Researchers pinpointed 17 genetic loci associated with aortic stenosis, with 11 of these loci showing no link to coronary artery disease, according to a recent study.

In the genome-wide association study, published in JAMA Cardiology, the researchers identified genetic loci that suggested distinct pathophysiologic pathways for aortic stenosis (AS) compared with coronary artery disease (CAD). This study, involving 18,792 patients with AS and 434,249 controls, uncovered 17 AS-associated loci, with 5 newly discovered loci—RNF114A, AFAP1, PDGFRA, ADAMTS7, and HAO1—that were validated independently. Among the 17 loci, 11 were found to be specific to AS, demonstrating no association with CAD and indicating only a moderate genetic overlap (genetic correlation = 0.15, SE = 0.05, P = 1.60 × 10−3).

Mendelian randomization analyses revealed serum phosphate as an AS-specific risk factor, showing a significant association (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.11−1.31, P = 1.27 × 10−5) absent in CAD (OR = 0.97, 95% CI = 0.94−1.00, P = .04). Other cardiovascular risk factors such as blood pressure, body mass index, and cholesterol showed weaker associations with AS than CAD, corroborating prior findings where interventions targeting these factors demonstrated limited efficacy in AS progression.

Pathway enrichment analysis showed AS-specific biological processes, including cell differentiation, immune response, and calcification; whereas tissue transcriptome analysis highlighted significant gene expression patterns in coronary artery, aorta, visceral adipose tissue, and skeletal muscle, distinguishing AS pathology from CAD.

The findings suggested that AS development may involve genetic pathways distinct from those of CAD. The identification of AS-specific genetic risk factors and pathways may guide future research exploring treatment strategies tailored to AS, distinct from CAD-focused interventions.

Full disclosures can be found in the published study.