A Replicated, Genome-Wide Significant Association of Aortic Stenosis With a Genetic Variant for Lipoprotein(a)
Meta-Analysis of Published and Novel Data
Trials of dedicated lipoprotein(a) (Lp(a))-lowering agents1 have refocused interest on Lp(a) as a causal risk factor for coronary artery disease (CAD), and potentially for aortic valve stenosis (AS). Elevated plasma Lp(a) concentrations have been linked to causal variants for CAD (chiefly rs10455872 and rs3798220) at the LPA locus on chromosome 6q26-27.2 The rs10455872 variant is also the sole genome-wide significant variant associated with aortic valve calcium.3 Several small studies have tentatively replicated this association, not only for aortic valve calcium, which does not necessarily cause functional impairment of the valve, but also for clinically relevant AS.3–5 However, none of these studies has definitively established that rs10455872 is associated with clinically relevant AS. We conducted a meta-analysis of associations of rs10455872 and rs3798220 variants with AS by using evidence from all published studies, together with novel data from the UK Biobank.
Approximately 152 000 UK Biobank participants had rs10455872 and rs3798220 assayed using Affymetrix Axiom arrays. All participants gave written informed consent to a protocol approved by the North West Multicentre Research Ethics Committee (UK). Genotype data were available for 112 186 eligible participants after exclusions for genomic quality control, genotype missingness, sex mismatch, relatedness, and non–British Caucasian ancestry. Minor allele frequencies were 0.08 for rs10455872 …