|Year : 2013 | Volume
| Issue : 1 | Page : 29-35
Plasminogen activator inhibitor-1 4G/5G gene polymorphism in hemodialysis patients with cardiovascular disease
Baheia H. Mostafa1, Doha A. Mokhtar2, Ahmed M. Badr1, Nasser M. Gamal el Din1
1 Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||15-Sep-2012|
|Date of Acceptance||02-Oct-2012|
|Date of Web Publication||20-Jun-2014|
Doha A. Mokhtar
MD, Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo
Source of Support: None, Conflict of Interest: None
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.
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.
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.
Keywords: cardiovascular disease, hemodialysis, plasminogen activator inhibitor-1
|How to cite this article:|
Mostafa BH, Mokhtar DA, Badr AM, Gamal el Din NM. Plasminogen activator inhibitor-1 4G/5G gene polymorphism in hemodialysis patients with cardiovascular disease. Egypt J Haematol 2013;38:29-35
|How to cite this URL:|
Mostafa BH, Mokhtar DA, Badr AM, Gamal el Din NM. Plasminogen activator inhibitor-1 4G/5G gene polymorphism in hemodialysis patients with cardiovascular disease. Egypt J Haematol [serial online] 2013 [cited 2022 Aug 8];38:29-35. Available from: http://www.ehj.eg.net/text.asp?2013/38/1/29/134800
| Introduction|| |
Plasminogen activator inhibitor-1 (PAI-1), a primary inhibitor of both tissue-type and urokinase-type plasminogen activators, plays a critical role in the regulation of intravascular fibrinolysis 1. As plasminogens and their inhibitors play an important role both in fibrinolysis and in extracellular matrix (ECM) degradation, a decreased synthesis of renal plasminogens and/or increased production of renal PAI-1 may result in an imbalance in the extracellular proteolytic process, thereby leading to the progression of glomerular sclerotic lesions 2. Several experimental and clinical studies support a role for PAI-1 in the renal fibrogenic process occurring in chronic glomerulonephritis and diabetic nephropathy 3. On the other hand, impaired fibrinolytic activity because of increased PAI-1 levels has been associated with coronary heart disease and atherosclerosis 4. Therefore, PAI-1 is also considered as a risk factor for cardiovascular diseases (CVD), which are the leading cause of mortality and morbidity in the dialysis population 5.
Interstitial fibrosis and tubular atrophy (IFTA) is a clinicopathological entity characterized by fibrosclerosis of the different renal structures leading to a progressive decrease in renal function after kidney transplantation 6. The molecular mechanisms that underlie the pathophysiology of IFTA remain unclear 7. Degrading proteases are important participants in tissue remodeling and repair and, therefore, their activation may play a role in the morphological changes observed in IFTA. Plasmin, which is a potent serine protease responsible for fibrinolysis, is also involved in matrix metalloproteinase activation, growth factor release (GFR), and direct degradation of ECM proteins. The PAI-1 controls plasmin formation and seems to be involved in the development of tissue fibrosis and IFTA 3. Upregulation of PAI-1 has been found in human IFTA accompanied by persistent fibrin deposition in the graft 8. Furthermore, the glomerular PAI-1 mRNA level has been shown to be predictive of long-term graft function 9 and is correlated with the intensity of interstitial fibrosis on a kidney graft biopsy 10. PAI-1 levels are related to the rate of renal failure progression after kidney transplantation 11.
A common 4G/5G polymorphism in the promoter region of the human PAI-1 gene has been described and is associated with different levels of serum PAI-1 activity 12. Patients with the 4G4G genotype have the highest levels of PAI-1 activity, whereas those with the 5G5G genotype have the lowest plasma PAI-1 activity 13. The 5G variant binds the E2F transcription repressor, whereas 4G fails to do so and is associated with the higher PAI-1 plasma level 14.
The aim of the present study was to evaluate the incidence of 4G/5G PAI-1 gene polymorphisms in hemodialysis patients with cardiovascular complications and to examine the possible link(s) between the different allelic frequencies to the atherogenic lipid profile and cardiovascular morbidity in these patients.
| Patients|| |
This study included 40 children with end-stage renal disease (ESRD) who had CVD. They included 26 males and 14 females.
All patients were followed in Chronic Renal Failure Clinic of Abo El Reish Children Hospital with regular monitoring of their GFR, serum electrolytes, ABG, hemogram, coagulation profile, lipid profile, Ca, P, parathormone assay, and bone density for all cases besides Kt/V and viral serology for the hemodialysis group, in addition to clinical assessment of all cases with a special focus on blood pressure monitoring, cardiovascular examination, and echocardiography to assess their ventricular function and volume, systolic pressure, and valvular incompetence.
Patients were grouped as follows:
- Group I (20 patients): with GFR less than 10 ml/min/1.7 m2 who were regularly maintained on a continuous hemodialysis program (3 days/week).
- Group II (10 patients): with GFR greater than 10 ml/min/1.7 m2 who were on conservative treatment and not included in a regular dialysis program.
- Group III (10 patients): with ESRD who had undergone renal transplantation seven of them received previous hemodialysis (HD) settings.
Thirty age and sex-matched healthy children from similar socioeconomic strata were enrolled in the study as a control group for a comparative analysis (group IV).
Informed consents was obtained from the parents of the participating children before enrollment.
| Materials and methods|| |
Blood samples were collected by sterile venipunctures in EDTA vacutainer tubes that were stored at −20°C for subsequent DNA extraction and further genotyping in addition to plain vacutainer tubes to separate serum, which was also stored at −20°C for subsequent analysis of the lipid profile and creatinine.
Determination of the PAI-1 4G/5G genotype
Genomic DNA was extracted from the whole blood of all patients and controls using the QIAamp DNA Kit (catalog number 51104; Qiagen, Hilden, Germany).
The allele-specific PCR technique was used to detect the PAI-1 (4G/5G) gene polymorphism 15.
This single allele deletion (4G)/insertion (5G) is situated at −675 bp of the promoter region of the gene. The genotypes of all patients’ were determined by PCR amplification of genomic DNA using the allele-specific primers: (a) insertion 5G allele: 5′-GTC TGG ACA CGT GGG GG-3′ and (b) deletion 4G allele: 5′-GTC TGG ACA CGT GGG GA-3′. Each was in combination with a common downstream primer, 5′-TGC AGC CAG CCA CGT GAT TGT CTA G-3′, which gave rise to a 139 base pair DNA fragment. A control upstream primer, 5′-AAG CTT TTA CCA TGG TAA CCC CTG GT-3′, was used as a positive control in the PCR.
The 25 μl PCR mixture contained 20 pmol from each primer, 12.5 μl Taq PCR Master Mix Kit (Catalog no. 201443; Qiagen, Hilden, Germany), 5μl template DNA, and 2.5 μl water, nuclease-free. The thermal cycling conditions were 95°C for 60 s, 61°C for 40 s, and 72°C for 40 s for 30 cycles using the Perkin Elmer PCR system 9600 (Illinois, USA).
Detection of PCR amplification products
The PCR products were separated by gel electrophoresis in a 2% agarose gel, which had been stained with ethidium bromide and viewed under ultraviolet irradiation. Interpretation: in all the samples, the fragment produced by amplification with the internal control primers must be observed (at about 300 bp). The presence or absence of a mutation is simply determined by the presence or absence of the expected fragment produced by amplification with the mutant ARMS primer and the common primer. The presence or absence of the normal allele is determined in the same way in the reaction that includes the normal ARMS primer. In this way, heterozygous, homozygous wild, and homozygous mutant genes can be distinguished. Each patient was classified into 4G4G, 4G5G, or 5G5G according to the presence of the 139 bp PCR product generated by the allele-specific primers.
Data were collected and tabulated. The statistical package for social science program version 17.0 (SPSS Inc., Chicago, Illinois, USA) was used for data analysis. Mean and SD or median and interquartile range were estimates of quantitative data, whereas frequency and percentage were estimates of qualitative data. χ2 was the test of comparison for qualitative data. Comparison of quantitative data was carried out using a Student t-test or the Mann–Whitney U-test when appropriate. P value was significant at 0.05 levels.
| Results|| |
General characteristics of the studied patients
We examined 40 children with ESRD, 26 males (65%) and 14 females (35%). Their ages ranged from 0.5 to 17 years, mean age 11.5±3.6 SD, in addition to 30 age-matched and sex-matched healthy children included as controls. The main primary causes of ESRD were as follows: renal scarring either with VUR (5/40) or without VUR (3/40); urinary tract obstruction (9/40); glomerulonephritis (12/40) because of hereditary or acquired causes; and unknown causes (11/40).
We classified our study population (40 patients and 30 controls) into four groups: group I: on hemodialysis [20/70 (28.5%)], group II: on conservative treatment [10/70 (14.3%)], group III: transplanted group [10/70 (14.3%)], and group IV: control group [30/70 (42.9%)]. This is shown in [Table 1].
Clinical and laboratory findings
All patients in groups I and II (30 patients) were hypertensive and showed echocardiographic findings. Among these patients, 12 of 30 (40%) had mild cardiac complications, 17 of 30 (56.7%) had moderate cardiac complications, and one of 30 (3.3%) had severe cardiac complications. The severity of cardiac complications was assessed on the basis of the findings of echocardiography, where patients with cardiomegaly alone were considered to have mild complications, whereas those with cardiomegaly and decreased systolic function or secondary mitral regurge were considered to have moderate complications, and those with cardiomegaly, decreased systolic function, and secondary mitral regurge were considered to have severe complications.
In terms of vascular access complications (in the form of recurrent fistula failure because of thrombosis that required a shift of the arteriovenous fistula to another site), we found that all patients on regular hemodialysis (group I) developed vascular access thrombosis with variable degrees, where four of 20 of our patients (20%) had mild complications, another four of 20 (20%) had moderate complications, and 12 of 20 (60%) had severe complications; fistula failure because of thrombosis that required two or less trials to shift to other sites was considered as a mild complication, repeated fistula failure with three to five trials was considered as a moderate complication, and repeated fistula failure with more than five trials was considered as a severe complication.
In terms of the patients who had undergone renal transplantation (10 patients), five patients (50%) had hypertension, two (20%) had moderate to severe cardiac complications, and two (20%) who were on hemodialysis had vascular access thrombosis before transplantation. Following transplantation, four of the five hypertensive patients still had hypertension that was controlled by treatment. Cardiac complications did not change in the previous two cases, whereas another new case (10%) developed vascular thrombosis at the site of renal anastomosis. Only one case (10%) had creatinine more than 1.5 mg/dl. Among the transplanted cases, 40% had repeated graft rejection.
The laboratory findings of all patients are shown in [Table 2].
[Table 3] shows the possible association between the severity of both cardiac and vascular complications and the presence of dyslipidemia (cases with an atherogenic lipid profile).
|Table 3: Possible association between the severity of cardiovascular complications and the presence of dyslipidemia|
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Results of genotyping
[Figure 1] shows the allele-specific PCR results in three of our cases.
|Figure 1: Different plasminogen activator inhibitor-1 (4G/5G) polymorphism genotyping. Lane 1: marker-ladder 100 bp (Fermentas). All lanes after lane 1 showed bands at 300 bp (representing the amplification of the control primer). After lane 1, each two subsequent lanes represent insertion (4G) and then the deletion (5G) polymorphism genotyping for every case. Lanes 2, 3 (case 1) and 6, 7 (case 3) show bands at 139 bp representing both the 4G and the 5G heterozygous genotype. Lanes 4, 5 (case 2): show a 139 bp band only at lane 4, representing the 4G genotype.|
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Among the 40 patients of ESRD genotyped for the PAI-1 promoter polymorphism, 32.5% of the cases were homozygous for the mutant allele 4G/4G compared with 13.3% of the controls with an almost high significant difference (P=0.01), whereas 32.5% of cases were homozygous for the wild allele 5G/5G compared with 53.3% of controls with a statistically significant difference (P=0.04). The heterozygous 4G/5G genotype frequencies were 35 and 33.3% for cases and controls, respectively. This difference was not significant statistically (P=0.4). However, the mutant 4G allele was found to be greater among the cases (67.5%) than the controls (46.7%), whereas the wild 5G allele was found to be greater among the controls (53.3%) than the cases (32.5%), with a statistically significant difference (P=0.04) [Table 4].
|Table 4: Comparison between cases and controls in the frequency of different PAI-1 gene polymorphisms|
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We also studied the frequency of different genotypes among the four groups and we found a highly significant difference between these groups in the 4G/5G polymorphisms, where the mutant 4G/4G genotype was greater in the HD group and the heterozygous 4G/5G genotype was greater in the transplanted group, whereas the wild 5G/5G genotype was greater in the control group with a P value of 0.005 as shown in [Figure 2].
|Figure 2: Bar chart showing the distribution of different genotypes of the 4G/5G polymorphisms of the PAI-1 gene among the four groups. PAI-1, plasminogen activator inhibitor-1.|
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[Table 5] shows the possible association between the severity of both cardiac and vascular complications and the presence of the 4G mutation.
|Table 5: Possible association between the severity of cardiovascular complications and the presence of the 4G mutation|
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|Table 6: Frequency of the 4G mutation and its possible association with different laboratory results among cases with ESRD|
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|Table 7: Possible associations between abnormal values of lipid profile and frequency of the 4G mutation among cases with ESRD|
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[Table 6] and [Table 7] show the genotype frequencies and their potential associations with different laboratory findings or abnormal values of the lipid profile. We did not find any significant relationship between them, except for lower high-density lipoprotein (HDL) levels, which showed an almost significant association with the presence of the mutant 4G allele (i.e. in both 4G/4G and 4G/5G genotypes) with a P value of 0.08.
All the transplanted patients who had or developed cardiovascular complications besides those with increased creatinine and/or repeated graft rejections had the heterozygous genotype (4G/5G), carrying the mutant 4G allele.
| Discussion|| |
PAI-1 is a multifunctional glycoprotein with impressive fibrosis promoting effects in the kidney 16. PAI-1 is not expressed in the normal human kidney, but is strongly expressed in various forms of renal disease, and it may play an important role in disease activity and progression 15. High renal PAI-1 levels also seem to predict a poor long-term outcome of renal grafts. Genetic variation in the PAI-1 gene is associated with varying levels of PAI-1 activity in healthy individuals as well as in patients with other diseases such as coronary artery disease or diabetes mellitus 3. A common 4G/5G polymorphism in the promoter region of the human PAI-1 gene at −675 bp has been described 12. Patients with the 4G4G genotype have the highest levels of PAI-1 activity, whereas those with the 5G5G genotype have the lowest plasma PAI-1 activity. The exact mechanism by which the 4G allele exerts its detrimental effect is not fully understood 13. Individuals carrying 4G alleles have an increased risk of thrombosis, acute myocardial infarction, and possibly sudden cardiac death compared with those homozygous for 5G 17. In the presence of the 5G allele, an additional binding site is created that produces an inhibitor of PAI-1 gene transcription, leading to an attenuated level of transcription 13. Thus, the presence of the 4G allele is associated with higher transcriptional activity, resulting in higher PAI-1 levels and activity compared with the presence of the 5G allele, whereas the heterozygous genotype is associated with intermediate levels 17.
The current study included 40 patients with ESRD who had cardiovascular complications and 30 controls and showed that the homozygous mutant 4G genotype (4G/4G) was more frequent than other genotypes (wild 5G/5G and heterozygous 4G/5G genotypes) among cases when compared with controls with an almost high significant difference (P=0.01). A statistically significant difference was also detected on comparing the presence of the mutant 4G allele (in 4G/4G and 4G/5G genotypes) or its absence (in 5G/5G genotype) between cases and controls (P=0.04). On studying the genotyping of the four different groups in our study (those on hemodialysis, those on conservative treatment, those subjected to renal transplantation, and control groups), we found that the 4G/4G genotype was more prevalent among hemodialysis group, the 4G/5G genotype was more among transplanted group (i.e. carrying the mutant 4G allele), and the 5G/5G genotype was more frequent in the control group; these differences were highly statistically significant (P=0.005). Trimachi et al. 18 also found that the 4G/5G genotype was the most prevalent variant in HD patients included in their study.
These results are in agreement with previous studies that reported that progression of renal disease occurred more frequently in patients with the 4G/4G genotype or the 4G mutation compared with those with the wild 5G/5G genotype, concluding that the presence of the 4G allele was associated with renal deterioration 15. This was also confirmed by a recent study by Weng et al. 19 in 2012 that showed that an elevated serum PAI-1 level was correlated with greater cognitive decline or deterioration in patients with good eGFR. These results had been attributed to the association of PAI-1 with the accumulation of ECM, glomerulosclerosis, and tubulointerstitial fibrosis, and consequently terminal renal failure 20.
Our study showed that all HD patients were at a risk of developing cardiac and thrombotic vascular complications of variable degrees. The increased incidence of vascular thrombosis in the HD group is probably a result of vascular access puncture and vascular injury with the consequent release of PAI-1 in the blood, but no statistically significant association was found between the severity of either cardiac or vascular complications and genetic variants of the PAI-1 gene. This may be attributed to the presence of many other factors contributing toward cardiovascular complications such as anemia, uremic toxins, and the efficiency of both dialysis and ultrafiltration in removing toxins and decreasing volume overload.
Other studies havereported that the PAI-1 antigen was not found to be associated with CVD in their dialysis patients 21 or that PAI-1 did not explain the variations in the prevalence of CVD in dialysis patients 22,23.
However, Trimachi et al. 18 suggested that the 4G/5G variant might be associated with an increased risk of thrombosis in HD patients with polytetrafluoroethylene grafts, but not with arteriovenous fistulae. In another study by Chen et al. 15, they found that the prevalence of coronary artery diseases was significantly higher in adult patients with the 4G/5G genotype than the other genotypes in patients with membranous nephropathy. They also found a higher prevalence of peripheral vascular events in patients with the 4G/5G and 4G/4G genotypes, concluding that patients carrying the 4G allele had a risk of developing coronary artery events and other peripheral vascular complications compared with patients carrying the 5G allele.
We also found an almost significant association between low HDL levels and the presence of the mutant 4G allele with a P value of 0.08. This result can be attributed to what has been described previously as there is a significant negative correlation between PAI-1 and HDL-C in dialysis patients 24.
We did not find a significant difference in the creatinine level between those with the mutant 4G allele and others among our cases with ESRD (P=0.7), whereas Chen et al. 15 found a significant increase in serum creatinine in patients with the 4G/4G genotype more than that in patients with the 4G/5G genotype and the 5G/5G genotype, with a P value equal to 0.02.
In patients who underwent renal transplantation, all cases that had or developed cardiovascular complications in addition to those with increased creatinine or repeated graft rejections had the heterozygous genotype (4G/5G) with the mutant 4G allele.
Chow et al. 16 found that the recipient PAI-1 genotype was associated with progressive renal dysfunction after acute rejection in renal transplant patients. However, Rérolle et al. 12 could not confirm these results. In their study, neither the donor nor the recipient PAI-1 genotype affected kidney graft survival in patients with a history of acute rejection.
Delarue et al. 9 showed for the first time that the PAI-1 mRNA level of expression is significantly upregulated in human acute rejection. This was in good agreement with the results published by other groups who used animal models of kidney transplantation. In a model of acute graft rejection in the rats, Wang et al. 25, using northern blot techniques, showed that the upregulation of PAI-1 mRNA was observed early (day 4 after transplantation) and along with fibrin deposits and microthrombosis of renal capillaries.
These data suggest that drugs that counteract thrombosis or more specific drugs that target PAI-1 synthesis may prove to be beneficial both in retarding renal failure and in preventing vascular events in patients with less severe renal diseases carrying the 4G allele.
In conclusion, we found that the 4G/4G genotype in addition to the mutant 4G allele were more frequent among cases with ESRD and showed an almost significant association with lower HDL-C levels, suggesting that it could play a role in the pathogenesis of accelerated atherosclerotic heart disease in uremic patients. However, a larger study population is necessary for better assessment of the prevalence and the role of PAI-1 polymorphisms in ESRD together with their correlation with PAI-1 serum levels.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]