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INTRODUCTION: Large observational and Mendelian randomization (MR) studies have demonstrated a strong association between both elevated LDL cholesterol (LDL-c) and triglycerides (TG) with risk of aortic stenosis (AS), although randomized trials showed no benefit of statins for AS. It consequently remains uncertain whether lipid-lowering therapies have a role to prevent or treat AS. We used a drug-target MR approach to investigate the genetically predicted effect of lipid-lowering therapies on risk of AS. METHODS AND RESULTS: We collected summary statistics for LDL-c, TG, and AS from genome-wide association studies (GWAS) including 1 320 016, 1 253 277, and 412 181 European participants from the Global Lipids Genetics Consortium and FinnGen study, respectively. We identified genetic proxies for PCSK9 inhibitors, statins, bempedoic acid, and ezetimibe as single nucleotide polymorphisms in or within 200 kb of the target genes (PCSK9, HMGCR, ACLY, and NPC1L1, respectively), which were also significantly associated with LDL-c at P 

Original publication

DOI

10.1093/ehjcvp/pvae092

Type

Journal article

Journal

Eur Heart J Cardiovasc Pharmacother

Publication Date

13/03/2025

Volume

11

Pages

136 - 142

Keywords

Aortic stenosis, Epidemiology, Genetic epidemiology, Lipid-lowering therapy, Mendelian randomization, Valvular heart disease, Humans, Mendelian Randomization Analysis, Aortic Valve Stenosis, Risk Factors, Genome-Wide Association Study, Cholesterol, LDL, Polymorphism, Single Nucleotide, Treatment Outcome, Biomarkers, Dyslipidemias, Hypolipidemic Agents, Triglycerides, Risk Assessment, Phenotype, Genetic Predisposition to Disease, Pharmacogenomic Variants, PCSK9 Inhibitors, Anticholesteremic Agents, Male, Proprotein Convertase 9, Hydroxymethylglutaryl-CoA Reductase Inhibitors