A Common Variant in Low-Density Lipoprotein Receptor–Related Protein 6 Gene (LRP6) Is Associated With LDL-Cholesterol

Objective: A rare mutation in low-density lipoprotein receptor-related protein 6 gene (LRP6) was identified as the primary molecular defect underlying monogenic form of coronary artery disease. We hypothesized that common variants in LRP6 could predispose subjects to elevated LDL-cholesterol (LDL-C). Methods and Results: Twelve common (minor allele frequency 0.1) single nucleotide polymorphisms in LRP6 were genotyped in 703 individuals from 213 Polish pedigrees (Silesian Cardiovascular Study families). The family-based analysis revealed that the minor allele of rs10845493 clustered with elevated LDL-C in offspring more frequently than expected by chance (P=0.0053). The quantitative analysis restricted to subjects free of lipid-lowering treatment confirmed the association between rs10845493 and age-, sex-, and BMI-adjusted circulating levels of LDL-C in families as well as 2 additional populations - 218 unrelated subjects from Silesian Cardiovascular Study replication panel and 1138 individuals from Young Men Cardiovascular Association cohort (P=0.0268, P=0.0476, and P=0.0472, respectively). In the inverse variance weighted meta-analysis of the 3 populations each extra minor allele copy of rs10845493 was associated with 0.14 mmol/L increase in age-, sex-, and BMI-adjusted LDL-C (SE=0.05, P=0.0038). Conclusions: Common polymorphism in the gene underlying monogenic form of coronary artery disease impacts on risk of LDL-C elevation. We have hypothesized that common alleles in the locus underlying monogenic form of coronary artery disease (low-density lipoprotein receptor-related protein 6 gene [LRP6]) are associated with LDL-cholesterol. Through genetic association analyses we identified a common variant (rs10845493) in LRP6 as a significant determinant of LDL-cholesterol.