Our findings suggest that certain polymorphisms of the factor VII gene may influence the risk of myocardial infarction. It is possible that this effect may be mediated by alterations in factor VII levels.

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...

Summary. Background: Obesity is a major modifiable risk factor for cardiovascular disease. Leptin, the hormone synthesized and released primarily by adipose tissue and found increased in obese individuals, has been implicated in the regulation of inflammation and arterial and venous thrombosis. Objective: To investigate the role of tissue factor (TF), the pivotal agonist of the clotting cascade, as a link between obesity and cardiovascular disease. Methods and results: In 15 obese patients, plasma levels of leptin and TF as well as TF expression in resting and endotoxin-stimulated mononuclear leukocytes (MN) were increased when compared with healthy donors. In a selected sample of obese patients, loss of body weight led to decreased circulating leptin levels, accompanied by a reduction in plasma TF as well as in TF expression, both in resting and endotoxin-stimulated MN. In subsequent in vitro experiments, leptin was incubated with MN from healthy subjects. Leptin induced TF activity and antigen in a dose-dependent fashion, as assessed by clotting assay and ELISA, respectively. Increased migration of c-Rel/p65 into the nucleus, as determined by EMSA, and development of TF mRNA in monocytes, as assessed by RT-PCR, were observed. Experiments with mitogen-activated protein kinase (MAPK) inhibitors, indicated the involvement of p38 and ERK1/2 pathways. Conclusions: The presence of TF-expressing MN in blood from obese subjects and the in vitro induction of TF by pharmacologic concentrations of leptin in MN from healthy subjects suggest that TF expression by leptin-stimulated monocytes may contribute to the cardiovascular risk associated with obesity.