Toll-like receptor 4 gene Asp299Gly polymorphism is associated with reductions in vascular inflammation, angiographic coronary artery disease, and clinical diabetes

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 greater than or equal to70% 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.