: Publication 14279

Publication 14279

Title:	Distinct Genetic Risk Profile in Aortic Stenosis Compared With Coronary Artery Disease
Journal:	JAMA Cardiology
Published:	1 Feb 2025
Pubmed:	https://pubmed.ncbi.nlm.nih.gov/39504041/
DOI:	https://doi.org/10.1001/jamacardio.2024.3738

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.

66 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

Abstract

12 Keywords

66 Authors