Rare Genetic Variants in , , and Are Associated With Aortic Stenosis.

Background: Despite a proposed causal role for LDL-C (low-density lipoprotein cholesterol) in aortic stenosis (AS), randomized controlled trials of lipid-lowering therapy failed to prevent severe AS. We aimed to assess the impact on AS and peak velocity across the aortic valve conferred by lifelong alterations in LDL-C levels mediated by protein-disrupting variants in 3 clinically significant genes for LDL (low-density lipoprotein) metabolism (, , and ).

Methods: We used sequencing data and electronic health records from UK Biobank (UKB) and All of Us and magnetic resonance imaging data from UKB. We identified predicted protein-disrupting variants with the Loss Of Function Transcript Effect Estimator (LOFTEE) and AlphaMissense algorithms and evaluated their associations with LDL-C and peak velocity across the aortic valve (UK Biobank), as well as diagnosed AS and aortic valve replacement (UK Biobank and All of Us).

Results: We included 421 049 unrelated participants (5621 with AS) in UKB and 195 519 unrelated participants (1087 with AS) in All of Us. Carriers of protein-disrupting variants in had higher mean LDL-C (UKB: +42.6 mg/dL; =4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39-5.20]; =2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26-6.32]; =4.0e-7). Carriers of protein-disrupting variants in or had lower mean LDL-C (UKB: -32.3 mg/dL; <5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31-0.75]; =0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30-0.97]; =0.04). Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in (+12.2 cm/s; =1.6e-5) and lower in carriers of protein-disrupting variants in (-6.9 cm/s; =0.022).

Conclusions: Rare genetic variants that confer lifelong higher or lower LDL-C levels are associated with substantially increased and decreased risk of AS, respectively. Early and sustained lipid-lowering therapy may slow or prevent AS development.