A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-cholesterol

Abstract

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 > or =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.

Figures

Figure 1. LRP6 and LDL-C in Silesian Cardiovascular Study – family-based association analysis

Top panel. -log transformed p-values from the association analysis. Middle panel. Structure of LRP6 gene. Bottom panel. The linkage disequilibrium (LD) map (r2-coefficients-based) of LRP6 (dark red corresponds to r2=1 – maximal LD and white to r2=0 – no LD)