© 1998 American Heart Association, Inc.
Original Contributions |
Metabolic Determinants Are Much More Important Than Genetic Polymorphisms in Determining the PAI-1 Activity and Antigen Plasma Concentrations
A Family Study With Part of the Stanislas Cohort
From the Laboratoire Hématologie, CHU Timone, CJF INSERM, Marseille (M.H., M.C.A., M.F.A., I.J.-V.); INSERM U258, Paris (D.A.T., L.T.); and the Laboratoire Centre Médecine Préventive and Université Henri Poincaré, Vandoeuvre les Nancy (S.V., G.S.), France.
Correspondence to Prof I. Juhan-Vague, Laboratoire Hématologie, CHU Timone, 13385 Marseille Cedex 5, France.
Abstract—Increased plasma plasminogen activator inhibitor-1 (PAI-1) concentration has been identified as a risk factor for coronary heart disease. We investigated the relative contribution of both metabolic factors involved in the insulin resistance (IR) syndrome and polymorphisms of the PAI-1 gene to plasma levels of PAI-1 in 228 healthy nuclear white families from the Stanislas Cohort. Variables related to IR included body mass index, waist-to-hip ratio, fasting insulin, triglyceride, and HDL cholesterol. Five PAI-1 gene polymorphisms were studied, including a newly described G+12078A substitution in the 3' region. A sex difference was observed, with fathers exhibiting higher IR state and PAI-1 levels and stronger correlations between PAI-1 and IR variables than mothers. Such a difference was not observed in offspring. Family correlations were of similar magnitude for fibrinolytic parameters and IR variables. The PAI-1 genotypes A-844G, -675 4G/5G, and G+12078A polymorphisms, which were in strong linkage disequilibrium, were associated with plasma PAI-1 levels. In multivariate analysis, IR explained a major part of PAI-1 variability (49% in fathers, 29% in mothers), whereas polymorphisms had only a minor contribution, explaining 3% of variability in women and having no significant effect in men. We conclude that plasma levels of PAI-1 are, in a healthy population, primarily determined by the IR syndrome, this relationship being stronger in males. The contribution of the PAI-1 gene seems larger in females. These results deserve special attention for understanding the relationships observed between fibrinolytic parameters and the risk of developing a cardiovascular ischemic event.
Key Words: plasminogen activator inhibitor 1 • risk factors • myocardial infarction • insulin resistance • genetics
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