Haplotypic analysis of tag SNPs of the interleukin-18 gene in relation to cardiovascular disease events: the MORGAM Project

Abstract

Interleukin-18 (IL-18) is a key inflammatory molecule suspected of being involved in the etiology of cardiovascular diseases (CVD). Five single nucleotide polymorphisms (SNPs) capturing the common genetic variation of the IL-18 gene (tag SNPs) were genotyped in five European prospective CVD cohorts including 1933 cases and 1938 non-cases as part of the MORGAM Project. Not a single SNP was found associated with CVD. However, a significant (P ¼ 0.002) gene-smoking interaction was observed. In smokers, the À105T allele was more frequent in cases than in non-cases (0.29 vs 0.25) and associated with an increased risk of disease (odds ratio (OR) ¼ 1.25 (1.07 -1.45), P ¼ 0.005), whereas the inverse relationship tended to be observed in non-smokers (OR ¼ 0.90 (0.78 -1.02), P ¼ 0.131). The gene-smoking interaction was broadly homogenous across the cohorts and was also observed through haplotype analyses. In conclusion, using the concerted effort of several European prospective CVD cohorts, we are able to show that one IL-18 tag SNP interacts with smoking to modulate the risk of developing CVD.

Interleukin 18 and coronary heart disease: Prospective study and systematic review

“…Future studies could also examine whether effect modifiers of any associations between IL-18 and CHD; previous studies have demonstrated interactions between IL-18 or IL-18 genotypes and factors related to CHD risk (e.g. metabolic syndrome [30], hypertension [45] or cigarette smoking [46]), any such interactions could change the predictive value of circulating IL-18 levels.…”

Current Genetics and Epigenetics of Smoking/Tobacco-Related Cardiovascular Disease

“…15 Nonetheless, the level of evidence for the vast majority of currently suggested gene-smoking interactions ultimately remains very limited. The evolution of findings concerning an interaction between tobacco-smoking and variants in glutathione S-transferase genes with respect to cardiovascular disease risk-which started out as a seemingly plausible effect modification supported by multiple lines of evidence 8 and was further sugested later meta-analysis, 16 only to vanish with subsequent sample size escalation 17 -should be taken as a reminder of the danger of prematurely overinterpreting gene-smoking interactions or even higher order interactions (eg, gene-age-smoking).…”

The polymorphism of IL18RAP and IL18R1 genes associated with risks of the development of myocardial infarction in patients with stable coronary artery disease

“…В другом, многоцентровом, исследовании Grisoni M.L. с соавторами [11] изучали вклад пяти полиморфных сайтов с однонуклеотидными заменами (SNP) в IL18R1, шести SNP в IL18RAP, и пяти SNP в IL18 и лиц, включенных в проект MORGAM с целью поиска вероятного взаимодействия между полиморфизмом генов комплекса сигнального пути ИЛ-18 и развитием инсультов (ишемических и геморрагических) и ИБС (включая установленный и возможный острый ИМ, коронарную смерть, нестабильную стенокардию и сердечную реваскуляризацию). Проект MORGAM основан на выборке 48 когорт из четырех регионов Европы.…”