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
Open Access
- 20 August 2008
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 3 (8), e2986
- https://doi.org/10.1371/journal.pone.0002986
Abstract
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. 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. 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. A common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD.Keywords
This publication has 42 references indexed in Scilit:
- Repeated Replication and a Prospective Meta-Analysis of the Association Between Chromosome 9p21.3 and Coronary Artery DiseaseCirculation, 2008
- LDL-cholesterol concentrations: a genome-wide association studyThe Lancet, 2008
- Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humansNature Genetics, 2008
- Genome-wide Association Study Identifies Genes for Biomarkers of Cardiovascular Disease: Serum Urate and DyslipidemiaAmerican Journal of Human Genetics, 2008
- A second generation human haplotype map of over 3.1 million SNPsNature, 2007
- Genomewide Association Analysis of Coronary Artery DiseaseNew England Journal of Medicine, 2007
- A common polymorphism decreases low-density lipoprotein receptor exon 12 splicing efficiency and associates with increased cholesterolHuman Molecular Genetics, 2007
- Sequence Variations inPCSK9,Low LDL, and Protection against Coronary Heart DiseaseNew England Journal of Medicine, 2006
- Prevalence of Known Diabetes and Antidiabetic Therapy Between 1984/1985 and 1999/2001 in Southern GermanyDiabetes Care, 2004
- Expression of the Familial Hypercholesterolemia Gene in Heterozygotes: Mechanism for a Dominant Disorder in ManScience, 1974