Abstract Body (Do not enter title and authors here): Introduction: Large observational and Mendelian randomization (MR) studies have demonstrated a strong association between elevated triglycerides (TG) and risk of aortic stenosis (AS). However, at present there remains no evidence for the use of lipid-lowering therapies to prevent or treat AS. To address this gap, we used a drug target MR approach to investigate whether emerging TG lowering therapies may reduce the risk of AS.

Methods: We collected summary statistics for TG levels and AS from genome-wide association studies including 1,253,277 and 653,867 European participants, respectively. We first performed conventional MR techniques to investigate a causal relationship between TG levels and AS risk. Next, we identified genetic proxies for the TG-lowering therapies fenofibrate, volanesorsen and evinacumab as single nucleotide polymorphisms (SNPs) within 200kb of the target genes (PPARA, APOC3 and ANGPTL3, respectively) which were also significantly associated with TG at p<5x10^-8 and clumped using threshold r²<0.1. Inverse-variance weighted (IVW) was the primary analysis method. We then performed sensitivity analyses including weighted-median and MR-Egger. Additional outlier-exclusion analyses were performed using MR-PRESSO and Cook’s distance. Finally, we completed sensitivity analyses using a more stringent clumping threshold of r²<0.01.

Results: Consistent with previous findings we found genetically predicted TG levels were significantly associated with increased risk of AS (IVW: OR 1.28 per standard deviation increase in genetically predicted log TG level, 95% CI 1.18-1.39, p<0.0001). We further found that genetically proxied volanesorsen was significantly associated with reduced risk of AS (OR 0.54, 95% CI 0.39-0.75, p=0.0002), which was robust in all sensitivity analyses. We did not find evidence of a causal relationship between genetically proxied fenofibrate (IVW: OR 0.50, 95% CI 0.09-2.76, p=0.43) or evinacumab (IVW: OR 1.03, 95% CI 0.73-1.44, p=0.88) and risk of AS.

Conclusions: Genetically proxied APOC3 inhibition, but not PPARA or ANGPTL3, was robustly associated with reduced risk of AS. This suggests that APOC3 inhibition may be a therapeutic opportunity for AS management and warrants further research in the clinical trial setting.