Background:The genomic structure that contributes to the risk of coronary artery disease (CAD) can be evaluated as a risk score of multiple variants. However, sex differences have not been fully examined in applications of genetic risk score (GRS) of CAD.Methods:Using data from the UK Biobank, we constructed a CAD-GRS based on all known loci, 3 mediating trait-based (blood pressure, lipids, and body mass index) subscores, and a genome-wide polygenic risk score based on 1.1 million variants. The differences in genetic associations with prevalent and incident CAD between men and women were investigated among 317 509 unrelated individuals of the European ancestry. We also assessed interactions with sex for 161 individual loci included in the comprehensive GRS.Results:For both prevalent and incident CAD, the associations of comprehensive and genome-wide GRSs were stronger among men than women. Using a score of 161 loci, we observed a 2.4× higher risk for incident CAD comparing men with high genetic risk to men with low genetic risk but an 80% greater risk comparing women with high genetic risk to women with low genetic risk (interaction P=0.002). Of the 3 subscores, the blood pressure–associated subscore exhibited sex differences (interaction P=0.0004 per SD increase in subscore). Analysis of individual variants identified a novel gene-sex interaction at locus 21q22.11.Conclusions:Sexual differences in genetic predisposition should be considered in future studies of CAD, and GRSs should not be assumed to perform equally well in men and women.

中文翻译：

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冠状动脉疾病遗传易感性的性别差异

背景：导致冠状动脉疾病 (CAD) 风险的基因组结构可以评估为多个变体的风险评分。然而，性别差异尚未在 CAD 的遗传风险评分 (GRS) 应用中得到充分检验。 、血脂和体重指数）子评分，以及基于 110 万个变异的全基因组多基因风险评分。在 317 509 名欧洲血统的无关个体中调查了男性和女性之间与流行和偶发 CAD 的遗传关联差异。我们还评估了综合 GRS 中包含的 161 个个体位点与性别的相互作用。结果：对于流行的和偶发的 CAD，综合和全基因组 GRS 的关联在男性中比在女性中更强。使用 161 个位点的评分，我们观察到，将具有高遗传风险的男性与具有低遗传风险的男性相比，发生 CAD 的风险高 2.4 倍，但将具有高遗传风险的女性与具有低遗传风险的女性相比，风险高 80%（相互作用P = 0.002）。在 3 个子评分中，与血压相关的子评分表现出性别差异（交互作用P = 0.0004 每增加一个 SD 子评分）。对个体变异的分析在基因座21q22.11处发现了一种新的基因-性别相互作用。结论：在未来的 CAD 研究中应考虑遗传易感性的性别差异，并且不应假设 GRSs 在男性和女性中表现相同。