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


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 < or =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.


CONCLUSIONS
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.
Tiret
Laurence
L
INSERM U525, Université Pierre et Marie Curie, Faculté de Médecine Pitié-Salpêtrière, Paris, France. laurence.tiret@chups.jussieu.fr
Godefroy
Tiphaine
T
Lubos
Edith
E
Nicaud
Viviane
V
Tregouet
David-Alexandre
DA
Barbaux
Sandrine
S
Schnabel
Renate
R
Bickel
Christoph
C
Espinola-Klein
Christine
C
Poirier
Odette
O
Perret
Claire
C
Münzel
Thomas
T
Rupprecht
Hans-Jurgen
HJ
Lackner
Karl
K
Cambien
François
F
Blankenberg
Stefan
S
D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D003327:Coronary Disease / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality; D014644:Genetic Variation; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics*; D018579:Patient Selection; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors; D016896:Treatment Outcome
D020382:Interleukin-18; D012333:RNA, Messenger