Stegnar M, Uhrin P, Peternel P, Mavri A, Salobir-Pajnic B, Stare J, Binder B R
University Medical Centre, Department of Angiology, Ljubljana, Slovenia.
Thromb Haemost. 1998 May;79(5):975-9.
Impaired fibrinolysis due to increased plasminogen activator inhibitor-1 (PAI-1) is observed in up to 40% of patients with venous thromboembolism and might be causally related to the disease. There is evidence that genetic variations in the promoter of the PAI-1 gene and metabolic factors contribute to increased plasma PAI-1 levels. A single nucleotide insertion/deletion (4G/5G) polymorphism in the promoter region of the PAI-1 gene and metabolic factors were studied in 158 unrelated patients below the age of 61 years (43 +/- 11 years, mean +/- standard deviation) with history of objectively confirmed venous thromboembolism and in 145 apparently healthy controls. Patients had on average two times higher PAI activity (11.9 vs. 6.1 IU/ml) and by 40% higher PAI-1 antigen (14.8 vs. 10.7 ng/ml) than healthy controls, and also higher body mass index, lipid levels, fasting glucose and insulin. Patients differed 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 controls) nor in the distribution of the 4G/5G genotypes. Possession of the 4G/4G or the 4G/5G genotype did not increase relative risk for venous thromboembolic disease and the distribution of the 4G/5G genotypes was neither associated with recurrent nor with spontaneous disease. In patients association between the 4G/5G genotypes and PAI activity (adjusted 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 the 5G/5G genotype (5.2 IU/ml, all values means). Association between PAI activity and triglyceride level was the strongest in the 4G/4G genotype (correlation coefficient r = 0.47, p < 0.01) and the weakest in the 5G/5G genotype (r = -0.04, not significant). In conclusion, the present case-control study shows an association between the 4G/5G polymorphism in the promoter of the PAI-1 gene and plasma PAI-1 levels in patients with venous thromboembolism. Similar distribution of the 4G/5G genotypes in patients and healthy controls suggests that this genetic variation by itself is not a major risk factor for venous thromboembolism.
在高达40%的静脉血栓栓塞患者中观察到由于纤溶酶原激活物抑制剂-1（PAI-1）增加导致的纤维蛋白溶解受损，这可能与该疾病存在因果关系。有证据表明，PAI-1基因启动子的基因变异和代谢因素会导致血浆PAI-1水平升高。在158名年龄在61岁以下（平均43±11岁，均值±标准差）且有客观确诊静脉血栓栓塞病史的无血缘关系患者以及145名明显健康的对照者中，研究了PAI-1基因启动子区域的单核苷酸插入/缺失（4G/5G）多态性和代谢因素。患者的PAI活性平均比健康对照者高两倍（11.9对6.1 IU/ml），PAI-1抗原高40%（14.8对10.7 ng/ml），并且体重指数、血脂水平、空腹血糖和胰岛素水平也更高。患者与健康对照者在4G和5G等位基因频率（患者为0.57/0.43，对照者为0.52/0.48）以及4G/5G基因型分布方面均无显著差异。拥有4G/4G或4G/5G基因型并不会增加静脉血栓栓塞性疾病的相对风险，且4G/5G基因型分布与复发性疾病或自发性疾病均无关联。在患者中观察到4G/5G基因型与PAI活性之间存在关联（根据体重指数、甘油三酯和血糖水平进行调整），4G/4G基因型的PAI活性值最高（14.6 IU/ml），4G/5G基因型居中（13.3 IU/ml），5G/5G基因型最低（5.2 IU/ml，所有值均为均值）。PAI活性与甘油三酯水平之间的关联在4G/4G基因型中最强（相关系数r = 0.47，p < 0.01），在5G/5G基因型中最弱（r = -0.04，无显著性）。总之，本病例对照研究表明PAI-1基因启动子中的4G/5G多态性与静脉血栓栓塞患者的血浆PAI-1水平之间存在关联。患者和健康对照者中4G/5G基因型的相似分布表明，这种基因变异本身并非静脉血栓栓塞的主要危险因素。
