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Comment
. 2025 Feb 1;10(2):145-154.
doi: 10.1001/jamacardio.2024.3738.

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

Teresa Trenkwalder  1   2 , Carlo Maj  3 , Baravan Al-Kassou  4 , Radoslaw Debiec  5   6 , Stefanie A Doppler  7   8 , Muntaser D Musameh  5   6 , Christopher P Nelson  5   6 , Pouria Dasmeh  3 , Sandeep Grover  3 , Katharina Knoll  1   2 , Joonas Naamanka  9 , Ify R Mordi  10 , Peter S Braund  5   6 , Martina Dreßen  7   8 , Harald Lahm  7   8 , Felix Wirth  7   8 , Stephan Baldus  11 , Malte Kelm  12 , Moritz von Scheidt  1   2 , Johannes Krefting  1   2 , David Ellinghaus  13 , Aeron M Small  14   15   16 , Gina M Peloso  17 , Pradeep Natarajan  15   16   18 , George Thanassoulis  19   20 , James C Engert  19   20 , Line Dufresne  20 , Andre Franke  13 , Siegfried Görg  21 , Matthias Laudes  22 , Ulrike Nowak-Göttl  23 , Mariliis Vaht  24 , Andres Metspalu  24 , Monika Stoll  25 , Klaus Berger  26 , Costanza Pellegrini  1   2 , Adnan Kastrati  1   2 , Christian Hengstenberg  27 , Chim C Lang  10 , Thorsten Kessler  1   2 , Iiris Hovatta  9 , Georg Nickenig  4 , Markus M Nöthen  28 , Markus Krane  2   7   8   29 , Heribert Schunkert  1   2 , Nilesh J Samani  5   6 , Johannes Schumacher  3   28 , Mart Kals  24 , Anu Reigo  24 , Maris Teder-Laving  24 , Jan Gehlen  3 , Thomas R Webb  5   6 , Ann-Sophie Giel  3 , Laura L Koebbe  3 , Nina Feirer  7   8 , Maximilian Billmann  28 , Sundar Srinivasan  10 , Sebastian Zimmer  4 , Colin N A Palmer  10 , Ling Li  1 , Chuhua Yang  1 , Oleg Borisov  30 , Matti Adam  11 , Verena Veulemans  12 , Michael Joner  1   2 , Erion Xhepa  1   2 ; TARGET Consortium; Estonian Biobank; and the European Consortium for Genetics of Aortic Stenosis (EGAS)
Affiliations
Comment

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

Teresa Trenkwalder et al. JAMA Cardiol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Baldus reported personal fees and grants from Abbott and Edwards Lifesciences outside the submitted work. Dr Kelm reported grants from Edwards Lifesciences, Microvision Medical, B. Braun, and Mars Scientific Advisory Council and personal fees from Bayer and Abiomed outside the submitted work. Dr Borisov reported grants from Deutsche Forschungsgemeinschaft during the conduct of the study. Dr Peloso reported grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Natarajan reported grants from Allelica, Amgen, Apple, AstraZeneca, Boston Scientific, Novartis, and Roche/Genentech; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, GV Pharmaceutical, HeartFlow, Magnet Biomedicine, Merck, Novartis, Roche/Genentech, Esperion Therapeutics, MyOme, Preciseli, TenSixteen Bio; owning stock in TenSixteen Bio, MyOme, and Preciseli; and spousal employment from Vertex Pharmaceuticals outside the submitted work. Dr Thanassoulis reported personal fees from Amgen, Sanofi, Novartis, HLS Therapeutics, and New Amsterdam outside the submitted work. Dr Laudes reported grants from Bundesministerium für Bildung und Forschung during the conduct of the study. Dr Veulemanns reported personal fees from Edwards Lifesciences and Boston Scientific and grants from Medtronic outside the submitted work. Dr Berger reported grants from German Ministry of Education and Research and research support from the German Centre for Cardiovascular Diseases during the conduct of the study. Dr Joner reported personal fees from Abbott, Alchimedics, AstraZeneca, Biotronik, Boston Scientific, Cardiac Dimensions, Edwards Lifesciences, ReCor, Shockwave, TriCares, and Veryan and grants from Cardiac Dimensions, Edwards Lifesciences, and Infraredx outside the submitted work. Dr Kastrati reported a patent for PCT/EP2021/053116 pending (from his institution). Dr Lang reported grants from Applied Therapeutics, Anacardia, Boehringer Ingelheim, Moderna, Novartis, AstraZeneca, Roche Diagnostics, and Novo Nordisk outside the submitted work. Dr Nöthen reported grants from Deutsche Forschungsgemeinschaft during the conduct of the study; receiving personal fees from HMG Systems Engineering, Medical-Scientific Editorial Office of the Deutsches Ärzteblatt, European Research Council, and EVERIS Belgique in a project of the European Commission; and receiving salary from and owning shares in Life & Brain outside the submitted work. Dr Krane reported personal fees from Sanamedi, EVOTEC, Moderna, Peter Duschek, Medtronic, and Terumo and the grants from German Research Foundation outside the submitted work. Dr Schunkert reported personal fees from Merck Sharp & Dohme, Amgen, Bayer Vital, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Servier, Bristol Myers Squibb, Sanofi-Aventis, Synlab, AstraZeneca, Pfizer, Sciarc, and CTI BioPharma outside the submitted work. No other disclosures were reported.

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References

    1. Osnabrugge RL, Mylotte D, Head SJ, et al. . Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. J Am Coll Cardiol. 2013;62(11):1002-1012. doi:10.1016/j.jacc.2013.05.015 - DOI - PubMed
    1. Small AM, Peloso GM, Linefsky J, et al. ; VA Million Veteran Program . Multiancestry genome-wide association study of aortic stenosis identifies multiple novel loci in the Million Veteran Program. Circulation. 2023;147(12):942-955. doi:10.1161/CIRCULATIONAHA.122.061451 - DOI - PMC - PubMed
    1. Yu Chen H, Dina C, Small AM, et al. ; Regeneron Genetics Center . Dyslipidemia, inflammation, calcification, and adiposity in aortic stenosis: a genome-wide study. Eur Heart J. 2023;44(21):1927-1939. doi:10.1093/eurheartj/ehad142 - DOI - PMC - PubMed
    1. Newby DE, Cowell SJ, Boon NA. Emerging medical treatments for aortic stenosis: statins, angiotensin converting enzyme inhibitors, or both? Heart. 2006;92(6):729-734. doi:10.1136/hrt.2005.066852 - DOI - PMC - PubMed
    1. Rajamannan NM, Bonow RO, Rahimtoola SH. Calcific aortic stenosis: an update. Nat Clin Pract Cardiovasc Med. 2007;4(5):254-262. doi:10.1038/ncpcardio0827 - DOI - PubMed