Polymorphisms of the Interleukin-1β Gene Affect the Risk of Myocardial Infarction and Ischemic Stroke at Young Age and the Response of Mononuclear Cells to Stimulation In Vitro

Abstract

on behalf of IGIGI InvestigatorsObjectives-To investigate the role of interleukin-1␤ (IL-1␤) gene polymorphisms as a link between inflammation, coagulation, and risk of ischemic vascular disease at young age. Methods and Results-A total of 406 patients with myocardial infarction (MI) at young age, frequency-matched for age, sex, and recruitment center, with 419 healthy population-based controls and 134 patients with ischemic stroke at young age, matched by age and sex, with 134 healthy population-based controls, were studied. Subjects carrying the TT genotype of the Ϫ511C/T IL-1␤ polymorphism showed a decreased risk of MI (odds ratio [OR], 0.36; 95% CI, 0.20 to 0.64) and stroke (OR, 0.32; 95% CI, 0.13 to 0.81) after adjustment for conventional risk factors. In both studies, the T allele showed a codominant effect (Pϭ0.0020 in MI; Pϭ0.021 in stroke). Mononuclear cells from volunteers carrying the T allele showed a decreased release of IL-1␤ and a decreased expression of tissue factor after stimulation with lipopolysaccharide compared with CC homozygotes. The presence of a monoclonal antibody against IL-1␤ during cell stimulation resulted in a marked reduction of tissue factor activity expression. Key Words: risk factors Ⅲ genetics Ⅲ stroke Ⅲ myocardial infarction Ⅲ inflammation Ⅲ coagulation I ncreased levels of inflammatory markers are associated with ischemic vascular disease. [1][2][3][4] Inflammation has a relevant role in the initiation and progression of atherosclerosis; 5 however, it can also play a primary role in thrombosis development by activating the coagulation process. 6 Interleukin-1␤ (IL-1␤), a proinflammatory cytokine, stimulates the synthesis of tissue factor (TF) from monocytes and endothelial cells. 7,8 TF triggers activation of the coagulation cascade toward thrombus formation. 9 Inflammatory responses show a high interindividual variability and have been associated with polymorphisms in IL-1␤ gene; 10,11 the latter have also been related to the risk of several chronic inflammatory diseases. 11,12 We hypothesized that IL-1␤ gene polymorphisms might modulate the inflammation-triggered pathway of thrombus formation and the risk of ischemic arterial disease such as myocardial infarction (MI) and ischemic stroke. Patients with early-onset disease represent a subset of individuals in whom the impact of genes is more expressed and can be more easily identified. [13][14][15] Therefore, we investigated whether the risk of MI and ischemic stroke at young age is associated with polymorphisms in IL-1␤ gene and whether these polymorphisms can influence thrombosis by modulating the IL-1␤-mediated TF activation in response to inflammation. Conclusions--511C/T IL- Methods Study Population Patients With MIBetween May 1995 and July 2002, 430 patients Ͻ45 (males) or Ͻ50 (females) years of age admitted to cardiology centers (see the list in the Appendix) with a first episode of MI were consecutively included into the study. Acute MI was defined as resting chest pain lasting Ͼ30 minutes accompanied by ST-segment...

Tissue factor gene polymorphisms and haplotypes and the risk of ischemic vascular events: four studies and a meta‐analysis

“…Recruitment of the Italian and US MI populations has been described elsewhere [16,18,19] (see Appendix S1). Patients with first-ever ischemic stroke (n = 267) occurring before the age of 45 years, consecutively admitted to the Department of Neurology, University of Brescia, and control subjects (n = 212) recruited from the general population in the area surrounding the medical centre, with no known history of vascular disease, frequency-matched to the cases by sex and age, were included in the study [20].…”

“…Our group have previously demonstrated that genetic variations of IL-1B were associated with the risk of both myocardial infarction and ischemic stroke at young age by affecting the release of IL-1B from stimulated mononuclear cells and in turn the expression of TF on cell membranes [16,17]. The aim of the present study was to evaluate the possible contribution to MI and/or ischemic stroke of tag-haplotypes in the TF gene in four case-control studies from different populations.…”

Role of inflammatory parameters in the susceptibility of cerebral thrombosis

“…Previous evidence supports our findings. IL-1B rs1864169 and rs3136558 have been indicated in various cerebrovascular phenotypes, such as stroke, ischemic injury and aneurysmal rupture (Boutin et al, 2001;Iacoviello et al, 2005;Slowik et al, 2006). These findings suggest that the IL-1B polymorphism is involved in the development of ischemic stroke.…”

Circulating Tissue Factor Levels and Risk of Stroke

“…18 The same genetic variants were found to be associated with either circulating levels of TF 41 or TF release from circulating lymphomonocytes. 19 Moreover, TF gene promoter haplotypes were associated with carotid intima-media thickness, a condition predisposing to ischemic stroke. 44 According to the principle of Mendelian randomization, 45 circulating TF should be considered more a causal risk factor for stroke rather than a marker of unrecognized exogenous factors.…”

“…A report from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study, indeed, evaluating the association between serum levels of TF and the risk of future coronary events in apparently healthy individuals, could not find any independent association. 17 Using a candidate gene approach, 18 we found that TF gene polymorphisms, associated with TF expression from human monocytes stimulated by LPS, 19 were associated with the risk of ischemic stroke at young age, whereas they did not affect ischemic coronary disease.…”