Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease
Authors: Trenkwalder Teresa , Maj Carlo , Al-Kassou Baravan , Debiec Radoslaw , Doppler Stefanie A. , Musameh Muntaser D. , Nelson Christopher P. , Dasmeh Pouria , Grover Sandeep , Knoll Katharina , Naamanka Joonas , Mordi Ify R. , Braund Peter S. , Dreßen Martina , Lahm Harald , Wirth Felix , Baldus Stephan , Kelm Malte , von Scheidt Moritz , Krefting Johannes , Ellinghaus David , Small Aeron M. , Peloso Gina M. , Natarajan Pradeep , Thanassoulis George , Engert James C. , Dufresne Line , Franke Andre , Görg Siegfried , Laudes Matthias , Nowak-Göttl Ulrike , Vaht Mariliis , Metspalu Andres , Stoll Monika , Berger Klaus , Pellegrini Costanza , Kastrati Adnan , Hengstenberg Christian , Lang Chim C. , Kessler Thorsten , Hovatta Iiris , Nickenig Georg , Nöthen Markus M. , Krane Markus , Schunkert Heribert , Samani Nilesh J. , Schumacher Johannes , Kals Mart , Reigo Anu , Teder-Laving Maris , Gehlen Jan , Webb Thomas R. , Giel Ann-Sophie , Koebbe Laura L. , Feirer Nina , Billmann Maximilian , Srinivasan Sundar , Zimmer Sebastian , Palmer Colin N. A. , Li Ling , Yang Chuhua , Borisov Oleg , Adam Matti , Veulemans Verena , Joner Michael , Xhepa Erion ,   TARGET Consortium; Estonian Biobank; and the European Consortium for Genetics of Aortic Stenosis (EGAS)
Published: November 2024

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.