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

journal contribution
posted on 2010-05-04, 12:55 authored 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, E. Zukowska-Szczechowska
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.



Zbigniew Kalarus, Wladyslaw Grzeszczak, Alison H. Goodall, Nilesh J. Samani and Agnieszka Sedkowska, Ewa Podolecka, Jacek Kowalczyk, Wendy Rathbone, Maciej Tomaszewski, Fadi J. Charchar, Timothy Barnes, Magdalena Gawron-Kiszka, Gene (LRP6) Is Associated With LDL-Cholesterol A Common Variant in Low-Density Lipoprotein Receptor Related Protein 6Arterioscler Thromb Vasc Biol 2009;29;1316-1321

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Zbigniew Kalarus


American Heart Association

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