Rare genetic variants in LDLR, APOB, and PCSK9 are associated with aortic stenosis in over 650,000 people

https://doi.org/10.1007/s00392-024-02526-y

Shinwan Kany (Hamburg)1, S. Juergens (Cambridge)2, J. Rämö (Cambridge)2, S. H. Choi (Cambridge)2, X. Wang (Cambridge)2, A. Smirnov (Cambridge)3, S. Friedman (Cambridge)3, M. Maddah (Cambridge)3, S. Khurshid (Cambridge)2, P. Ellinor (Cambridge)2, J. Pirruccello (Cambridge)2

1Universitäres Herz- und Gefäßzentrum Hamburg Klinik für Kardiologie Hamburg, Deutschland; 2Broad Institute of MIT and Harvard Cardiovascular Disease Initiative Cambridge, USA; 3Broad Institute of MIT and Harvard Data Sciences Platform Cambridge, USA

 

Background: Aortic stenosis (AS) is the most common cardiac valvular disease in the developed world. Although AS is associated with substantial morbidity and mortality, current treatment options are limited to invasive procedures and reserved for severe symptomatic disease. Genetic studies have linked common variants near lipid genes to AS and cohort studies have linked diagnoses of familial hypercholesterolemia to AS. In contrast, randomized controlled trials have shown no benefit of lipid-lowering therapy in AS. 


Objectives: To assess the impact on AS and peak velocity across the aortic valve conferred by lifelong higher or lower LDL-C levels mediated by protein-disrupting variants in three clinically significant genes for LDL metabolism (LDLR, APOB, PCSK9).


Methods: We utilized 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 LOFTEE and AlphaMissense and evaluated their associations with LDL-C, diagnosed AS, and peak velocity across the aortic valve using magnetic resonance imaging. Linear regression analyses were used to assess the impact of the variant groupings on LDL levels in the UK Biobank, adjusting for sex, age, age^2, and principal components of ancestry. We then conducted Firth’s logistic regression analyses in UK Biobank and AllofUs with AS as outcome and variant status as predictor, adjusting for the same covariates; we used an inverse-variance-weighted meta-analysis to combine results.  


Results: We included 421,049 unrelated participants (5,621 with AS) in UKB and 232,170 unrelated participants (1,087 with AS) in All of Us. Across both cohorts, we identified 198 LDLRtv carriers, 1095 LDLR-AM carriers, 662 APOBtv carriers, 1422 APOB-AM carriers, 712 PCSK9tv carriers and 794 PCSK9-AM carriers. Carriers of protein-disrupting variants in LDLR had higher LDL-C (UKB: +1.10mmol/l, P=4.4e-237) and greater risk of AS (meta-analysis: OR=3.52 [95% CI 2.39–5.20], P=2.3e-10). Carriers of protein-disrupting variants in APOB or PCSK9 had lower LDL-C (UKB: -0.84 mmol/l, P<5e-324) and lower risk of AS (meta-analysis: OR=0.49 [0.31–0.75], P=0.001). Among 57,371 UKB imaging substudy participants, peak velocities across the aortic valve in magnetic resonance imaging were greater in carriers of protein-disrupting variants in LDLR (+12.2cm/s, P=1.6e-5) and lower in carriers of protein-disrupting variants in PCSK9 (-6.9cm/s, P=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.
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