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Title: Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study.
Authors: Linsel-Nitschke, P.
Götz, A.
Erdmann, J.
Braenne, I.
Braund, Peter
Hengstenberg, C.
Stark, K.
Fischer, M.
Schreiber, S.
El Mokhtari, N. E.
Schaefer, A.
Schrezenmeir, J.
Rubin, D.
Hinney, A.
Reinehr, T.
Roth, C.
Ortlepp, J.
Hanrath, P.
Hall, A. S.
Mangino, M.
Lieb, W.
Lamina, C.
Heid, I. M.
Doering, A.
Gieger, C.
Peters, A.
Meitinger, T.
Wichmann, H. E.
König, I. R.
Ziegler, A.
Kronenberg, F.
Samani, Nilesh J.
Schunkert, H.
Wellcome Trust Case Control Consortium (WTCCC)
Cardiogenics, Consortium
First Published: 20-Jul-2008
Publisher: Public Library of Science
Citation: PLoS ONE, 2008, 3 (8), pp. e2986-e2986
Abstract: Background Rare mutations of the low-density lipoprotein receptor gene (LDLR) cause familial hypercholesterolemia, which increases the risk for coronary artery disease (CAD). Less is known about the implications of common genetic variation in the LDLR gene regarding the variability of cholesterol levels and risk of CAD. Methods Imputed genotype data at the LDLR locus on 1 644 individuals of a population-based sample were explored for association with LDL-C level. Replication of association with LDL-C level was sought for the most significant single nucleotide polymorphism (SNP) within the LDLR gene in three European samples comprising 6 642 adults and 533 children. Association of this SNP with CAD was examined in six case-control studies involving more than 15 000 individuals. Findings Each copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11%) was related to a decrease of LDL-C levels by 0.19 mmol/L (95% confidence interval (CI) [0.13–0.24] mmol/L, p = 1.5×10−10). This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82, 95% CI [0.76–0.89], p = 2.1×10−7). Adjustment for LDL-C levels by logistic regression or Mendelian Randomisation models abolished the significant association between rs2228671 with CAD completely, indicating a functional link between the genetic variant at the LDLR gene locus, change in LDL-C and risk of CAD. Conclusion A common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD.
DOI Link: 10.1371/journal.pone.0002986
ISSN: 1932-6203
eISSN: 1932-6203
Type: Journal Article
Rights: Copyright: 2008 Linsel-Nitschke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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