Investigators. Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease. Circulation

Background—Interleukin (IL)-18 plays a key role in atherosclerosis and its complications. The present study investigated the genetic variability of 4 genes of the IL-18 system—IL18, IL18R1, IL18RAP, and IL18BP—in relation to circulating IL-18 levels and cardiovascular mortality. Methods and Results—Twenty-two polymorphisms were genotyped in 1288 patients with coronary artery disease prospectively followed up during a median period of 5.9 years. The end point was death from cardiovascular causes (n142). Baseline IL-18 levels were predictive of cardiovascular deaths occurring during 4 years of follow-up (HR2.96, 95 % CI 1.54 to 5.70, P0.001 for the top compared with the bottom quartile) but not of later deaths. Haplotypes of the IL18 gene were associated with IL-18 levels (P0.002) and cardiovascular mortality (P0.006) after adjustment for cardiovascular risk factors. The same haplotype was associated with both a 9 % lowering effect on IL-18 levels and a protective effect on risk (HR0.57, 95 % CI 0.36 to 0.92). IL18 haplotypes explained only 2 % of IL-18 variability. Adjustment for baseline IL-18 levels abolished the association of haplotypes with cardiovascular risk. The haplotype associated with phenotypes was the only one carrying the minor allele of the IL18/A183G polymorphism located in the 3untranslated region and potentially affecting mRNA stability. The other genes of the system were not related to IL-18 levels or cardiovascular outcome. Conclusion—Variations of the IL18 gene consistently influence circulating levels of IL-18 and clinical outcome in patient