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
{"title":"主动脉瓣狭窄与冠状动脉疾病的遗传风险特征截然不同","authors":"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","doi":"10.1001/jamacardio.2024.3738","DOIUrl":null,"url":null,"abstract":"<p><strong>Importance: </strong>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.</p><p><strong>Objective: </strong>To identify genetic risk loci and cardiovascular risk factors with AS-specific associations.</p><p><strong>Design, setting, and participants: </strong>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.</p><p><strong>Exposures: </strong>Genetic variants.</p><p><strong>Main outcomes and measures: </strong>Cardiovascular traits associated with AS adjusted for CAD. Replication was performed in 2 independent AS GWAS cohorts.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions and relevance: </strong>This GWAS adjusted for CAD found a distinct genetic risk profile for AS at the single-marker and polygenic level. 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Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease.
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.
JAMA cardiologyMedicine-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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