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.
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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.
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.
The authors declare no conflict of interest.
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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
Scientific Reports (2019)