeks, D. E. et al. Genome-wide association scan for childhood caries implicates novel genes. J. Dent. Res. 90, 1457–1462 (2011).

    CAS  Article  Google Scholar 

  10. 10

    Wang, X., Shaffer, J. R., Zeng, Z., Begum, F., Vieira, A. R., Noel, J. et al. Genome-wide association scan of dental caries in the permanent dentition. BMC Oral Health 12, 57 (2012).

    CAS  Article  Google Scholar 

  11. 11

    Stanley, B. O., Feingold, E., Cooper, M., Vanyukov, M. M., Maher, B. S., Slayton, R. L. et al. Genetic association of MPPED2 and ACTN2 with dental caries. J. Dent. Res. 93, 626–632 (2014).

    CAS  Article  Google Scholar 

  12. 12

    Fisher, L. W. DMP1 and DSPP: evidence for duplication and convergent evolution of two SIBLING proteins. Cells Tissues Organs 194, 113–118 (2011).

    CAS  Article  Google Scholar 

  13. 13

    Fisher, L. W. & Fedarko, N. S. Six genes expressed in bones and teeth encode the current members of the SIBLING family of proteins. Connect Tissue Res. 44 (Suppl 1), 33–40 (2003).

    CAS  Article  Google Scholar 

  14. 14

    Kawasaki, K. & Weiss, K. M. Mineralized tissue and vertebrate evolution: the secretory calcium-binding phosphoprotein gene cluster. Proc. Natl Acad. Sci. USA 100, 4060–4065 (2003).

    CAS  Article  Google Scholar 

  15. 15

    MacDougall, M., Simmons, D., Gu, T. T. & Dong, J. MEPE/OF45, a new dentin/bone matrix protein and candidate gene for dentin diseases mapping to chromosome 4q21. Connect Tissue Res. 43, 320–330 (2002).

    CAS  Article  Google Scholar 

  16. 16

    Qin, C., Brunn, J. C., Jones, J., George, A., Ramachandran, A., Gorski, J. P. et al. A comparative study of sialic acid-rich proteins in rat bone and dentin. Eur. J. Oral Sci. 109, 133–141 (2001).

    CAS  Article  Google Scholar 

  17. 17

    Gibson, M. P., Zhu, Q., Wang, S., Liu, Q., Liu, Y., Wang, X. et al. The rescue of dentin matrix protein 1 (DMP1)-deficient tooth defects by the transgenic expression of dentin sialophosphoprotein (DSPP) indicates that DSPP is a downstream effector molecule of DMP1 in dentinogenesis. J. Biol. Chem. 288, 7204–7214 (2013).

    CAS  Article  Google Scholar 

  18. 18

    Fedarko, N. S., Jain, A., Karadag, A. & Fisher, L. W. Three small integrin binding ligand N-linked glycoproteins (SIBLINGs) bind and activate specific matrix metalloproteinases. FASEB J. 18, 734–736 (2004).

    CAS  Article  Google Scholar 

  19. 19

    Caron, C., Xue, J., Sun, X., Simmer, J. P., Bartlett, J. D. & Gelatinase, A. MMP-2) in developing tooth tissues and amelogenin hydrolysis. J. Dent. Res. 80, 1660–1664 (2001).

    CAS  Article  Google Scholar 

  20. 20

    Feng, J., McDaniel, J. S., Chuang, H. H., Huang, O., Rakian, A., Xu, X. et al. Binding of amelogenin to MMP-9 and their co-expression in developing mouse teeth. J. Mol. Histol. 43, 473–485 (2012).

    CAS  Article  Google Scholar 

  21. 21

    Ogbureke, K. U. & Fisher, L. W. Expression of SIBLINGs and their partner MMPs in salivary glands. J. Dent. Res. 83, 664–670 (2004).

    CAS  Article  Google Scholar 

  22. 22

    Khonsari, R. H., Ohazama, A., Raouf, R., Kawasaki, M., Kawasaki, K., Porntaveetus, T. et al. Multiple postnatal craniofacial anomalies are characterized by conditional loss of polycystic kidney disease 2 (Pkd2). Hum. Mol. Genet. 22, 1873–1885 (2013).

    CAS  Article  Google Scholar 

  23. 23

    Honda, M. J., Nakashima, F., Satomura, K., Shinohara, Y., Tsuchiya, S., Watanabe, N. et al. Side population cells expressing ABCG2 in human adult dental pulp tissue. Int. Endod. J. 40, 949–958 (2007).

    CAS  Article  Google Scholar 

  24. 24

    Li, L., Kwon, H. J., Harada, H., Ohshima, H., Cho, S. W. & Jung, H. S. Expression patterns of ABCG2, Bmi-1, Oct-3/4, and Yap in the developing mouse incisor. Gene Expr. Patterns 11, 163–170 (2011).

    CAS  Article  Google Scholar 

  25. 25

    Kumamoto, H. & Ohki, K. Detection of CD133, Bmi-1, and ABCG2 in ameloblastic tumors. J. Oral Pathol. Med. 39, 87–93 (2010).

    CAS  Article  Google Scholar 

  26. 26

    Anjomshoaa, I., Briseno-Ruiz, J., Deeley, K., Poletta, F. A., Mereb, J. C., Leite, A. L. et al. Aquaporin 5 interacts with fluoride and possibly protects against caries. PLoS ONE 10, e0143068 (2015).

    Article  Google Scholar 

  27. 27

    Shaffer, J. R., Carlson, J. C., Stanley, B. O., Feingold, E., Cooper, M., Vanyukov, M. M. et al. Effects of enamel matrix genes on dental caries are moderated by fluoride exposures. Hum. Genet. 134, 159–167 (2015).

    CAS  Article  Google Scholar 

  28. 28

    Polk, D. E., Weyant, R. J., Crout, R. J., McNeil, D. W., Tarter, R. E., Thomas, J. G. et al. Study protocol of the Center for Oral Health Research in Appalachia (COHRA) etiology study. BMC Oral Health 8, 18 (2008).

    Article  Google Scholar 

  29. 29

    Slayton, R. L., Cooper, M. E. & Marazita, M. L. Tuftelin, mutans streptococci, and dental caries susceptibility. J. Dent. Res. 84, 711–714 (2005).

    CAS  Article  Google Scholar 

  30. 30

    Wang, X., Willing, M. C., Marazita, M. L., Wendell, S., Warren, J. J., Broffitt, B. et al. Genetic and environmental factors associated with dental caries in children: the Iowa Fluoride Study. Caries Res. 46, 177–184 (2012).

    CAS  Article  Google Scholar 

  31. 31

    Aiyer, A. N., Kip, K. E., Marroquin, O. C., Mulukutla, S. R., Edmundowicz, D. & Reis, S. E. 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 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Vanyukov, M. M., Maher, B. S., Devlin, B., Tarter, R. E., Kirillova, G. P., Yu, L. M. et al. Haplotypes of the monoamine oxidase genes and the risk for substance use disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 125B, 120–125 (2004).

    Article  Google Scholar 

  33. 33

    Attin, T. & Hornecker, E. Tooth brushing and oral health: how frequently and when should tooth brushing be performed? Oral Health Prev. Dent. 3, 135–140 (2005).

    CAS  PubMed  Google Scholar 

  34. 34

    Shaffer, J. R., Polk, D. E., Feingold, E., Wang, X., Cuenco, K. T., Weeks, D. E. et al. Demographic, socioeconomic, and behavioral factors affecting patterns of tooth decay in the permanent dentition: principal components and factor analyses. Community Dent. Oral Epidemiol. 41, 364–373 (2013).

    Article  Google Scholar 

  35. 35

    International HapMap Consortium The International HapMap Project. Nature 426, 789–796 (2003).

    Article  Google Scholar 

  36. 36

    Bayram, M., Deeley, K., Reis, M. F., Trombetta, V. M., Ruff, T. D., Sencak, R. C. et al. Genetic influences on dental enamel that impact caries differ between the primary and permanent dentitions. Eur. J. Oral Sci. 123, 327–334 (2015).

    CAS  Article  Google Scholar 

  37. 37

    Li, J. & Ji, L. Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity (Edinb.) 95, 221–227 (2005).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We express our gratitude to the participants of the six studies, whose contributions have enabled this work. This effort was supported by the following National Institutes of Health grants: R03-DE024264, 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 the Commonwealth of Pennsylvania Department of Health grant ME-02-384.

Author contributions

JRS and MLM conceived of the study; SE performed the statistical analyses; JRS, EF, MC and MLM designed the genotyping panel and performed the genetic data cleaning and quality control; EF, MC, MMV, BSM, RLS, MCW, SER, DWM, RJC, RJW, SML, ARV, MLM and JRS were involved in the study design, data collection and data cleaning of the parent studies; JRS wrote the manuscript; all the authors interpreted the results, revised the manuscript and approved the manuscript for publication.

Author information

Affiliations

Authors

Corresponding author

Correspondence to John R Shaffer.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on Journal of Human Genetics website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Eckert, S., Feingold, E., Cooper, M. et al. Variants on chromosome 4q21 near PKD2 and SIBLINGs are associated with dental caries. J Hum Genet 62, 491–496 (2017). https://doi.org/10.1038/jhg.2016.161

Download citation

Further reading

Search

Quick links