AIMS: Inflammation is a key component of coronary heart disease, and genes coding for cytokines are candidates for predisposing to coronary heart disease risk. We have examined the effect of two polymorphisms (-174G>C and -572G>C) in the promoter of the interleukin-6 (IL-6) gene on risk of coronary heart disease, and on intermediate risk traits including fibrinogen and systolic blood pressure, in 2751 middle-aged healthy U.K. men. RESULTS: The -174C allele (frequency 0.43, 95% CI 0.42-0.44) was not associated with significant effects on fibrinogen levels, but was associated with a significantly (P=0.007) higher systolic blood pressure (mean mmHg (95% CI): GG=135.5 (134.3-136.7); GC=137.9 (136.9-138.9); CC= 138.0 (136.3-139.8)). This effect was of similar magnitude in smokers and non-smokers, and was greater in men in the top two tertiles of body mass index (>24.86 kg x m(-2)) than in those in the bottom tertile. Compared to those with the genotype GG, men carrying the -174C allele had a relative risk of coronary heart disease of 1.54 (95% CI 1.0-2.23, P=0.048) and this effect was greatest in smokers (compared to GG non-smokers, RR 2.66, CI 1.64-4.32). These effects remained statistically significant after adjusting for classical risk factors including blood pressure (P=0.04). The -572C allele (frequency 0.05, 0.04-0.06) was not associated with a significant effect on blood pressure, fibrinogen or relative risk of coronary heart disease. In a subset of the genotyped men (n=494), carriers of the -174C allele had higher levels of C-reactive protein than non-carriers. CONCLUSIONS: 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.
