A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms

High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from fve genome-wide association studies (n = 13,781). We identifed 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be signifcantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide signifcant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10^-30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be signifcantly associated with Lp(a) concentrations (P = 3.47 × 10^-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to 15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one signifcant association of the TLR2 gene with Lp(a) (P = 3.4 × 10fl4). In summary, we identifed a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be signifcantly associated with Lp(a) concentrations.