title: Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes.
abstract: BACKGROUND
  Coronary artery disease (CAD) and, increasingly, diabetes are recognized as having an inflammatory basis. Membrane toll-like receptors (TLRs) activate signaling pathways that up-regulate inflammation. We evaluated whether the Asp299Gly polymorphism in the TLR4 gene, which impairs inflammatory responses, is associated with reduced vascular inflammation (assessed by C-reactive protein [CRP]) and a decreased risk for CAD and diabetes.
  
  
  METHODS
  1894 patients without acute myocardial infarction undergoing coronary angiography were studied. Genotyping was performed by real-time polymerase chain reaction. CAD was defined as >or=70% stenosis. Diabetes was diagnosed by patients' referring physicians. CRP was measured by fluorescence polarization immunoassay. Regression analyses adjusted for traditional cardiac risk factors.
  
  
  RESULTS
  Patients averaged 64 +/- 11 years of age, and 69% were male. Asp299Gly genotype frequencies were: AA = 0.911 (n = 1725), AG = 0.086 (n = 164), and GG = 0.003 (n = 5), in keeping with Hardy-Weinberg equilibrium. CRP was lower among G-allele carriers (median = 1.11 mg/dL) than wild-type (AA) subjects (1.23 mg/dL, adjusted P = .044). G-allele carriers also had a lower prevalence of CAD (65% vs. 73%, OR = 0.67, CI = 0.46-0.99, adjusted P = .048) and diabetes (11% vs. 18%, OR = 0.63, CI = 0.42-0.95, adjusted P = .029), which persisted in multivariate logistic regression analyses. 299Gly carriage did not affect clinical outcomes nor interact with statin therapy.
  
  
  CONCLUSIONS
  The TLR4 299Gly allele was associated with reduced CRP levels and, in parallel, a decreased risk of angiographic CAD and clinical diabetes. These findings suggest that down-regulation of innate immune responsiveness could beneficially modify CAD and diabetes risk and might provide a novel basis for genetic risk stratification and therapeutic targeting.
authors.affiliation: Cardiovascular Department, Division of Cardiology, LDS Hospital, Salt Lake City, Utah 84143, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Kolek
authors.forename: John F
authors.initials: JF
authors.lastname: Carlquist
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Muhlestein
authors.forename: Bryant M
authors.initials: BM
authors.lastname: Whiting
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Horne
authors.forename: Tami L
authors.initials: TL
authors.lastname: Bair
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Anderson
mesh_terms: D000368:Aged; D002097:C-Reactive Protein / Q000032:analysis*; D017023:Coronary Angiography; D003327:Coronary Disease / Q000097:blood / Q000235:genetics*; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007249:Inflammation / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics / Q000401:mortality / Q000517:prevention & control; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics*; D012307:Risk Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D005819:Genetic Markers; 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; D002097:C-Reactive Protein