Eckert Scott, Feingold Eleanor, Cooper Margaret, Vanyukov Michael M, Maher Brion S, Slayton Rebecca L, Willing Marcia C, Reis Steven E, McNeil Daniel W, Crout Richard J, Weyant Robert J, Levy Steven M, Vieira Alexandre R, Marazita Mary L, Shaffer John R
Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
J Hum Genet. 2017 Apr;62(4):491-496. doi: 10.1038/jhg.2016.161. Epub 2017 Jan 19.
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.
最近一项针对龋齿的全基因组关联研究（GWAS）确定了位于ABCG2、PKD2和SIBLING（小整合素结合配体N-连接糖蛋白）基因家族附近的4q21染色体区域。在本研究中，我们采用标签单核苷酸多态性（SNP）方法，对来自6项独立研究的13个按年龄和种族分层的样本（N = 4089）进行随访并对该区域进行精细定位。通过口腔内检查对参与者的龋齿情况进行评估，并对49个标签SNP进行基因分型，以捕获4q21基因座的大部分变异。使用线性模型来检验基因关联性，同时对性别、年龄和祖先成分进行校正。PKD2内部及附近的SNP在黑人成年人（rs17013735，P值 = 0.0009）和白人成年人（rs11938025；P值 = 0.0005；rs2725270，P值 = 0.003）的个体样本中显示出显著的关联证据。对黑人成年人样本进行的荟萃分析重现了与rs17013735的关联（P值 = 0.003），该SNP在非非洲人群中出现频率较低，这可能解释了该效应的种族特异性。除了种族特异性关联外，我们还在白人成年人中观察到PKD2上游SNP rs2725233存在基因-氟暴露交互作用效应的证据（P = 0.002）。我们的结果显示了区域重复性的证据，尽管没有单一变异能够明确解释最初的GWAS信号。因此，虽然我们将结果解释为支持4号染色体q21区域可能影响龋齿的假说，但仍需要进一步的研究。
