Linkage of large-vessel carotid atherosclerotic stroke to inflammatory genes via a systematic screen

Background Inflammatory cytokines including the IL-1 family, TNF-alpha and IL-6 mediate the formation of thrombosis on the luminal surface of atherosclerotic plaques. Gene polymorphisms that regulate these cytokines' expression may explain part of the variation in susceptibility to stroke in patients with carotid atherosclerosis. The aim of this study was to evaluate the role of single-nucleotide polymorphisms (SNPs) and haplotypes in inflammatory genes as they relate to symptomatic carotid atherosclerosis. Methods The study included 95 subjects with symptomatic (transient ischaemic attacks or stroke) and 113 subjects with asymptomatic carotid atherosclerotic disease. A panel of evenly spaced SNPs including previously reported functionally significant polymorphisms were genotyped for IL-1 beta (10 SNPs), IL-1 alpha (nine SNPs), IL-1RN (11 SNPs), IL-6 (seven SNPs) and TNF-alpha and TNF-beta (seven SNPs). Results Using single SNP analysis, IL-1RN rs315934 (P=0 center dot 025), IL-1RN rs315946 (P=0 center dot 042), IL-1RN rs315921 (P=0 center dot 035), IL-6 rs1180243 (P=0 center dot 018) and IL-1 alpha rs2071373 (P=0 center dot 025) were associated with decreased odds of symptomatic carotid disease. Additionally, two diplotypes of the IL-1RN gene (P=0 center dot 023 and 0 center dot 0064) and one diplotype in the IL-1 alpha gene (P=0 center dot 02) were associated with a protective affect from cerebral ischaemic events. Logistic analysis for interaction of the protective SNPs reveals an additive effect of all SNP pair combinations. Conclusion These results suggest that genetic polymorphisms in proinflammatory genes may contribute to interindividual differences in the development of symptomatic carotid atherosclerotic disease.