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

Autor:	Trenkwalder T; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Maj C; Institute of Human Genetics, Philipps University of Marburg, Marburg, Germany., Al-Kassou B; Department of Medicine II, Heart Center Bonn, University of Bonn and University Hospital Bonn, Bonn, Germany., Debiec R; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.; National Institute for Health and Care Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom., Doppler SA; Department of Cardiovascular Surgery, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany.; Institute Insure, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany., Musameh MD; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.; National Institute for Health and Care Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom., Nelson CP; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.; National Institute for Health and Care Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom., Dasmeh P; Institute of Human Genetics, Philipps University of Marburg, Marburg, Germany., Grover S; Institute of Human Genetics, Philipps University of Marburg, Marburg, Germany., Knoll K; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Naamanka J; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Mordi IR; Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom., Braund PS; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.; National Institute for Health and Care Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom., Dreßen M; Department of Cardiovascular Surgery, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany.; Institute Insure, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany., Lahm H; Department of Cardiovascular Surgery, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany.; Institute Insure, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany., Wirth F; Department of Cardiovascular Surgery, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany.; Institute Insure, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany., Baldus S; Department of Cardiology, Faculty of Medicine, Heart Center, University of Cologne, Cologne, Germany., Kelm M; Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany., von Scheidt M; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Krefting J; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Ellinghaus D; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany., Small AM; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts.; Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Peloso GM; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts., Natarajan P; Center for Genomic Medicine and Cardiovascular Research Center, Massachusetts General Hospital, Boston.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Department of Medicine, Harvard Medical School, Boston, Massachusetts., Thanassoulis G; Division of Experimental Medicine, McGill University, Montreal, Canada.; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada., Engert JC; Division of Experimental Medicine, McGill University, Montreal, Canada.; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada., Dufresne L; Preventive and Genomic Cardiology, McGill University Health Centre and Research Institute, Montreal, Canada., Franke A; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany., Görg S; Institute of Transfusion Medicine, University Hospital of Schleswig-Holstein, Kiel, Germany., Laudes M; Institute for Diabetes and Clinical Metabolic Research, University Medical Center Schleswig-Holstein, Kiel, Germany., Nowak-Göttl U; Thrombosis and Hemostasis Unit, Institute of Clinical Chemistry, University Hospital Kiel, Kiel, Germany., Vaht M; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Metspalu A; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Stoll M; Institute of Human Genetics, Division of Genetic Epidemiology, University of Muenster, Muenster, Germany., Berger K; Institute of Epidemiology and Social Medicine, University of Münster, Munster, Germany., Pellegrini C; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Kastrati A; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Hengstenberg C; Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria., Lang CC; Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom., Kessler T; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Hovatta I; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Nickenig G; Department of Medicine II, Heart Center Bonn, University of Bonn and University Hospital Bonn, Bonn, Germany., Nöthen MM; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Krane M; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany.; Department of Cardiovascular Surgery, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany.; Institute Insure, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany.; Yale School of Medicine, Division of Cardiac Surgery, Department of Surgery, New Haven, Connecticut., Schunkert H; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Samani NJ; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.; National Institute for Health and Care Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom., Schumacher J; Institute of Human Genetics, Philipps University of Marburg, Marburg, Germany.; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Kals M; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Reigo A; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Teder-Laving M; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia., Gehlen J; Institute of Human Genetics, Philipps University of Marburg, Marburg, Germany., Webb TR; Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom.; National Institute for Health and Care Research Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom., Giel AS; Institute of Human Genetics, Philipps University of Marburg, Marburg, Germany., Koebbe LL; Institute of Human Genetics, Philipps University of Marburg, Marburg, Germany., Feirer N; Department of Cardiovascular Surgery, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany.; Institute Insure, German Heart Center Munich, School of Medicine and Health, TUM University Hospital, Technical University of Munich, Munich, Germany., Billmann M; Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany., Srinivasan S; Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom., Zimmer S; Department of Medicine II, Heart Center Bonn, University of Bonn and University Hospital Bonn, Bonn, Germany., Palmer CNA; Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom., Li L; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany., Yang C; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany., Borisov O; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany., Adam M; Department of Cardiology, Faculty of Medicine, Heart Center, University of Cologne, Cologne, Germany., Veulemans V; Department of Cardiology, Pulmonology and Vascular Medicine, Medical Faculty of the Heinrich Heine University, Düsseldorf, Germany., Joner M; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany., Xhepa E; Technical University of Munich, School of Medicine and Health, Department of Cardiovascular Diseases, German Heart Centre Munich, TUM University Hospital, Munich, Germany.; German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany.
Jazyk:	angličtina
Zdroj:	JAMA cardiology [JAMA Cardiol] 2024 Nov 06. Date of Electronic Publication: 2024 Nov 06.
DOI:	10.1001/jamacardio.2024.3738
Abstrakt:	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.
Databáze:	MEDLINE
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