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

By F. J. Charchar, T. Barnes, M. Gawron-Kiszka, A. Sedkowska, E. Podolecka, J. Kowalczyk, W. Rathbone, Z. Kalarus, W. Grzeszczak, A. H. Goodall, N. J. Samani and E. Zukowska-Szczechowska

Abstract

This is the author’s final draft of the paper. The final published version is available at the DOI below: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.This study was supported by NIH Fogarty International Research Collaboration Award (R03 TW007165; to M.T.). T.B. is supported by a British Heart Foundation project grant (PG/06/097; to M.T.). N.J.S. holds a British Heart Foundation Chair of Cardiology

Topics: gene, genetics, LDL-cholesterol, lipids, association
Publisher: American Heart Association
Year: 2009
DOI identifier: 10.1161/ATVBAHA.109.185355
OAI identifier: oai:lra.le.ac.uk:2381/7860

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