Importance Aortic stenosis (AS) and coronary artery disease (CAD) frequently coexist. However, it is unknown which genetic and cardiovascular risk factors might be AS-specific and which could be shared between AS and CAD. Objective To identify genetic risk loci and cardiovascular risk factors with AS-specific associations. Design, Setting, and Participants This was a genomewide association study (GWAS) of AS adjusted for CAD with participants from the European Consortium for the Genetics of Aortic Stenosis (EGAS) (recruited 2000-2020), UK Biobank (recruited 2006-2010), Estonian Biobank (recruited 1997-2019), and FinnGen (recruited 1964-2019). EGAS participants were collected from 7 sites across Europe. All participants were of European ancestry, and information on comorbid CAD was available for all participants. Follow-up analyses with GWAS data on cardiovascular traits and tissue transcriptome data were also performed. Data were analyzed from October 2022 to July 2023. Exposures Genetic variants. Main Outcomes and Measures Cardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts. Results A total of 18 792 participants with AS and 434 249 control participants were included in this GWAS adjusted for CAD. The analysis found 17 AS risk loci, including 5 loci with novel and independently replicated associations (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1). Of all 17 associated loci, 11 were associated with risk specifically for AS and were not associated with CAD (ALPL, PALMD, PRRX1, RNF144A, MECOM, AFAP1, PDGFRA, IL6, TPCN2, NLRP6, HAO1). Concordantly, this study revealed only a moderate genetic correlation of 0.15 (SE, 0.05) between AS and CAD (P = 1.60 × 10-3). Mendelian randomization revealed that serum phosphate was an AS-specific risk factor that was absent in CAD (AS: odds ratio [OR], 1.20; 95% CI, 1.11-1.31; P = 1.27 × 10-5; CAD: OR, 0.97; 95% CI 0.94-1.00; P = .04). Mendelian randomization also found that blood pressure, body mass index, and cholesterol metabolism had substantially lesser associations with AS compared with CAD. Pathway and transcriptome enrichment analyses revealed biological processes and tissues relevant for AS development. Conclusions and Relevance This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. These findings provide new targets for future AS research.

中文翻译：

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与冠状动脉疾病相比，主动脉瓣狭窄的遗传风险特征不同。


重要性 主动脉瓣狭窄 （AS） 和冠状动脉疾病 （CAD） 经常共存。然而，尚不清楚哪些遗传和心血管危险因素可能是 AS 特异性的，哪些可能在 AS 和 CAD 之间共享。目的 确定具有 AS 特异性关联的遗传风险位点和心血管危险因素。设计、设置和参与者这是一项针对 CAD 调整的 AS 全基因组关联研究 （GWAS），参与者来自欧洲主动脉瓣狭窄遗传学联盟 （EGAS）（2000-2020 年招募）、英国生物样本库（2006-2010 年招募）、爱沙尼亚生物样本库（1997-2019 年招募）和 FinnGen（1964-2019 年招募）。EGAS 参与者来自欧洲的 7 个地点。所有参与者均具有欧洲血统，所有参与者均可获得共病 CAD 的信息。还对心血管性状的 GWAS 数据和组织转录组数据进行了随访分析。数据分析了 2022 年 10 月至 2023 年 7 月的数据。暴露 遗传变异。主要结局和指标 与 AS 相关的心血管特征经过 CAD 调整。在 2 个独立的 AS GWAS 队列中进行复制。结果 共有 18 792 名 AS 参与者和 434 249 名对照参与者被纳入该 GWAS 调整后的 CAD。分析发现 17 个 AS 风险位点，包括 5 个具有新颖且独立重复关联的位点 （RNF114A、AFAP1、PDGFRA、ADAMTS7、HAO1）。在所有 17 个相关基因座中，11 个与 AS 特异性风险相关，与 CAD 无关 （ALPL、PALMD、PRRX1、RNF144A、MECOM、AFAP1、PDGFRA、IL6、TPCN2、NLRP6、HAO1）。一致地，这项研究揭示了 AS 和 CAD 之间只有 0.15 （SE， 0.05） 的中等遗传相关性 （P = 1.60 × 10-3）。 孟德尔随机化显示，血清磷酸盐是 CAD 中不存在的 AS 特异性危险因素 （AS：比值比 [OR]，1.20;95% CI，1.11-1.31;P = 1.27 × 10-5;加元：OR，0.97;95% CI 0.94-1.00;P = .04）。孟德尔随机化还发现，与 CAD 相比，血压、体重指数和胆固醇代谢与 AS 的相关性要小得多。通路和转录组富集分析揭示了与 AS 发展相关的生物过程和组织。结论和相关性：针对 CAD 调整的 GWAS 在单标记和多基因水平上发现了 AS 的不同遗传风险特征。这些发现为未来的 AS 研究提供了新的目标。