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

Linsel-Nitschke, Patrick, Gotz, Anika, Braenne, Ingrid, Erdmann, Jeanette, Braund, Peter, Hengstenberg, Christian, Stark, Klaus, Fischer, Marcus, Chreiber, Stefan, El Mokhtari, Nour Eddine, Schaefer, Arne, Schrezenmeier, Jurgen, Rubin, Diana, Hinney, Anke, Reinehr, Thomas, Roth, Christian, Ortlepp, Jan, Hanrath, Peter, Hall, Alistair, S., Mangino, Massimo, Lieb, Wolfgang, Lamina, Claudia, Heid, Iris M., Doering, Angela, Gieger, Christian, Peters, Annette, Meitinger, Thomas, Wichmann, H.-Erich, Konig, Inke R., Ziegler, Andreas, Kronenberg, Florian, Samani, Nilesh J., Schunkert, Heribert, for the Wellcome Trust Case Control Consortium (WTCCC), Bradbury, Linda A., Brown, Matthew A. and Cardiogenics Consortium (2008) 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. PLoS One, 3 8: e2986-1-e2986-9. doi:10.1371/journal.pone.0002986

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Author Linsel-Nitschke, Patrick
Gotz, Anika
Braenne, Ingrid
Erdmann, Jeanette
Braund, Peter
Hengstenberg, Christian
Stark, Klaus
Fischer, Marcus
Chreiber, Stefan
El Mokhtari, Nour Eddine
Schaefer, Arne
Schrezenmeier, Jurgen
Rubin, Diana
Hinney, Anke
Reinehr, Thomas
Roth, Christian
Ortlepp, Jan
Hanrath, Peter
Hall, Alistair, S.
Mangino, Massimo
Lieb, Wolfgang
Lamina, Claudia
Heid, Iris M.
Doering, Angela
Gieger, Christian
Peters, Annette
Meitinger, Thomas
Wichmann, H.-Erich
Konig, Inke R.
Ziegler, Andreas
Kronenberg, Florian
Samani, Nilesh J.
Schunkert, Heribert
for the Wellcome Trust Case Control Consortium (WTCCC)
Bradbury, Linda A.
Brown, Matthew A.
Cardiogenics Consortium
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
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2008-08-20
Sub-type Article (original research)
DOI 10.1371/journal.pone.0002986
Open Access Status DOI
Volume 3
Issue 8
Start page e2986-1
End page e2986-9
Total pages 9
Editor Christopher Surridge
Place of publication San Francisco, CA, U.S.A.
Publisher Public Library of Science
Language eng
Subject 1103 Clinical Sciences
Formatted 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 allele: of rs2228671 was associated with a significantly lower, risk of CAD (Odds Ratio per copy of the T allele: 0.82, 95% CI [0.76.89], p=2.1 × 10-7). Adjustment for LDL-C levels by logistic regression or Mendelian Randomisation model 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.
© 2008 Linsel-Nitschke et al.
Keyword Anticholesteremic agents
Cholesterol, LDL
Chromosome mapping
Coronary disease
Genetic variation
Oligonucleotide array sequence analysis
Polymorphism
Single Nucleotide
Q-Index Code C1
Q-Index Status Provisional Code
Additional Notes Article number e2986 Editor: Michael Nicholas Weedon, Peninsula Medical School, United Kingdom.

 
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