Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Endodontics, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania.
J Endod. 2023 Oct;49(10):1276-1288. doi: 10.1016/j.joen.2023.07.018. Epub 2023 Jul 25.
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 molecular mechanisms involved. Here, we report the first genome-wide association study of AP in a large and well-characterized population.
Male and female adults (n = 932) presenting with deep caries and AP (cases), or deep caries without AP (controls) were included. Genotyping was performed using the Illumina Expanded Multi-Ethnic Genotyping Array (MEGA). Single-variant association testing was performed adjusting for sex and 5 principal components. Subphenotype association testing, analyses of genetically regulated gene expression, polygenic risk score, and phenome-wide association (PheWAS) analyses were also conducted.
Eight loci reached near genome-wide significant association with AP (P < 5 × 10); gene-focused analyses replicated 3 previously reported associations (P < 8.9 × 10). Sex-specific and subphenotype-specific analyses revealed additional significant associations with variants genome-wide. Functionally oriented gene-based analyses revealed 8 genes significantly associated with AP (P < 5 × 10), and PheWAS analysis revealed 33 phecodes associated with AP risk score (P < 3.08 × 10).
This study identified novel genes/loci contributing to AP and specific contributions to AP risk in men and women. 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）是根管感染的常见后果，导致根尖周骨吸收。已证实微生物和宿主遗传因素及其相互作用在 AP 的发展和进展中起作用。已经报道了少数几个与 AP 相关的基因变异；然而，全基因组研究的缺乏阻碍了对涉及的分子机制的理解。在这里，我们报告了在一个大型且特征良好的人群中进行的 AP 的全基因组关联研究的首次报告。
纳入患有深龋和 AP（病例）或深龋无 AP（对照）的男性和女性成年人（n=932）。使用 Illumina 扩展多民族基因分型阵列（MEGA）进行基因分型。单变体关联测试在调整性别和 5 个主要成分后进行。还进行了亚表型关联测试、遗传调控基因表达分析、多基因风险评分和表型全基因组关联（PheWAS）分析。
有 8 个基因座与 AP 接近全基因组显著相关（P<5×10）；基因焦点分析复制了 3 个先前报道的关联（P<8.9×10）。性别特异性和亚表型特异性分析揭示了全基因组范围内与变体相关的其他显著关联。面向功能的基因基分析显示 8 个基因与 AP 显著相关（P<5×10），PheWAS 分析显示 33 个 phecodes 与 AP 风险评分相关（P<3.08×10）。
本研究确定了新的基因/基因座有助于 AP，并且在男性和女性中对 AP 风险有特定的贡献。重要的是，我们确定了与 AP 风险显著相关的其他系统性疾病。我们的研究结果为宿主介导的 AP 易感性提供了强有力的证据。
