ImportancePolygenic risk scores (PRSs) have proven to be as strong as or stronger than established clinical risk factors for many cardiovascular phenotypes. Whether this is true for aortic stenosis remains unknown.ObjectiveTo develop a novel aortic stenosis PRS and compare its aortic stenosis risk estimation to established clinical risk factors.Design, Setting, and ParticipantsThis was a longitudinal cohort study using data from the Million Veteran Program (MVP; 2011-2020), UK Biobank (2006-2010), and 6 Thrombolysis in Myocardial Infarction (TIMI) trials, including DECLARE-TIMI 58 (2013-2018), FOURIER (TIMI 59; 2013-2017), PEGASUS-TIMI 54 (2010-2014), SAVOR-TIMI 53 (2010-2013), SOLID-TIMI 52 (2009-2014), and ENGAGE AF-TIMI 58 (2008-2013), which were a mix of population-based and randomized clinical trials. Individuals from UK Biobank and the MVP meeting a previously validated case/control definition for aortic stenosis were included. All individuals from TIMI trials were included unless they had a documented preexisting aortic valve replacement. Analysis took place from January 2022 to December 2023.ExposuresPRS for aortic stenosis (developed using data from MVP and validated in UK Biobank) and other previously validated cardiovascular PRSs, defined either as a continuous variable or as low (bottom 20%), intermediate, and high (top 20%), and clinical risk factors.Main OutcomesAortic stenosis (defined using International Classification of Diseases or Current Procedural Terminology codes in UK Biobank and MVP or safety event data in the TIMI trials).ResultsThe median (IQR) age in MVP was 67 (57-73) years, and 135 140 of 147 104 participants (92%) were male. The median (IQR) age in the TIMI trials was 66 (54-78) years, and 45 524 of 59 866 participants (71%) were male. The best aortic stenosis PRS incorporated 5 170 041 single-nucleotide variants and was associated with aortic stenosis in both the MVP testing sample (odds ratio, 1.41; 95% CI, 1.37-1.45 per 1 SD PRS; P = 4.6 × 10−116) and TIMI trials (hazard ratio, 1.44; 95% CI, 1.27-1.62 per 1 SD PRS; P = 3.2 × 10−9). Among genetic and clinical risk factors, the aortic stenosis PRS performed comparably to most risk factors besides age, and within a given age range, the combination of clinical and genetic risk factors was additive, providing a 3- to 4-fold increased gradient of risk of aortic stenosis. However, the addition of the aortic stenosis PRS to a model including clinical risk factors only improved risk discrimination of aortic stenosis by 0.01 to 0.02 (C index in MVP: 0.78 with clinical risk factors, 0.79 with risk factors and aortic stenosis PRS; C index in TIMI: 0.71 with clinical risk factors, 0.73 with risk factors and aortic stenosis PRS).ConclusionsThis study developed and validated 1 of the first aortic stenosis PRSs. While aortic stenosis genetic risk was independent from clinical risk factors and performed comparably to all other risk factors besides age, genetic risk resulted in only a small improvement in overall aortic stenosis risk discrimination beyond age and clinical risk factors. This work sets the stage for further development of an aortic stenosis PRS.

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用于主动脉瓣狭窄风险评估的新型多基因风险评分和已建立的临床风险因素

重要性多基因风险评分 (PRS) 已被证明与许多心血管表型的既定临床风险因素一样强，甚至更强。主动脉瓣狭窄是否属实仍不得而知。目的开发一种新型主动脉瓣狭窄 PRS，并将其主动脉瓣狭窄风险评估与已确定的临床风险因素进行比较。设计、设置和参与者这是一项纵向队列研究，使用来自百万退伍军人计划 (MVP) 的数据; 2011-2020）、英国生物银行（2006-2010）和 6 项心肌梗塞溶栓 (TIMI) 试验，包括 DECLARE-TIMI 58 (2013-2018)、FOURIER (TIMI 59; 2013-2017)、PEGASUS-TIMI 54 (2010-2014)、SAVOR-TIMI 53 (2010-2013)、SOLID-TIMI 52 (2009-2014) 和 ENGAGE AF-TIMI 58 (2008-2013)，这些都是基于人群的随机临床试验。来自英国生物银行和 MVP 的个人符合先前验证的主动脉瓣狭窄病例/对照定义。TIMI 试验中的所有个体都被纳入其中，除非他们有预先存在的主动脉瓣置换术记录。分析于 2022 年 1 月至 2023 年 12 月进行。 主动脉瓣狭窄的暴露 PRS（使用 MVP 的数据开发并在英国生物银行验证）和其他先前验证的心血管 PRS，定义为连续变量或低（底部 20%）、中、和高（前 20%）和临床危险因素。主要结果主动脉瓣狭窄（使用定义国际疾病分类或者当前的程序术语结果 MVP 的中位 (IQR) 年龄为 67 (57-73) 岁，147 104 名参与者中有 135 140 名 (92%) 为男性。TIMI 试验的中位年龄 (IQR) 为 66 (54-78) 岁，59 866 名参与者中有 45 524 名 (71%) 为男性。最佳主动脉瓣狭窄 PRS 包含 5 170 041 个单核苷酸变异，并且与 MVP 测试样本中的主动脉瓣狭窄相关（比值比，1.41；95% CI，每 1 SD PRS 1.37-1.45；磷= 4.6 × 10−116）和 TIMI 试验（风险比，1.44；95% CI，每 1 SD PRS 1.27-1.62；磷= 3.2 × 10−9）。在遗传和临床危险因素中，主动脉瓣狭窄PRS的表现与除年龄外的大多数危险因素相当，并且在给定的年龄范围内，临床和遗传危险因素的组合是相加的，使风险梯度增加3至4倍主动脉瓣狭窄。然而，将主动脉瓣狭窄 PRS 添加到包含临床危险因素的模型中，仅将主动脉瓣狭窄的风险辨别力提高了 0.01 至 0.02（MVP 中的 C 指数：临床危险因素为 0.78，危险因素和主动脉瓣狭窄 PRS 为 0.79；C 指数TIMI 中：临床危险因素为 0.71，危险因素和主动脉瓣狭窄 PRS 为 0.73。 结论 本研究开发并验证了第一个主动脉瓣狭窄 PRS。虽然主动脉瓣狭窄的遗传风险独立于临床风险因素，并且与除年龄之外的所有其他风险因素的表现相当，但遗传风险仅导致除年龄和临床风险因素之外的总体主动脉瓣狭窄风险辨别力的微小改善。这项工作为主动脉瓣狭窄 PRS 的进一步发展奠定了基础。