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

J Lipid Res. 2017 May 16. pii: jlr.M076232. doi: 10.1194/jlr.M076232. [Epub ahead of print]

Authors/Editors: Mack S, Coassin S, Rueedi R, Yousri NA, Seppälä I, Gieger C, Schönherr S, Forer L, Erhart G, Marques-Vidal P, Ried J, Waeber G, Bergmann S, Dähnhardt D, Stöckl A, Raitakari OT, Kähönen M, Peters A, Meitinger T, Strauch K, Kedenko L, Paulweber B, Lehtimäki T, Hunt SC, Vollenweider P, Lamina C, Kronenberg F.
Publication Date: 2017

2017_05_mack

Abstract

High lipoprotein(a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) KIV 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 (OR=1.73, p=3.35x10-30). Median Lp(a) values increased from 2.1 mg/dL 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=3.47x10-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dL corresponding to ≈15% of the populations 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 = 3.4x10-4). 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.

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