Stromelysin-1 and interleukin-6 gene promoter polymorphisms are determinants of asymptomatic carotid artery atherosclerosis

The functional 5A/6A polymorphism of the stromelysin-l promoter has been im plicated as a potential genetic marker for the progression of angiographica lly determined atherosclerosis in patients with coronary artery disease. Re cently, a novel interleukin-6 (IL-6) gene functional G/C polymorphism at -1 74 in the promoter has also been reported. In this study, we analyzed the r elation of these two polymorphisms with carotid artery atherosclerosis in 1 09 randomly selected, middle-aged men without exercise-induced ischemia. At herosclerosis was quantified as intima-media thickness (IMT) by high-resolu tion ultrasonography. Univariately, stromelysin genotype was significantly (P=0.015) associated with IMT, and this relation remained (P=0.033) after a djustments for age, cardiorespiratory fitness, body mass index, smoking, LD L cholesterol, and systolic blood pressure and for sonographers. The 5A/6A polymorphism independently explained 7% of the variance in carotid bifurcat ion IMT. The IL-6 polymorphism was also significantly associated (P=0.036) with increased WIT, with men homozygous for the G allele having IMT that wa s 11% greater than men homozygous for the C allele. Men who were homozygous for both the 6A and G alleles had an covariate adjusted IMT that was 36% g reater than men who were homozygous for neither allele (P<0.003). These dat a suggest that genetic factors that predispose to reduced matrix remodeling (stromelysin 6A allele) and to increased inflammation (IL-6 G allele) comb ine to increase susceptibility for intima-media thickening in the carotid b ifurcation, a predilection site for atherosclerosis.