on July 25, 2005
Published online before print July 25, 2005, doi: 10.1161/CIRCULATIONAHA.104.519702
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Submitted on November 5, 2004
From INSERM U525, Paris, and the Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, Paris, France (L.T., T.G., V.N., D.-A.T., S.B., O.P., C.P., F.C.); and the Department of Medicine II, Johannes Gutenberg-University Mainz, Mainz, Germany (E.L., R.S., C.B., C.E.-K., T.M., H.-J.R., K.L., S.B.). * To whom correspondence should be addressed. E-mail: laurence.tiret{at}chups.jussieu.fr.
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 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.
Revised on March 29, 2005
Accepted on April 4, 2005
Genetic Analysis of the Interleukin-18 System Highlights the Role of the Interleukin-18 Gene in Cardiovascular Disease
Laurence Tiret PhD*,
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.
Key words: coronary disease • genetics • interleukins • inflammation • prognosis
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