Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease.

IF 14.8 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Teresa Trenkwalder, Carlo Maj, Baravan Al-Kassou, Radoslaw Debiec, Stefanie A Doppler, Muntaser D Musameh, Christopher P Nelson, Pouria Dasmeh, Sandeep Grover, Katharina Knoll, Joonas Naamanka, Ify R Mordi, Peter S Braund, Martina Dreßen, Harald Lahm, Felix Wirth, Stephan Baldus, Malte Kelm, Moritz von Scheidt, Johannes Krefting, David Ellinghaus, Aeron M Small, Gina M Peloso, Pradeep Natarajan, George Thanassoulis, James C Engert, Line Dufresne, Andre Franke, Siegfried Görg, Matthias Laudes, Ulrike Nowak-Göttl, Mariliis Vaht, Andres Metspalu, Monika Stoll, Klaus Berger, Costanza Pellegrini, Adnan Kastrati, Christian Hengstenberg, Chim C Lang, Thorsten Kessler, Iiris Hovatta, Georg Nickenig, Markus M Nöthen, Markus Krane, Heribert Schunkert, Nilesh J Samani, Johannes Schumacher, Mart Kals, Anu Reigo, Maris Teder-Laving, Jan Gehlen, Thomas R Webb, Ann-Sophie Giel, Laura L Koebbe, Nina Feirer, Maximilian Billmann, Sundar Srinivasan, Sebastian Zimmer, Colin N A Palmer, Ling Li, Chuhua Yang, Oleg Borisov, Matti Adam, Verena Veulemans, Michael Joner, Erion Xhepa
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引用次数: 0

Abstract

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.

主动脉瓣狭窄与冠状动脉疾病的遗传风险特征截然不同
重要性:主动脉瓣狭窄(AS)和冠状动脉疾病(CAD)经常同时存在。然而,目前尚不清楚哪些遗传和心血管风险因素可能是主动脉狭窄特异性的,哪些可能是主动脉狭窄和冠状动脉疾病共有的:目的:确定与强直性脊柱炎特异性相关的遗传风险位点和心血管风险因素:这是一项针对强直性脊柱炎的全基因组关联研究(GWAS),研究对象包括欧洲主动脉瓣狭窄遗传学联合会(EGAS)(2000-2020年招募)、英国生物库(2006-2010年招募)、爱沙尼亚生物库(1997-2019年招募)和芬兰基因组(1964-2019年招募)。EGAS 的参与者来自欧洲的 7 个地点。所有参与者都有欧洲血统,所有参与者都有合并 CAD 的信息。此外,还利用心血管特征的 GWAS 数据和组织转录组数据进行了后续分析。数据分析时间为 2022 年 10 月至 2023 年 7 月:主要结果和测量:与强直性脊柱炎相关的心血管特征,并对CAD进行调整。在2个独立的强直性脊柱炎GWAS队列中进行了复制:共有 18 792 名强直性脊柱炎患者和 434 249 名对照组患者参加了这项针对 CAD 进行调整的 GWAS 研究。分析发现了17个强直性脊柱炎风险基因位点,其中5个基因位点(RNF114A、AFAP1、PDGFRA、ADAMTS7、HAO1)与强直性脊柱炎有新的、独立的关联。在所有 17 个相关位点中,有 11 个位点与强直性脊柱炎风险相关,而与 CAD 无关(ALPL、PALMD、PRRX1、RNF144A、MECOM、AFAP1、PDGFRA、IL6、TPCN2、NLRP6、HAO1)。与此相一致,该研究发现强直性脊柱炎与 CAD 之间仅存在 0.15(SE,0.05)的中度遗传相关性(P = 1.60 × 10-3)。孟德尔随机分析显示,血清磷酸盐是强直性脊柱炎的特异性风险因素,但在 CAD 中却不存在(强直性脊柱炎:几率比 [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)。孟德尔随机分析还发现,与 CAD 相比,血压、体重指数和胆固醇代谢与 AS 的关系要小得多。通路和转录组富集分析揭示了与强直性脊柱炎发展相关的生物过程和组织:这项针对 CAD 进行调整的 GWAS 研究发现,在单标记和多基因水平上,强直性脊柱炎具有独特的遗传风险特征。这些发现为未来的强直性脊柱炎研究提供了新的目标。
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来源期刊
JAMA cardiology
JAMA cardiology Medicine-Cardiology and Cardiovascular Medicine
CiteScore
45.80
自引率
1.70%
发文量
264
期刊介绍: JAMA Cardiology, an international peer-reviewed journal, serves as the premier publication for clinical investigators, clinicians, and trainees in cardiovascular medicine worldwide. As a member of the JAMA Network, it aligns with a consortium of peer-reviewed general medical and specialty publications. Published online weekly, every Wednesday, and in 12 print/online issues annually, JAMA Cardiology attracts over 4.3 million annual article views and downloads. Research articles become freely accessible online 12 months post-publication without any author fees. Moreover, the online version is readily accessible to institutions in developing countries through the World Health Organization's HINARI program. Positioned at the intersection of clinical investigation, actionable clinical science, and clinical practice, JAMA Cardiology prioritizes traditional and evolving cardiovascular medicine, alongside evidence-based health policy. It places particular emphasis on health equity, especially when grounded in original science, as a top editorial priority.
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