A GENOME-wide association study (GWAS) has identified 17 genetic loci linked to the risk of developing aortic stenosis (AS), including five novel and externally validated loci. Importantly, 11 of these loci are specific to AS and show no association with coronary artery disease (CAD), highlighting the distinct genetic risk profiles and pathogenic pathways involved in each condition. Given the common co-occurrence of AS and CAD, this study aimed to disentangle their genetic bases to identify AS-specific genetic variants and cardiovascular risk factors that are not shared with CAD.
The study drew on data from four major biobanks—EGAS, UK Biobank, Estonian Biobank, and FinnGen—encompassing a participant base of 18,792 individuals with AS and 434,249 control participants, all of European ancestry. All participants had documented information on comorbid CAD status, allowing for a GWAS adjusted specifically for CAD. Data analysis spanned from October 2022 to July 2023, incorporating follow-up GWAS analyses on cardiovascular traits and transcriptomic data from relevant tissues. The study identified 17 AS risk loci, five of which (RNF114A, AFAP1, PDGFRA, ADAMTS7, HAO1) were novel findings that were independently replicated. Eleven loci (including ALPL, PALMD, PRRX1, RNF144A, MECOM, and IL6) were determined to be unique to AS and not related to CAD. The genetic correlation between AS and CAD was only moderate (0.15, SE 0.05, p = 1.60 × 10⁻³), indicating a divergence in genetic pathways. Moreover, Mendelian randomisation analyses suggested serum phosphate as an AS-specific risk factor, with an odds ratio of 1.20 (95% CI, 1.11–1.31), contrasting with its lack of association in CAD.
These findings underscore that AS pathogenesis is genetically distinct from CAD and likely involves varied biological pathways and tissue-specific gene expression patterns. Clinically, this distinction emphasises the need for tailored therapeutic strategies in AS, moving away from CAD-centric risk management in patients with AS. Future research should focus on the identified loci as potential targets for AS-specific interventions and preventive strategies. Additionally, further exploration into how serum phosphate and other AS-specific factors influence disease progression may open new avenues for treatment. This study marks a significant step towards precision medicine in AS, highlighting genetic markers that could eventually guide targeted therapies and risk assessment, specifically within AS patient populations.
Reference
Trenkwalder T et al. distinct genetic risk profile in aortic stenosis compared with coronary artery disease. JAMA Cardiol. Published online November 06, 2024. doi:10.1001/jamacardio.2024.3738
