title: Variation in the toll-like receptor 4 gene and susceptibility to myocardial infarction.
abstract: Variation in the gene encoding toll-like receptor 4 (TLR4), a transmembrane receptor that mediates inflammatory responses to bacterial endotoxin, has been associated with susceptibility to atherosclerosis and its complications, such as myocardial infarction (MI), the pathogenesis of which involves inflammation. A recent study has also indicated that TLR4 gene variation influences the effect of statin treatment on reducing atherosclerosis complications. We studied the TLR4 gene Asp299Gly polymorphism in relation to susceptibility to myocardial infarction in a cohort of patients with angiographically documented coronary artery disease, and performed a meta-analysis using data sets from three independent studies. The meta-analysis showed that overall, odds ratio (OR) for MI was 0.73 [95% confidence interval (CI) 0.55-0.96, P=0.024] in 299Gly carriers compared to non-carriers, and there was no evidence of heterogeneity among the sample sets (P=0.679). In our patient cohort, a significant association of 299Gly bearing genotypes with lower susceptibility to myocardial infarction was observed only in patients receiving statin treatment, with 299Gly carriers having an OR of 0.49 (95% CI 0.27-0.78, P=0.015) for MI compared to non-carriers. These results are consistent with the notion that variation in the TLR4 gene contributes to inter-individual variability in susceptibility to coronary ischaemic events, and that TLR4 genotype and statin treatment may have a synergistic effect.
authors.affiliation: Human Genetics Division, School of Medicine, University of Southampton, Southampton, UK.
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.forename: Ian A
authors.initials: IA
authors.lastname: Yang
authors.forename: Shu
authors.initials: S
authors.lastname: Ye
mesh_terms: D000368:Aged; D000483:Alleles; D001161:Arteriosclerosis; D002784:Cholesterol / Q000378:metabolism; D015331:Cohort Studies; D004198:Disease Susceptibility; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007249:Inflammation; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D016017:Odds Ratio; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D012306:Risk; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D002784:Cholesterol