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.
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: Mercedes García-Bermúdez; Raquel López-Mejías; Carlos González-Juanatey; Santos Castañeda; José A Miranda-Filloy; Ricardo Blanco; Benjamín Fernández-Gutiérrez; Alejandro Balsa; Isidoro González-Alvaro; Carmen Gómez-Vaquero; Javier Llorca; Javier Martín; Miguel A González-Gay Journal: DNA Cell Biol Date: 2012-02-23 Impact factor: 3.311
Authors: Madlyn I Frisard; Yaru Wu; Ryan P McMillan; Kevin A Voelker; Kristin A Wahlberg; Angela S Anderson; Nabil Boutagy; Kyle Resendes; Eric Ravussin; Matthew W Hulver Journal: Metabolism Date: 2014-11-28 Impact factor: 8.694
Authors: Daniel A Enquobahrie; Nicholas L Smith; Joshua C Bis; Cara L Carty; Kenneth M Rice; Thomas Lumley; Lucia A Hindorff; Rozenn N Lemaitre; Michelle A Williams; David S Siscovick; Susan R Heckbert; Bruce M Psaty Journal: Am J Cardiol Date: 2008-04-09 Impact factor: 2.778