Abstract 15496: Combined Effect of an Interleukin-6 Gene Variant and Smoking on Endothelial Function, Inflammatory and Thrombotic Processes and Prevalence of Coronary Artery Disease

Abstract

Introduction: Smoking is a well known risk factor for coronary artery disease (CAD). Moreover, controversial data suggest that the -174 G/C polymorphism on Interleukin-6 (IL-6) gene promoter (rs1800795) may represent an early marker of inflammatory activation, closely related to the initiation and evolution of atherosclerosis. However, no data exist concerning a combined effect of smoking and this IL-6 genetic variant on several aspects of inflammation and thrombosis, endothelial function and the presence of CAD. Methods: 646 subjects (361 non smokers) were subjected to appropriate genotyping. Endothelial function was assessed by the flow mediated dilatation (FMD) of brachial artery. IL-6 (pg/ml), Tumor Necrosis Factor-a (TNF-a) (pg/ml), high sensitivity CRP (hsCRP) (mg/l) and D-dimers (μg/l) were measured with appropriate methods. Results: An increased incidence of CAD was found among the carriers of the allele C, compared to GG homozygotes, (OR:1.59, CI:1.26-2.93, p=0.032) in smokers, while a decreased incidence was observed in non smokers (OR:0.42, CI:0.26-0.68, p<0.001), after adjustment for all risk factors for CAD. The C allele carriers, compared to GG homozygotes, were associated with significantly higher serum levels of IL-6 (3.09±1.4 vs 1.3±0.7), TNF-a (5.3±2.4 vs 2.57±1.8), hsCRP (2.09±0.9 vs 1.05±0.69) in smokers as well as in non smokers (IL-6: 2.62±1.2 vs 1.64±0.89, TNF-a: 3.57±1.67 vs 4.43±2.1, hsCRP: 1.84±0.82 vs 1.62±0.77), p<0.01 for all. Importantly, the C allele, compared to GG homozygotes, enhanced the expression of fibrinogen (488.3±115.1 vs 318.5±61.1 p<0.001) and D-dimers (513±313.4 vs 355.1±218.4, p=0.025) in smokers, while it down-regulated the expression of fibrinogen in non-smokers (351.9±84.5 vs 479.4±126.4, p<0.001). Impressively, the C allele carriers were correlated with significantly impaired endothelial function in the smoking group (3.9±2.7 vs 5.2±3.3, p=0.003), while no effect was observed among non-smokers (4.8±2.9 vs 5.04±2.6, p=0.64). Conclusions: The C allele of rs1800795 exerts a synergistic effect on smoking resulting to a significantly increased risk for CAD. This action is mediated by inflammatory and thrombotic mechanisms as well as by the impairment of endothelial function.