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

Article

关键词: CORONARY-HEART-DISEASE;    STOCHASTIC-EM ALGORITHM;    BINDING-PROTEIN;    ASSOCIATION ANALYSIS;    IL-18;    INFLAMMATION;    EXPRESSION;    RISK;    MEN;    CYTOKINE;   

DOI  :  10.1161/CIRCULATIONAHA.104.519702

来源: SCIE

【 摘 要 】

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 ( n = 142). Baseline IL-18 levels were predictive of cardiovascular deaths occurring during <= 4 years of follow-up ( HR = 2.96, 95% CI 1.54 to 5.70, P = 0.001 for the top compared with the bottom quartile) but not of later deaths. Haplotypes of the IL18 gene were associated with IL-18 levels ( P = 0.002) and cardiovascular mortality ( P = 0.006) 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 ( HR = 0.57, 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/A + 183G polymorphism located in the 3 'untranslated 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 patients with coronary artery disease, which supports the hypothesis of a causal role of IL-18 in atherosclerosis and its complications.

【 授权许可】

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