Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Bristol Dental School, University of Bristol, Bristol BS1 2LY, UK.
Genes (Basel). 2022 Dec 24;14(1):59. doi: 10.3390/genes14010059.
Although genetics affects early childhood caries (ECC) risk, few studies have focused on finding its specific genetic determinants. Here, we performed genome-wide association studies (GWAS) in five cohorts of children (aged up to 5 years, total N = 2974, cohorts: Center for Oral Health Research in Appalachia cohorts one and two [COHRA1, COHRA2], Iowa Fluoride Study, Iowa Head Start, Avon Longitudinal Study of Parents and Children [ALSPAC]) aiming to identify genes with potential roles in ECC biology. We meta-analyzed the GWASs testing ~3.9 million genetic variants and found suggestive evidence for association at genetic regions previously associated with caries in primary and permanent dentition, including the β-defensin anti-microbial proteins. We then integrated the meta-analysis results with gene expression data in a transcriptome-wide association study (TWAS). This approach identified four genes whose genetically predicted expression was associated with ECC (p-values < 3.09 × 10−6; CDH17, TAS2R43, SMIM10L1, TAS2R14). Some of the strongest associations were with genes encoding members of the bitter taste receptor family (TAS2R); other members of this family have previously been associated with caries. Of note, we identified the receptor encoded by TAS2R14, which stimulates innate immunity and anti-microbial defense in response to molecules released by the cariogenic bacteria, Streptococcus mutans and Staphylococcus aureus. These findings provide insight into ECC genetic architecture, underscore the importance of host-microbial interaction in caries risk, and identify novel risk genes.
尽管遗传学影响幼儿龋（ECC）的风险，但很少有研究关注寻找其特定的遗传决定因素。在这里，我们对五个儿童队列（年龄最大为 5 岁，总 N = 2974 人，队列：阿巴拉契亚口腔健康研究中心队列 1 和 2 [COHRA1、COHRA2]、爱荷华州氟化物研究、爱荷华州 Head Start、雅芳纵向研究父母和孩子 [ALSPAC]）进行了全基因组关联研究（GWAS），旨在确定具有 ECC 生物学潜在作用的基因。我们对 GWAS 进行了荟萃分析，检测了约 390 万个遗传变异，发现了先前与原发性和永久性牙齿龋病相关的遗传区域的关联的提示性证据，包括β-防御素抗菌蛋白。然后，我们将荟萃分析结果与转录组全基因组关联研究（TWAS）中的基因表达数据进行整合。这种方法确定了四个基因，其遗传预测表达与 ECC 相关（p 值 < 3.09×10−6；CDH17、TAS2R43、SMIM10L1、TAS2R14）。一些最强的关联是与编码苦味受体家族成员的基因（TAS2R）相关的基因；该家族的其他成员以前与龋病有关。值得注意的是，我们确定了由 TAS2R14 编码的受体，该受体对变形链球菌和金黄色葡萄球菌释放的分子产生反应，刺激先天免疫和抗菌防御。这些发现提供了对 ECC 遗传结构的深入了解，强调了宿主-微生物相互作用在龋病风险中的重要性，并确定了新的风险基因。
