THE 4G 5G SEQUENCE POLYMORPHISM IN THE PROMOTER OF PLASMINOGEN-ACTIVATOR INHIBITOR-1 (PAI-1) GENE - RELATIONSHIP TO PLASMA PAI-1 LEVEL IN VENOUS THROMBOEMBOLISM/

Impaired fibrinolysis due to increased plasminogen activator inhibitor -1 (PAI-1) is observed in up to 40% of patients with venous thromboemb olism and might be causally related to the disease. There is evidence that genetic variations in the promoter of the PAI-1 gene and metaboli c factors contribute to increased plasma PAI-I levels. A single nucleo tide insertion/deletion (4G/5G) polymorphism in the promoter region of the PAI-1 gene and metabolic factors were studied in 158 unrelated pa tients below the age of 61 years (43 +/- 11 years, mean +/- Standard d eviation) with history of objectively confirmed venous thromboembolism and in 145 apparently healthy controls. Patients had on average two t imes higher PAI activity (11.9 vs. 6.1 IU/ml) and by 40% higher PAI-I antigen (14.8 vs. 10.7 ng/ml) than healthy controls, and also higher b ody mass index, lipid levels, fasting glucose and insulin. Patients di ffered significantly from healthy controls neither in the frequency of the 4G and 5G alleles (0.57/0.43 in patients and 0.52/0.48 in control s) nor in the distribution of the 4G/5G genotypes. Possession of the 4 G/4G or the 4G/5G genotype did not increase relative risk for venous t hromboembolic disease and the distribution of the 4G/5G genotypes was neither associated with recurrent nor with spontaneous disease. In pat ients association between the 4G/5G genotypes and PAI activity (adjust ed for body mass index, triglyceride and glucose level) was observed, with the highest PAI activity values in the 4G/4G genotype (14.6 IU/ml ), intermediate in the 4G/5G genotype (13.3 IU/ml) and the lowest in t he 5G/5G genotype (5.2 IU/ml, all values means). Association between P AI activity and triglyceride level was the strongest in the 4G/4G geno type (correlation coefficient r = 0.47, p <0.01) and the weakest in th e 5G/5G genotype (r = -0.04, not significant). In conclusion, the pres ent case-control study shows an association between the 4G/5G polymorp hism in the promoter of the PAI-I gene and plasma PAI-I levels in pati ents with venous thromboembolism. Similar distribution of the 4G/5G ge notypes in patients and healthy controls suggests that this genetic va riation by itself is not a major risk factor for venous thromboembolis m.