Rare Genetic Variants in <i>LDLR</i>, <i>APOB</i>, and <i>PCSK9</i> Are Associated With Aortic Stenosis.

Abstract

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 (<i>LDLR</i>, <i>APOB</i>, and <i>PCSK9</i>). 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). 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 <i>LDLR</i> had higher mean LDL-C (UKB: +42.6 mg/dL; <i>P</i>=4.4e-237) and greater risk of AS (meta-analysis: odds ratio, 3.52 [95% CI, 2.39-5.20]; <i>P</i>=2.3e-10) and aortic valve replacement (meta-analysis: odds ratio, 3.78 [95% CI, 2.26-6.32]; <i>P</i>=4.0e-7). Carriers of protein-disrupting variants in <i>APOB</i> or <i>PCSK9</i> had lower mean LDL-C (UKB: -32.3 mg/dL; <i>P</i><5e-324) and lower risk of AS (meta-analysis: odds ratio, 0.49 [95% CI, 0.31-0.75]; <i>P</i>=0.001) and aortic valve replacement (meta-analysis: odds ratio, 0.54 [95% CI, 0.30-0.97]; <i>P</i>=0.04). Among 57 371 UKB imaging substudy participants, peak velocities across the aortic valve were greater in carriers of protein-disrupting variants in <i>LDLR</i> (+12.2 cm/s; <i>P</i>=1.6e-5) and lower in carriers of protein-disrupting variants in <i>PCSK9</i> (-6.9 cm/s; <i>P</i>=0.022). 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.