Plasminogen activator inhibitor-1 4G/5G gene polymorphism in hemodialysis patients with cardiovascular disease

Abstract

Background Plasminogen activator inhibitor-1 (PAI-1) exerts antifibrinolytic and profibrotic activities and it plays an important role in renal fibrosis. Moreover, PAI-1 is also considered as a risk factor for cardiovascular disease. A 4G/5G polymorphism of the PAI-1 gene has been described associating the 4G haplotype with higher PAI-1 plasma activity. The aim of this study was to examine the frequency and distribution of the 4G/5G PAI-1 genotypes in patients with end-stage renal disease (ESRD) who developed cardiovascular complications in the form of hypertension, echocardiographic changes, and vascular thrombosis and the possible link(s) between them. Materials and methods We studied 40 patients with ESRD who had cardiovascular complications: 20 patients on hemodialysis (50%), 10 on conservative treatment (25%), and 10 subjected to renal transplantation (25%), in addition to 30 healthy individuals who served as controls. Genotyping of the PAI-1 gene was performed using allele-specific PCR method. Results The homozygous 4G/4G genotype was more frequent than the other genotypes (heterozygous 4G/5G and wild 5G/5G) among patients when compared with controls with a statistically significant difference (P=0.01). A significant difference was also found on comparing the presence of the mutant 4G allele (in 4G/4G and 4G/5G genotypes) or its absence (in the 5G/5G genotype) between patients and controls (P=0.04). On studying the genotyping of the four different groups, we found that the 4G/4G genotype was more prevalent among hemodialysis group, the 4G/5G was more prevalent among transplanted group, whereas the 5G/5G genotype was more frequent in the control group, and these differences were highly significant statistically (P=0.005). For the genotype frequencies and their potential associations with cardiovascular complications and/or different laboratory findings, we only found a nearly significant association between the presence of the mutant 4G allele and lower high-density lipoprotein cholesterol levels (P=0.08). Among patients who were subjected to renal transplantation, all patients who developed cardiovascular complications (50%), increased creatinine (10%), or repeated graft rejections (40%) had the heterozygous genotype (4G/5G) with the mutant 4G allele. Conclusion We found that the 4G/4G genotype in addition to the mutant 4G allele was more frequent among patients with ESRD compared with controls. The presence of the 4G mutation showed a nearly significant association with lower high-density lipoprotein cholesterol levels, suggesting that it could play a role in the pathogenesis of accelerated atherosclerotic heart disease in uremic patients.