Shrestha P, Graff M, Gu Y, Wang Y, Avery C L, Ginnis J, Simancas-Pallares M A, Ferreira Zandoná A G, Alotaibi R N, Orlova E, Ahn H S, Nguyen K N, Highland H M, Lin D Y, Preisser J S, Slade G D, Marazita M L, North K E, Divaris K
Department of Pediatric Dentistry and Dental Public Health, Adams School of Dentistry, University of North Carolina at Chapel Hill, NC, USA.
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, USA.
J Dent Res. 2025 Mar;104(3):280-289. doi: 10.1177/00220345241291528. Epub 2024 Dec 19.
Early childhood caries (ECC) is the most common noncommunicable childhood disease-an important health problem with known environmental and social/behavioral influences lacking consensus genetic risk loci. To address this knowledge gap, we conducted a genome-wide association study of ECC in a multiancestry population of U.S. preschool-age children ( = 6,103) ages 3 to 5 y participating in a community-based epidemiologic study of early childhood oral health. Calibrated examiners used International Caries Detection and Assessment System criteria to measure ECC; the primary trait was the number of primary tooth surfaces with caries experience (i.e., dmfs index). We estimated heritability and concordance rates and conducted genome-wide association analyses to estimate overall genetic effects as well as stratified by sex, household water fluoride, and dietary sugar and leveraged combined gene/gene-environment effects using 2-degree-of-freedom joint tests. Common genetic variants explained 24% of ECC phenotypic variance among unrelated individuals, while concordance rates were 0.64 (95% confidence interval [CI] = 0.42-0.79) among monozygotic twins and 0.44 (95% CI = 0.34-0.53) among first-degree relatives. Across all analyses, we identified 21 novel nonoverlapping genome-wide significant loci ( < 5 × 10) and 1 genome-wide significant gene () associated with ECC. The taste receptor activity gene set, with known roles in chemosensing, bacterial recognition, and innate immunity in the oral cavity, was strongly associated with ECC. While no locus remained significant after studywise multiple-testing correction, 3 loci were nominally significant ( < 0.05) and directionally consistent in external cohorts of 285,248 adults (rs1442369, and rs74606067, ) and 18,994 children (rs71327750, ). Meanwhile, the strongest marker known to be associated with adult caries (rs1122171, tagging the long noncoding RNA ) was nominally significant ( = 0.01) and directionally consistent with ECC in our study. Taken together, the results of this study add to the genomics knowledge base for early childhood caries, offer several plausible candidates for future mechanistic studies, and underscore the importance of accounting for sex and pertinent environmental exposures in genetic investigations.
幼儿龋（ECC）是最常见的儿童非传染性疾病——这是一个重要的健康问题，已知其受环境及社会/行为影响，但缺乏公认的遗传风险位点。为填补这一知识空白，我们在美国3至5岁学龄前儿童的多祖先群体（n = 6103）中开展了一项ECC全基因组关联研究，这些儿童参与了一项基于社区的幼儿口腔健康流行病学研究。经过校准的检查人员使用国际龋病检测与评估系统标准来测量ECC；主要性状是有龋病经历的乳牙牙面数量（即dmfs指数）。我们估计了遗传度和一致性率，并进行全基因组关联分析以估计总体遗传效应，以及按性别、家庭饮用水氟含量和膳食糖进行分层分析，并使用双自由度联合检验来利用基因/基因 - 环境综合效应。常见遗传变异解释了无关个体中ECC表型变异的24%，而单卵双胞胎之间的一致性率为0.64（95%置信区间[CI] = 0.42 - 0.79），一级亲属之间的一致性率为0.44（95% CI = 0.34 - 0.53）。在所有分析中，我们鉴定出21个新的非重叠全基因组显著位点（p < 5×10⁻⁸）和1个与ECC相关的全基因组显著基因（p < 5×10⁻⁸）。味觉受体活性基因集在口腔化学传感、细菌识别和先天免疫中具有已知作用，与ECC密切相关。虽然在研究层面的多重检验校正后没有位点仍然显著，但有3个位点在285248名成年人（rs1442369、rs74606067和rs71327750）和18994名儿童（rs71327750）的外部队列中名义上显著（p < 0.05）且方向一致。同时，已知与成人龋相关的最强标记（rs1122171，标记长链非编码RNA）在我们的研究中名义上显著（p = 0.01）且与ECC方向一致。综上所述，本研究结果增加了幼儿龋的基因组学知识库，为未来的机制研究提供了几个合理的候选基因，并强调了在基因研究中考虑性别和相关环境暴露的重要性。
