Juhan-Vague, I and Morange, PE and Frere, C and Aillaud, MF and Alessi, MC and Hawe, E and Boquist, S and Tornvall, P and Yudkin, JS and Tremoli, E and Margaglione, M and Di Minno, G and Hamsten, A and Humphries, SE and HIFMECH Study Grp, (2003) The plasminogen activator inhibitor-1-675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH Study. J THROMB HAEMOST , 1 (11) 2322 - 2329.
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Although the potential role of plasminogen activator inhibitor-1 (PAI-1) in the development of coronary artery disease is strongly supported by its biological characteristics, results of clinical studies remain controversial. Objectives: To investigate whether plasma PAI-1 concentrations and the -675 4G/5G polymorphism located in the PAI-1 gene could constitute risk markers for myocardial infarction (MI). Patients and methods: We used a European case-control study, the HIFMECH study, comparing 598 men with MI and 653 age-matched controls. Results: Insulin resistance explained a major part of the variation in PAI-1 (24%) whereas inflammation had only a minor contribution (0.01%). For both cases and controls plasma PAI-1 concentrations were significantly higher in the North than the South, and in both regions were higher in individuals with MI compared with control subjects [overall odds ratio (OR) for a 1 SD increase = 1.54, 95% confidence interval (CI) 1.34, 1.77]. This difference was observed in all the centers studied. Overall, the difference between cases and control subjects remained significant after controlling for inflammation variables (OR = 1.30, 95% CI 1.08, 1.57), but lost significance after controlling for insulin resistance variables (OR = 1.17, 95% CI 0.98, 1.40). The 4G allele was associated with significantly higher PAI-1 levels in cases but not controls and, taken independently, did not modify the risk of MI (P = 0.9). However, a significant interaction was observed with both insulin or proinsulin and the risk of MI (P = 0.05 and 0.02, respectively), but not with triglycerides or body mass index (BMI). The insulin or proinsulin effect on risk was observed only in the carriers of the 4G/4G genotype. This interaction appeared not to be mediated by plasma PAI-1 antigen concentrations (P = 0.01 and 0.02 after adjustment for PAI-1 plasma levels). The interaction with proinsulin but not insulin remained statistically significant after further adjustment for other factors associated with insulin resistance (triglycerides and BMI) and C-reactive protein (P = 0.01). Conclusion: This study suggests that PAI-1 has a role in risk of MI in the presence of underlying insulin resistance. A significant interaction between insulin or proinsulin and the -675 4G/5G polymorphism was observed in risk for MI. The mechanisms for these interactions remain to be determined.
|Title:||The plasminogen activator inhibitor-1-675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH Study|
|Keywords:||insulin resistance, myocardial infarction, PAI-1, PAI-1 gene polymorphism, CORONARY HEART-DISEASE, PAI-1 GENE, RESISTANCE ATHEROSCLEROSIS, FIBRINOLYTIC FACTORS, ENDOTHELIAL-CELLS, ANGINA-PECTORIS, POLYMORPHISM, PROMOTER, TYPE-1, TISSUE|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
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