This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 29/9/1316    most recent ATVBAHA.109.185355v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Tomaszewski, M. Articles by Zukowska-Szczechowska, E. PubMed PubMed Citation Articles by Tomaszewski, M. Articles by Zukowska-Szczechowska, E. Related Collections Risk Factors Genomics Genetics of cardiovascular disease

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1316.)
© 2009 American Heart Association, Inc.

National Cholesterol Awareness Month

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

Maciej Tomaszewski; Fadi J. Charchar; Timothy Barnes; Magdalena Gawron-Kiszka; Agnieszka Sedkowska; Ewa Podolecka; Jacek Kowalczyk; Wendy Rathbone; Zbigniew Kalarus; Wladyslaw Grzeszczak; Alison H. Goodall; Nilesh J. Samani; Ewa Zukowska-Szczechowska

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.

Correspondence to Dr Maciej Tomaszewski, Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, LE3 9QP, UK. E-mail mt142{at}le.ac.uk

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 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.

Key Words: gene • genetics • LDL-cholesterol • lipids • association