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.

Keywords: coronary artery disease; epidemiology; genetics.

Fig. 1.

Regional plot showing the genomic region around the LPA gene (chr6:159,991,850-161,753,083; LD refers to rs55730499, based on 1000G EUR); P values are derived from the meta-analysis on the five cohorts including 13,781 individuals on inverse-normal transformed Lp(a) concentrations, adjusted for age and sex. All 48 SNPs, which are independently associated with Lp(a) in a joint model, are circled.

Fig. 2.

Regional plot showing the genomic region defined by the APOE lead SNP, rs7412, ±500 kb (LD refers to rs7412, based on 1000G EUR); P values are derived from the meta-analysis on the five cohorts on inverse-normal transformed Lp(a) concentrations, adjusted for age and sex.

Fig. 3.

Boxplot of Lp(a) concentration for groups of a SNP-score [sum of Lp(a)-increasing alleles] derived from the 48 independent SNPs in the broad LPA gene region. An underlying bar plot shows the distribution of the score in KORA F3 and KORA F4. The blue line indicates the predicted values of Lp(a) for mid-interval values of the SNP-score, based on a linear regression from the SNP-score on Lp(a).

Fig. 4.

Results of a mixed model (using data from KORA F3, KORA F4, and SAPHIR combined) evaluating the effects from APOE genotypes, defined as described in supplemental Table S3, on untransformed Lp(a) values in milligrams per deciliter (A), as well as on inverse-normal transformed Lp(a) (B). Both panels show β estimates and 95% CI for age- and sex-adjusted models (in black), as well as age-, sex-, and isoform-adjusted models (in blue). P values are derived from the model using inverse-normal transformed Lp(a).

Fig. 5.

Scatterplot showing the effect estimates on inverse normally transformed Lp(a) levels (±95% CI) on the x axis and the ORs for CAD risk (±95% CI) on the y axis (derived from theCARDIoGRAMplusC4D consortium) for all 40 SNPs, which were identified in model 1 (age- and sex-adjusted) and which were available in the CARDIoGRAMplusC4D results. All SNPs, which are also genome-wide significantly associated with CAD risk, are marked in green.