The 4G/5G Genetic Polymorphism in the Promoter of the Plasminogen Activator Inhibitor-1 (PAI-1) Gene Is Associated with Differences in Plasma PAI-1 Activity but not with Risk of Myocardial Infarction in the ECTIM Study

Abstract

SummaryWe have investigated the interrelationships of plasma PAI-1 activity, the PAI-1 4G/5G polymorphism and risk of myocardial infarction (MI) in the ECTIM study, a case-control study of MI based in Belfast, Lille, Strasbourg and Toulouse. Mean PAI-1 levels in cases were similar across all centres but in controls, levels in the French centres were significantly higher. Only in Belfast were PAI-1 levels higher in cases (11.7AU/ml) than controls (10.5AU/ml). The PAI-1 4G allele frequency was similar in cases and controls (0.55 and 0.54). In all groups, 4G homozygotes had the highest mean plasma PAI-1 level (4G4G vs 5G5G; cases overall: 14.2 vs 12.1 AU/ml; controls overall: 15.0 vs 12.6AU/ml), with the heterozygotes generally intermediate. The data from Belfast are consistent with the literature implicating PAI-1 level as an MI risk factor. In ECTIM, the PAI-1 4G/5G polymorphism is not a genetic risk factor for MI but is associated with PAI-1 activity. Thus homozygosity for the 4G allele may predispose to elevated PAI-1 and impaired fibrinolysis, perhaps requiring interaction with other genetic or environmental factors to influence MI risk.

Plasminogen Activator Inhibitor 4G Polymorphism Is Associated With Decreased Risk of Cerebrovascular Mortality in Older Women

“…18,19 These findings must be considered as spurious, because all large studies, including ours, did not confirm such an association. 4,20 The only study on PAI-1 genotype and cerebrovascular disease was suggestive of a reduced risk of stroke incidence for the PAI-1 4G allele compared with the PAI-1 5G allele, although this did not reach statistical significance. 21 Other large studies on PAI-1 4G/5G genotype and stroke have not yet been reported.…”

“…Additional support for the validity of our findings is provided by the relationship between plasma tPA levels and increased risk of myocardial infarction and stroke, which was consistently found in 4 large studies. [1][2][3][4][5] Furthermore, an abnormally high PAI-1 4G allele frequency was found in centenarians, 29 which suggests a better survival rate for those with PAI-1 4G genotype.…”

“…18,19 However, all large studies reported no association between PAI-1 4G/5G genotype and myocardial infarction. 4,20 In contrast, PAI-1 4G genotype may be inversely associated with morbidity of stroke. 21 We had the opportunity to study the relationship between PAI-1 4G/5G genotype and both myocardial infarction and stroke mortality in a cohort study of 12 239 women initially aged 52 to 67 years who were followed up with regard to mortality for 16 to 18 years.…”

“…ncreased plasma levels of tissue-type plasminogen activator (tPA) and its inhibitor, plasminogen activator inhibitor (PAI-1), are both associated with an increased risk of myocardial infarction [1][2][3][4] and stroke. 5 Although the relationship between these proteins and cardiovascular disease is evident, the interpretation is controversial.…”

Segregation Analysis of Plasminogen Activator Inhibitor-1 and Fibrinogen Levels in the NHLBI Family Heart Study

“…A common deletion/insertion polymorphism (4G/5G) has been identified in the 5Ј promoter region; in vitro, there is a 5-to 6-fold greater responsiveness of the deletion allele (4G) to stimulation by interleukin-1, 30 possibly because of differential binding of a repressor protein. 31 One small cross-sectional study indicated that individuals with 2 copies of the 4G allele had a 2-fold greater prevalence of myocardial infarction, but this finding has not been replicated in large-scale cross-sectional 32 or prospective studies. 33 Several cross-sectional studies have also reported a positive correlation between the number of 4G alleles and plasma PAI-1 activity or antigen levels.…”