AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Genetic Lipidomic Analyses Reveal Specific Circulating Lipids as Potentially Causal Risk Factors for Aortic Stenosis in Contrast with Coronary Artery Disease
By Yang G, Small A, Levin M et al.
Background: Aortic stenosis (AS) has shared pathophysiology with coronary artery disease (CAD), including lipid deposition, inflammation, and calcification. A recent genome-wide association study (GWAS) for AS revealed numerous loci harboring genes involved in complex lipid metabolism. Large-scale GWAS data permit a genetic approach to understanding the putative causal role of circulating lipids in the pathogenesis of AS compared with CAD. Methods: We used summary statistics of large-scale plasma lipidomic GWASs to construct genetic instruments for 639 circulating lipids. Leveraging data from the International Aortic Valve Genetics Consortium (80,823 AS cases and 2,383,572 controls) and a meta-analysis of CARDIoGRAMplusC4D Consortium and the UK Biobank (181,522 CAD cases and 984,168 controls), we conducted Mendelian randomization (MR) analyses using these genetic instruments to investigate the potential causal relationships of specific circulating lipids with the risk of AS compared with CAD. Results: Multiple circulating lipids were genetically associated with CAD risk, but all of these associations were eliminated after adjustment for apolipoprotein B (apoB). In contrast, 130 lipidomic traits were specifically associated with the risk of AS but not CAD, many of which remained significant after adjusting for apoB. Circulating lipids genetically associated with AS risk were primarily polyunsaturated fatty acid (PUFA)-enriched glycerophospholipids. Multi-response MR prioritized n-3 PUFA and specifically docosahexaenoic acid (DHA) as distinct risk factors for AS compared with CAD. Genetic and observational analyses further validated that DHA was associated with higher AS risk (OR 1.36 [95% CI, 1.26-1.47] and 1.04 [95% CI, 1.00-1.07] per 1-SD increase, respectively) and adverse aortic valve hemodynamics, but not with higher CAD risk. Proteome-wide MR identified eight plasma proteins as potential mediators of the effect of DHA on AS risk, involving phospholipid metabolism, extracellular matrix remodeling, and osteogenic differentiation. Functional experiments are currently underway to evaluate whether specific lipids increase calcification in human valvular interstitial cells. Conclusions: We found that specific circulating lipids, primarily PUFA, were genetically associated with the risk of AS but not CAD and remained significant after adjustment for apoB, suggesting that certain circulating lipid species may be in the causal pathway for AS.