Petty L E, Silva R, de Souza L Chaves, Vieira A R, Shaw D M, Below J E, Letra Ariadne
Vanderbilt University Medical Center.
University of Pittsburgh School of Dental Medicine.
Res Sq. 2023 Jan 26:rs.3.rs-2515434. doi: 10.21203/rs.3.rs-2515434/v1.
Apical periodontitis (AP) is a common consequence of root canal infection leading to periapical bone resorption. Microbial and host genetic factors, and their interactions, have been shown to play a role in AP development and progression. Variations in a few genes have been reported in association with AP, however, the lack of genome-wide studies has hindered progress in understanding the mechanisms involved in AP. Here, we report the first genome-wide association study of AP in a well-characterized population. Male and female adults (n=932) presenting with deep caries with AP (cases) or without AP (controls) were included. Genotyping was performed using the Illumina Expanded Multi-Ethnic Genotyping Array. Single-variant association testing was performed adjusting for sex and five principal components. Subphenotype association testing, analyses of genetically regulated gene expression, polygenic risk score and phenome-wide association (PheWAS) analyses were also performed. Eight loci reached near-genome-wide significant association with AP (p < 5 x 10-6); gene-focused analyses replicated three previously reported associations (p < 8.9 x 10-5). Sex-specific and subphenotype analyses revealed additional significant associations with variants genome-wide. Functionally oriented gene-based analyses revealed eight genes significantly associated with AP (p < 5 x 10-5), and PheWAS analysis revealed 33 phecodes associated with AP risk score (p < 3.08 x 10-5). This study identified novel genes/loci contributing to AP and revealed specific contributions to AP risk in males and females. Importantly, we identified additional systemic conditions significantly associated with AP risk. Our findings provide strong evidence for host-mediated effects on AP susceptibility.
根尖周炎（AP）是根管感染导致根尖周骨吸收的常见后果。微生物和宿主遗传因素及其相互作用已被证明在AP的发生和发展中起作用。已有报道称少数基因的变异与AP有关，然而，缺乏全基因组研究阻碍了对AP相关机制的理解。在此，我们报告了在一个特征明确的人群中首次进行的AP全基因组关联研究。纳入了患有深龋并伴有AP（病例）或不伴有AP（对照）的成年男性和女性（n = 932）。使用Illumina扩展多民族基因分型阵列进行基因分型。进行单变量关联测试时对性别和五个主成分进行了校正。还进行了亚表型关联测试、基因调控基因表达分析、多基因风险评分和全表型关联（PheWAS）分析。八个位点与AP达到近全基因组显著关联（p < 5 × 10⁻⁶）；基于基因的分析重复了三个先前报道的关联（p < 8.9 × 10⁻⁵）。性别特异性和亚表型分析揭示了与全基因组变异的其他显著关联。基于功能的基因分析揭示了八个与AP显著相关的基因（p < 5 × 10⁻⁵），PheWAS分析揭示了33个与AP风险评分相关的表型编码（p < 3.08 × 10⁻⁵）。本研究确定了导致AP的新基因/位点，并揭示了男性和女性对AP风险的特定贡献。重要的是，我们确定了与AP风险显著相关的其他全身状况。我们的发现为宿主介导的对AP易感性的影响提供了有力证据。
