on August 10, 2009
Published online before print August 10, 2009, doi: 10.1161/ATVBAHA.109.185355
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Submitted on July 25, 2008
Accepted on June 15, 2009
A Common Variant in Low-Density Lipoprotein Receptor–Related Protein 6 Gene (LRP6) Is Associated With LDL-Cholesterol
Maciej Tomaszewski *;
From the Department of Cardiovascular Sciences (M.T., T.B., W.R., A.H.G., N.J.S.), University of Leicester, UK; the School of Science and Engineering (F.J.C.), University of Ballarat, Australia; and the Department of Internal Medicine, Diabetology, and Nephrology (M.G.-K., E.P., W.G., E.Z.-S.) and the First Department of Cardiology (A.S., J.K., Z.K.), Medical University of Silesia, Zabrze, Poland.
* To whom correspondence should be addressed. E-mail: mt142{at}le.ac.uk.
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.
Key words: gene • genetics • LDL-cholesterol • lipids • association