背景:观察性研究报道了原发性醛固酮增多症(PA)与心血管结局之间的关联,包括冠状动脉疾病(CAD),充血性心力衰竭(CHF),和中风。然而,由于缺乏有关该主题的随机对照试验数据,因此建立因果关系仍然是一项挑战.因此,我们旨在调查PA和发展CAD的风险之间的因果关系,CHF,和中风。
结果:结合东亚和欧洲血统(1560例PA病例和742139例对照)进行了全基因组关联研究的跨血统荟萃分析,以鉴定与PA相关的单核苷酸变体。然后,使用确定的遗传变异作为工具变量,我们进行了2个样本孟德尔随机分析,以调查PA和意外CAD之间的因果关系,CHF,东亚和欧洲血统中的中风。总结关联结果是从大型全基因组关联研究中提取的。我们对东亚和欧洲人群的交叉血统荟萃分析确定了7个与PA风险显着相关的遗传位点,最接近前导变异的基因是CASZ1,WNT2B,HOTTIP,LSP1、TBX3、RXFP2和NDP。在东亚人口中,使用这7种PA遗传工具的合并比值比估计为CAD的1.07(95%CI,1.03-1.11),CHF为1.10(95%CI,1.01-1.20),中风为1.13(95%CI,1.09-1.18)。结果在欧洲人群中是一致的。
结论:我们的2个样本孟德尔随机研究表明,PA增加了CAD的风险,CHF,和中风。这些发现强调,早期和积极的PA筛查对于预防未来的心血管事件至关重要。
BACKGROUND: Observational studies have reported associations between primary aldosteronism (PA) and cardiovascular outcomes, including coronary artery diseases (CAD), congestive heart failure (CHF), and stroke. However, establishing causality remains a challenge due to the lack of randomized controlled trial data on this topic. We thus aimed to investigate the causal relationship between PA and the risk of developing CAD, CHF, and stroke.
RESULTS: Cross-ancestry meta-analysis of genome-wide association studies combining East Asian and European ancestry (1560 PA cases and 742 139 controls) was conducted to identify single-nucleotide variants that are associated with PA. Then, using the identified genetic variants as instrumental variables, we conducted the 2-sample Mendelian randomization analysis to investigate the causal relationship between PA and incident CAD, CHF, and stroke among both East Asian and European ancestry. Summary association results were extracted from large genome-wide association studies consortia. Our cross-ancestry meta-analysis of East Asian and European populations identified 7 genetic loci significantly associated with the risk of PA, for which the genes nearest to the lead variants were CASZ1, WNT2B, HOTTIP, LSP1, TBX3, RXFP2, and NDP. Among the East Asian population, the pooled odds ratio estimates using these 7 genetic instruments of PA were 1.07 (95% CI, 1.03-1.11) for CAD, 1.10 (95% CI, 1.01-1.20) for CHF, and 1.13 (95% CI, 1.09-1.18) for stroke. The results were consistent among the European population.
CONCLUSIONS: Our 2-sample Mendelian randomization study revealed that PA had increased risks of CAD, CHF, and stroke. These findings highlight that early and active screening of PA is critical to prevent future cardiovascular events.