Abstract
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 five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly 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 significant 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 significantly 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 significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10−4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.
Highlights
High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes
The clinical impact of the SNPs found to be associated with Lp(a) concentrations was underscored by the observation that seven SNPs were even significantly associated with coronary artery disease (CAD) on a genome-wide scale in the CARDIoGRAMplusC4D consortium
Our findings add to the growing evidence that lowering Lp(a) levels might be a valuable strategy to reduce the risk of CAD [61]. This is even more important in the light of emerging therapies, such as PCSK9-inhibitors or specific oligonucleotide therapies, that are able to lower Lp(a) levels by up to 30% and 90%, respectively [62, 63]. This genome-wide association study (GWAS) meta-analysis in 13,781 participants from five different cohorts revealed up to 48 independent SNPs in the broad LPA gene region that are associated with Lp(a)
Summary
High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. We 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). The concentration of Lp(a) is mostly influenced by the size of the apo(a) isoforms, which are caused by a coding copynumber-variation (CNV) in the LPA gene [2, 4, 5] This CNV contains 1 to >40 repeated plasminogen-like kringle IV (KIV) domains, the so-called KIV repeats, leading to a high heterogeneity of the apo(a) isoform distribution in populations. Our project aimed to identify gene loci that are associated with Lp(a) concentrations on a hypothesis-free approach using genome-wide SNP chips in studies of European ancestry. Five different primarily population-based studies with 13,781 individuals were included and about 10 million SNPs analyzed
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