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

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.

Investigation of anLPAKIV-2 nonsense mutation in 11,000 individuals: the importance of linkage disequilibrium structure inLPAgenetics

“…However, no study up to now has investigated the contribution of R21X to the Lp(a) levels in general or high risk populations nor it is known whether this variant is captured by any of the many GWAS hits that have been reported for LPA [14][15][16] .…”

“…We used the genome-wide SNP data available for the GCKD study to search for a proxy SNP for R21X that would allow linking R21X to existing results from GWAS. Following the rationale that a SNP in LD with R21X will present a similar effect on Lp(a) and that the observed effect of R21X on Lp(a) should have been easily detected by our recent GWAS on Lp(a) (n=13,781) 14 , we created a contingency table of each of the 66 top hits of the isoform-adjusted model of our recent GWAS metaanalysis on the Lp(a) concentrations with the R21X 14 and analyzed it using the Fisher´s exact test. We selected the two SNPs with the most significant p-values (rs2489940, rs41272114) and calculated the LD using CubeX 34 .…”

“…Genetic variants located in the KIV-2 region are not represented in GWAS datasets. To investigate whether any of the lately reported GWAS hits 14 may pick up the signal of R21X and to assess the contribution of the R21X nonsense variant to cardiovascular outcomes, we searched among the 66 top hits of our recent GWAS on Lp(a) 14 for a proxy SNP for R21X. This identified two possible proxy SNPs: rs2489940 in PLG (MAF=0.5%, R 2 = 0.38, D´=0.74) and rs41272114 in LPA KIV-8 17 (MAF=2.6%, R 2 = 0.275, D'=0.957).…”

“…This indicates that genetic variants exist that regulate the Lp(a) concentrations in addition to isoform size 12,13 . Genome-wide association studies (GWAS) have identified dozens of SNPs distributed over a two megabases region [14][15][16] , but few bona-fide functional variants have been identified 13,[17][18][19] .…”

“…1.2% mutation level), the R21X variant was not further explored in large epidemiological studies. Accordingly, R21X has never been put into the context of the findings from GWAS on Lp(a) [14][15][16] and it is unknown whether any of the LPA SNPs detected in GWAS studies is in LD with R21X.…”