Abstract 2076: Common Genetic Variants Associated With Higher Lp(a) Concentrations and Increased Risk of Coronary Heart Disease
Background: Lipoprotein(a) [Lp(a)] is an emerging risk factor for coronary artery disease (CAD) that is highly heritable, but little is known about the genetic determinants of Lp(a) and their relevance for CAD.
Methods: We used a novel chip containing 49,000 single nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for association in 3146 CAD cases. Replication was tested in 3 independent populations involving 4846 additional CAD cases.
Results: Three chromosomal regions (6q26 –27, 9p21, 1p13) were strongly associated with CAD risk, and the LPA locus on 6q26 –27 encoding Lp(a) had the strongest effects. We identified a common variant (rs10455872; minor allele frequency [MAF] 7%) at the LPA locus associated with an odds ratio (OR) for CAD of 1.70 (95%CI: 1.49 –1.95), and another independent variant (rs3798220, MAF 2%) with an OR of 1.92 (95%CI: 1.48 –2.49). Both variants were strongly associated with higher Lp(a) concentrations (p=4× 10−166 for rs10455872 and 6 ×10−51 for rs3798220), and with lower Kringle copy number and small Lp(a) size. Replication studies confirmed the effects of both variants on Lp(a) concentrations and CAD risk. In a meta-analysis, an LPA genotype score involving both SNPs had OR for CAD of 1.51 (95%CI: 1.38 –1.66) for one and 2.57 (95%CI: 1.80 –3.67) for two alleles.
Conclusions: About 1 in 6 people have one of these two LPA variants with a 1.5-fold higher CAD risk, and 1in 100 have 2 variants with a 2.5-fold higher risk. These findings provide compelling support for a causal role of Lp(a) in CAD.