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

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.