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 OJEMD  Vol.7 No.6 , June 2017
Genetic and Metabolic Determinants of Plasminogen Activator Inhibitor 1 (PAI-1) in Tunisian Type 2 Diabetes Patients
Abstract: Background: PAI-1 (plasminogen activator inhibitor-1) is a powerful regulator of fibrinolysis and plasma level is high in type 2 diabetes and cardio-vascular disease, which is determined by genetic polymorphisms in PAI-1 gene and environmental factors. The aim of the study was to examine the determinants of plasma PAI-1 Ag level among type 2 diabetes patients. Methods: 491 Tunisian type 2 diabetes patients had clinical evaluation (weight, high, BMI, Waist Circumference), laboratory investigations including FBG Hb1Ac, cholesterol, triglyceride; HDL-cholesterol was done; plasma PAI-1 antigen level was done with ELISA; −675 4G/5G and −844 G/A polymorphisms of PAI-1 gene was done by PCR-ASA and PCR-RFLP respectively. Results: The mean age for our patients was 58.3 ± 10.5 years; sex-ratio = 0.92; mean PAI-1 level was 34.6 ± 21.3 ng/ml. We didn’t find correlation between PAI-1 level and BMI, but we have found significant correlation between PAI-1 and waist circumference (p = 0.032), most enhanced in men (P = 0.002), T2D patients who have FBG > 11 mmol/l had PAI-1 Ag level higher than those who have FBG < 11 mmol/l (P = 0.034), but no difference found between T2D with high Hb1Ac > 8% and those with Hb1Ac < 8%, significant correlation was seen between PAI-1 level and LDL-cholesterol (P = 0.05), high correlation between PAI-1 Ag level and −675 4G/5G polymorphism genotype was seen, 4G/4G carriers had the highest PAI-1 level, 4G/5G had intermediary level and 5G/5G had the lowest level (P < 0.001). No correlation was seen between PAI-1 Ag level and −844G/A polymorphism genotypes. Using multiple variable linear regression analysis, the independent factor associated with plasma PAI-1 level was −675 4G/5G polymorphism (regression coefficient β = 4.6, P < 0.01). Conclusion: the present study identifies −675 4G/5G not −844 G/A polymorphism of PAI gene as the principal determinant of plasma PAI-1 level in Tunisian T2D patients, the android fat distribution, dyslipidemia and hyperglycemia play a modest role in this variation.

1. Introduction

Most patients with type 2 diabetes (T2D) die from complication of atherosclerosis [1] .

PAI-1 (plasminogen activator inhibitor-1) is a major regulator of fibrinolysis [2] , plasma PAI-1 Antigen (PAI-1Ag) level is increased in type 2 diabetes patients [3] [4] and that may explain excess risk of cardiovascular disease. It also elevated in coronary artery disease patients [5] and its plasma level is determined by genetic [6] and environmental factors [7] .

The PAI-1 gene has been localized to q21.3-q22 of chromosome 7 [8] . Several polymorphisms within the PAI-1 gene influence PAI-1 levels [9] . The most known polymorphism which influences PAI-1 level is −675 4G/5G insertion-deletion mutation-of PAI-1 promotor gene [6] and another single nucleotide polymorphism is −844 G/A [10] [11] [12] .

Environmental factors, like obesity and metabolic syndrome features also plays a role in Plasma PAI-1 variation in type 2 diabetes patients and in non diabetics [7] [13] . The aim of this study was to examine the determinants of plasma PAI-1Ag level among adult patients with type 2 diabetes in Tunisia.

2. Patients and Methods

This was a cross sectional study involving 491 type 2 diabetic patients recruited from the outpatient’s endocrinology department at Farhat-Hachad hospital in Sousse-Tunisia during 2005-2006 period, written informed consent was obtained from participants, the study was approved by hospital ethic comity, inclusion criteria was: known type 2 diabetes, exclusion criteria were: cancer, coagulation disorders, pregnancy, end stage chronic kidney disease, all patients had clinical examination including (weight, high, BMI, Waist Circumference (WC)), laboratory investigations (Fasting blood glucose (FBG), Hb1Ac, cholesterol, triglyceride, HDL-cholesterol,) LDL was calculated by Fridewald formula(LDL (mmol/l) = total cholesterol -HDL-TG/2.26), after clear write consent plasma PAI-1 antigen level was done with ELISA, −675 4G/5G. PAI-1 gene promoter polymorphism genotyping was done by PCR-ASA(allele specific amplification) using common primer for 2 alleles in 5’P side and 2 specific primers for 2 alleles in 3’OH side and −844 G/A polymorphism genotyping was done by PCR-RFLP (restriction fragment length polymorphism) using 2 specific primers for 2 alleles and DNA was digested with restriction enzyme, allelic frequency was calculated with hardy-Weinberg law (p + q)2 = p2 + 2pq + q2 = 1, with p = n1 + n2/2n and q = n3 + n2/2n, n = number total of patients, n1 = 4G/4G carriers, n2 = 4G/5G, and n3 = 5G/5G, P = allele 4G frequency, q = 5G frequency. The same procedure was made with −844 G/A, and statistical analyses was performed using SPSS version 10.0 software.

3. Results

The mean age of our T2D population was 58.3 ± 10.5 years, male/female-ratio = 0.92, mean PAI-1 level was 34.6 ± 21.3 ng/ml.

Table 1 shows PAI-1Ag level was not correlated with BMI, but was significantly correlated with waist circumference (P = 0.032), this correlation was most evidenced in men (P = 0.002) (Table 2).

No significant difference found in PAI-1 Ag level between type 2 diabetes patients with hypertension and T2D without hypertension (Table 3).

In multivariate analysis, we found significant relationship between PAI-1 level and LDL-cholesterol (P = 0.05) (Figure 1).

T2D patients who have FBG > 11 mmol/l had PAI-1 Ag level higher than those who have FBG < 11 mmol/l (P = 0.034), but no difference found between T2D with high Hb1Ac > 8% and those with Hb1Ac < 8% (Table 4).

The Table 5 shows high correlation between PAI-1 Ag level and -675 4G/5G polymorphism genotypes, 4G/4Gcarriers had the highest PAI-1 level, 4G/5G had intermediary level and 5G/5G had the lowest level (P ˂ 0.001), No correlation was seen between PAI-1 Ag level and −844G/A polymorphism genotypes.

Using multiple variable linear regression analysis, the independent factor associated with plasma PAI-1 level was −675 4G/5G polymorphism (regression coefficient β = 4.6, P < 0.05).

Table 1. PAI-1 Ag level in diabetics in function of BMI (kg/m2).

SD: Standard Deviation; P: P-Value; NS: Non Significant.

Table 2. Mean PAI-1 Ag level in type 2 diabetes patients in function of WC (cm) and sex.

SD: Standard Deviation; P: P-Value; NS: Non Significant.

Figure 1. MeanPAI-1-Ag in relation to LDL in T2D patients.

Table 3. Mean PAI-1 Ag level in T2D patients in function of hypertension.

SD: Standard Deviation; P: P-Value; NS: Non Significant.

Table 4. Mean PAI-1 Ag in T2D in function of FBG (fast blood glucose) and Hb1Ac.

SD: Standard Deviation; P: P-Value; NS: Non Significant.

Table 5. Correlation between PAI-1 -Ag level and −675 4G/5G and -844G/A genotypes in T2D patients.

P: P-Value; NS: Non Significant.

4. Discussion

PAI-1 level is increased in type 2 diabetic patients [3] [8] [14] [15] [16] in comparison with non diabetic.

In IRAS (insulin resistance atherosclerosis study) [17] high level of PAI-1 was a predictor of type 2 diabetes incidence, in multiple regression analyses, PAI-1 level still significantly linked to type 2 diabetes incidence. In the same study high PAI-1 level was linked to diabetes incidence. [18] , In Health, Aging and Body Composition Study [19] similar results were found.

In Framingham Offspring Study [20] , high PAI-1level was a risk factor of type 2 diabetes with relative risk (RR) of 1.4 for people who have PAI-1 level in upper normal range, this risk is independent of obesity and classical risk factors. In Strong Heart Study [21] , relationship between PAI-1 level and diabetes incidence was found but this relationship become non-significant after adjustment with other variables (age, sex, BMI, BP, triglyceride, CRP, fibrinogen and insulin), antidiabetic drug vildagliptin decrease PAI-1 level [22] .

A recent metanalysis [23] shows moderate association between PAI-1 and T2D independent of established diabetes risk factors.

In our study mean PAI-1 Ag level was 34.6 ± 21.4 ng/ml. we didn’t have control group due to financial limits (cost of dosage) and the comparison with other studies is difficult because measurements methods are different and non-standardized.

The PAI-1 level is correlated to insulin resistance markers (BMI, Waist circumference, glucose level and insulin) [4] [24] .

In our study we didn’t find a positive correlation between BMI and PAI-1 but we found correlation between PAI-1 and WC which was most evident in men.

We had found correlation between PAI-1 and LDL cholesterol, LDL and VLDL cholesterol stimulate PAI-1 gene expression in vitro [8] , that may explain this correlation

The patients who have FBG > 11 mmol/l have PAI-1 level more than patients who have FBG < 11 mmol/l.

Glucose stimulate PAI-1 gene expression in vitro and that may explain relationship between PAI-1 and diabetes [8] , but this relationship is largely explained by metabolic syndrome.

Some studies found that PAI-1 level is linked to android fat distribution and endocrines and metabolic features of metabolic syndrome [4] [5] [25] .

People who have Metabolic syndrome with or without diabetes had elevated PAI-1 level [3] [24] improvement of metabolic syndrome with weight loss decrease PAI-1 level [13] .

Some studies had found higher PAI-1 level in people with hypertension [26] .

In our study, we didn’t find significant difference between mean PAI-1 level of diabetic patients who have hypertension and diabetics without hypertension.

Pronounced elevations of PAI-1 antigen levels were seen in 4G carriers of −675 4G/5G polymorphism of T2D patients in a large number of studies, [4] as well as non-diabetic and in different ethnic populations like Tunisians [27] [28] [29] .

The most significant variation in PAI-1 expression resides in the PAI-1 4G/5G alleles. Unlike the 5G allele that binds a transcription repressor, resulting in low PAI-1 expression, the 4G allele does not bind a transcription repressor, thus conferring a “high PAI-1 expressor” nature to the allele I [30] .

Martinez-Calatrava [31] , had found that 4G allele is the principal determinant of PAI-1 level in study of 631 persons, independent of metabolic disorders.

These results are in agreements with our study who shown that −675 4G/5G polymorphism not metabolic disorders was the principal determinant of PAI-1 level. Another study show metabolic syndrome components explain only 12% of PAI-1variability in T2D patients [4] .

4G allele has been shown as a risk factor in cardio vascular disease in some studies [32] not others [6] , some studies show 4G as a risk factor of diabetes [33] [34] , some studies show 4G allele association with obesity [35] [36] and metabolic syndrome [37] [38] .

About second polymorphism −844 G/A, we don’t found relationship between this polymorphism and PAI-1 level, this results is in agreement with the literature [11] [12] [27] .

A Mexican study revealed a relationship between −844 G/A and metabolic syndrome [39] . Another study revealed an association with cardio-vascular disease and dyslipidemia [40] .

5. Conclusion

The present study identifies −675 4G/5G not −844 G/A polymorphism of PAI gene as the principal determinant of plasma PAI-1 level in adult type 2 diabetes patients in Tunisia, and the android fat distribution, dyslipidemia and hyperglycemia play a modest role in this variation.

Conflicts of Interest

All authors declare no conflicts of interest.

Author’s Participation

All authors had participated actively in manuscript realization.

Cite this paper: Moustapha, M. , Chadhli-Chaieb, M. , Mahjoub, T. and Chaieb, L. (2017) Genetic and Metabolic Determinants of Plasminogen Activator Inhibitor 1 (PAI-1) in Tunisian Type 2 Diabetes Patients. Open Journal of Endocrine and Metabolic Diseases, 7, 141-150. doi: 10.4236/ojemd.2017.76013.
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