Abstract-Interleukin-6 (IL-6) synthesized in response to diverse stimuli may play an important role in bridging the inflammatory and atherosclerotic processes. The acute-phase response after coronary artery bypass graft surgery (CABG) is associated with the induction and release of cytokines, such as IL-6. We have examined the effect of common polymorphisms in the IL-6 gene promoter (Ϫ174GϾC, Ϫ572GϾC, and Ϫ597GϾA) on IL-6 levels after elective CABG. DNA extracted from the peripheral blood of 127 patients was amplified by polymerase chain reaction. IL-6 genotypes were resolved by gel electrophoresis after restriction enzyme digestion. Serum IL-6 was measured before surgery and in serial samples at 6, 24, 48, and 72 hours after CABG. Genotype distribution was as expected for a population in Hardy-Weinberg equilibrium for all polymorphisms. Rare allele frequencies (Ϯ95% CIs) were similar to those reported previously: Ϫ597A 0.36 (0.30 to 0.42), Ϫ572C 0.07 (0.04 to 0.10), and Ϫ174C 0.37 (0.31 to 0.43). The Ϫ174GϾC and Ϫ597GϾA genotypes were in strong allelic association (⌬ϭ0.97, PϽ0.001). Baseline IL-6 levels did not significantly differ between patients with different genotypes for any polymorphism. However, 6 hours after CABG, peak IL-6 levels were significantly higher (Pϭ0.03) in carriers of the Ϫ572C allele than in those of the Ϫ572GG genotype (355Ϯ67 versus 216Ϯ13 pg/mL, respectively) and in those with genotype Ϫ174CC compared with Ϫ174G allele carriers (287Ϯ31 versus 227Ϯ15 pg/mL, respectively; Pϭ0.04). These effects remained statistically significant after adjusting for possible confounders, including age, sex, smoking, duration of cardiopulmonary bypass, aortic cross-clamp time, and total duration of surgery. These data demonstrate that IL-6 promoter polymorphisms influence peak IL-6 production after CABG, suggesting that these polymorphisms, which are functional in vitro, are also functional in vivo, suggesting a genetic influence on IL-6 levels after acute severe injury. (Arterioscler Thromb Vasc

These data confirm the importance of the inflammatory system in the development of coronary heart disease. They suggest that, at least in part, the effect of the IL-6 -174G>C polymorphism on blood pressure is likely to be operating through inflammatory mechanisms, but the genotype effect on coronary heart disease risk is largely unexplained by its effect on blood pressure. The molecular mechanisms whereby genetically determined differences in plasma levels of IL-6 are having these effects remain to be determined.

Objective-Interleukin (IL)-6 -mediated inflammation is involved in cardiovascular disease (CVD). We assessed IL-6 levels and the Ϫ174GϾC genotype in a case-control study of men and women (average age 73 years) within the Cardiovascular Health Study. Methods and Results-Cases included incident angina, myocardial infarction (MI), and stroke (5-year follow-up), prevalent MI, and MRI-detectable infarcts. A control group and a group free of subclinical CVD were used for comparison. The Ϫ174C allele was associated with higher C-reactive protein (11% higher, Pϭ0.02), fibrinogen (3% higher, Pϭ0.02), and IL-6 (5% higher; Pϭ0.16). IL-6 was associated with increased atherosclerosis when the control group was compared with the group free of subclinical CVD. No further association with CVD events was found when case groups were compared with the control group. Compared with its absence, presence of the Ϫ174C allele was associated with risk of MRI infarcts (odds ratio 1.5). Conclusions-IL-6 levels differentiated those with subclinical CVD from those without. Although the Ϫ174C allele was not associated with incident events, associations of the genotype with inflammation and MRI infarcts, combined with the plasma IL-6 results, suggest that IL-6 may chronically predispose an individual to develop atherosclerosis.