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.

DOI: 10.1194/jlr.M076232

Cite this paper

@article{Mack2017AGA, title={A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms.}, author={Salome Mack and Stefan Coassin and Rico Rueedi and Noha A Yousri and Ilkka Sepp{\"a}l{\"a} and Christian Gieger and Sebastian Sch{\"{o}nherr and Lukas Forer and Gertraud Erhart and Pedro Marques-Vidal and Janina S Ried and Gerard Waeber and Sven Bergmann and Doreen D{\"a}hnhardt and Andrea St{\"{o}ckl and Olli T Raitakari and Mika K{\"a}h{\"{o}nen and Annette Peters and Thomas Meitinger and Konstantin Strauch and Ludmilla Kedenko and Bernhard Paulweber and Terho Lehtim{\"a}ki and Steven C Hunt and Peter Vollenweider and Claudia Lamina and Florian Kronenberg}, journal={Journal of lipid research}, year={2017}, volume={58 9}, pages={1834-1844} }