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.
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.
Henry
M
M
Laboratoire Hématologie, CHU Timone, CJF INSERM, Marseille, France.
Tregouët
D A
DA
Alessi
M C
MC
Aillaud
M F
MF
Visvikis
S
S
Siest
G
G
Tiret
L
L
Juhan-Vague
I
I
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000483:Alleles; D015992:Body Mass Index; D002648:Child; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood* / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic; D012737:Sex Factors; D010959:Tissue Plasminogen Activator / Q000276:immunology; D014280:Triglycerides / Q000097:blood; D005723:gamma-Glutamyltransferase / Q000097:blood
D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D014280:Triglycerides; D005723:gamma-Glutamyltransferase; D010959:Tissue Plasminogen Activator