Association between the -11377 C/G and -11391 G/A polymorphisms of adiponectin gene and adiponectin levels with susceptibility to type 1 and type 2 diabetes mellitus in population from the west of Iran, correlation with lipid profile.

Adipose tissue, an endocrine organ, secretes bioactive factors including adiponectin. Adiponectin is a protein hormone that enhances insulin sensitivity through increased fatty acid oxidation and inhibition of hepatic glucose production. We assessed the association of the adiponectin promoter region polymorphisms -11391 G/A and -11377 C/G with susceptibility to type 1 (T1DM) and type 2 (T2DM) diabetes mellitus in the population of west Iran. Also, we investigated the effect of adiponectin level and lipid profile on T1DM and T2DM development. In this case-control study, we recruited 189 patients with diabetes (100 T2DM and 89 T1DM) and 161 sex and age-matched unrelated healthy controls. Adiponectin mutations were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the protein level was measured by the enzyme-linked immunosorbent assay. Other biochemical parameters were determined by routine laboratory methods. The G allele of adiponectin gene at -11377 position (C/G) significantly increased the risk of T1DM. With respect to genotype models, codominant (2.97 times), dominant (3.6-fold), and over-codominant (2.9-fold) patients with T1DM who carried -11377 C > G single-nucleotide polymorphisms were significantly susceptible to the development of the disease. A significantly higher level of adiponectin in T1DM was oberved compared with the control group. In contrast, patients with T2DM had lower adiponectin levels compared with healthy controls. The genotype distributions of -11391 G/A polymorphisms were the same for patients with diabetes and control groups. The presence of G allele at -11377 C/G adiponectin gene significantly increased serum adiponectin level and may be a risk factor for T1DM susceptibility among the western Iranian population.

Chemerin rs17173608 and vaspin rs2236242 gene variants on the risk of end stage renal disease (ESRD) and correlation with plasma malondialdehyde (MDA) level.

INTRODUCTION: End-stage renal disease (ESRD) is associated with critical kidney illness that seriously affects the lifespan. Genetic factors and oxidative stress could play critical role in the development of ESRD. We assessed the association between chemerin rs17173608 T/G and vaspin rs2236242 T/A genes variants with the risk of ESRD and their correlation with plasma malondialdehyde (MDA) level. MATERIALS AND METHODS: In a case-control study, 131 gender and age-matched unrelated healthy controls and 110 ESRD patients were enrolled. The chemerin rs17173608 T/G and vaspin rs2236242 T/A were detected by Tetra primer-amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR). The MDA concentration was determined by HPLC. RESULTS: Our findings for the first time revealed that in codominant genetic model (T/G vs. T/T genotype), the T/G genotype of chemerin gene significantly had a protective role against ESRD susceptibility. Also, in the presence of chemerin G allele, the risk of ESRD decreased by 0.79-fold (p = .048) in Kurdish population of Iran. The MDA serum levels in ESRD patients carrying the chemerin T/G + G/G genotype of rs17173608 T/G and also in carriers of A/A + T/A genotype of vaspin rs2236242 T/A were significantly higher compared to those in control subjects. The overall distribution of vaspin rs2236242 T/A genotypes and alleles comparing ESRD patients and healthy subjects were not statistically significant. CONCLUSION: We found that the G allele of chemerin rs17173608 compared to T allele decreased the risk of ESRD, and there was a significant association between chemerin and vaspin variants with plasma MDA level in a sample of the Iranian population.

ACE I/D and MMP-7 A-181G variants and the risk of end stage renal disease.

The variants of angiotensin converting enzyme (ACE) and matrix metalloproteinases (MMPs) genes might be involved in the pathogenesis of end stage renal disease (ESRD) and hypertension. We studied the ACE insertion/deletion (I/D) and MMP-7 A-181G variants in 99 unrelated ESRD patients and 117 individuals without renal complications from Western Iran with Kurdish ethnic background. The frequency of ACE I/D variants was not significantly different between ESRD patients and controls. However, the presence of ACE D allele increased the risk of hypertension in ESRD patients by 2.14-fold (P=0.036). The MMP-7 -181 AG genotype increased the risk of ESRD by 2.04 times (P=0.026). The present study indicated the absence of an association between the ACE I/D polymorphism with the risk of ESRD. However, the ACE D allele increased the risk of hypertension in ESRD patients. Also, the present study suggests a role for MMP-7 AG genotype in the pathogenesis of ESRD.

Association between GSTM1, GSTT1, and GSTP1 variants and the risk of end stage renal disease.

INTRODUCTION: There are some evidences indicating DNA damage by oxidant and mutant agents has an essential role in the chronic renal failure and end stage renal disease (ESRD). To investigate the possible association of GSTs variants with ESRD, we investigated the frequency of GST- T1, M1, and P1 genotypes, and the level of malondialdehyde (MDA) in patients with ESRD. MATERIALS AND METHODS: The present case-control study consisted of 136 ESRD patients treated with maintenance hemodialysis and 137 gender- and age-matched, unrelated healthy controls from the population of west of Iran. The GST- T1, M1, and P1 genotypes were determined in all individuals using multiplex-PCR and PCR-RFLP. The level of MDA was measured by high-performance liquid chromatography (HPLC). RESULTS: We found that GSTM1 and GSTT1 null genotypes (GSTT1-/GSTM1-) increased the risk of ESRD by 1.8 times (p < 0.001) and the increased risk of ESRD for GSTM-null (T1+-M1-) genotype was 3.04 times (p = 0.002). ESRD patients carriers the GST (GSTM1-null + GSTT1-null + GST-null) genotypes compared to GST normal genotype increased the risk of ESRD by 3.3 (p < 0.001) times. ESRD patients carriers of GST-null, GSTM1-null, and GSTT1-null genotypes had greater MDA concentration compared with the same genotypes of control subjects. Our results indicated that the GST-null allele (GSTT1-null/GSTM1-null) is a risk factor for ESRD and carriers of this allele have high levels of MDA. CONCLUSION: Our findings indicate that oxidative stress, impairment of the antioxidant system and abnormal lipid metabolism may play a role in the pathogenesis and progression of ESRD and its related complications. These data suggest that patients with ESRD are more susceptible to vascular diseases.

The association between GSTT1, M1, and P1 polymorphisms with coronary artery disease in Western Iran.

DNA damage which occurred by the effect of oxidant and mutant agents has an essential role in the development of atherosclerosis. To investigate the possible association between GSTs polymorphism with coronary artery disease (CAD), we investigated the frequency of GSTT1, M1, and P1 genotypes in patients with CAD compared to controls. The genotypes of GSTT1, M1, and P1 were determined in 209 angiographically documented CAD patients and 108 normal coronary artery cases (as controls) by Multiplex Polymerase Chain Reaction and PCR-RFLP. In CAD patients, the frequency of GSTT1-null genotype was significantly (P = 0.025) lower than that in control. The presence of this genotype was associated with 2.2-fold increased risk of CAD. However, the frequency of GSTM1 and GSTP1 genotypes were not significantly different comparing both groups (P = 0.405 and P = 0.521, respectively). Moreover, non smokers patients had a lower frequency of GSTM1-null genotype (29.2%) compared to non smoker controls (43.5%, P = 0.043). Also, the frequency of both GSTT1-null and GSTM1-null genotypes in patients (3.8%) was significantly lower compared to controls with the same genotypes (10.2%, P = 0.014). Our results indicated that a reduction in the frequency of GSTT1-null and GSTM1-null genotypes that observed in our study might be involved in the pathogenesis of CAD in our population.

The angiotensin converting enzyme D allele is an independent risk factor for early onset coronary artery disease.

OBJECTIVE: The role of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in early onset coronary artery disease age < 55years (ECAD) is controversial. The aim of this study was to further evaluate the role of this ACE(I/D) gene polymorphism on the risk of premature CAD in patients from western Iran. METHODS: The ACE(I/D) genotypes were detected by PCR-RFLP in 323 individuals undergoing their first coronary angiography. Patients were placed into two groups: ECAD and late onset CAD age ≥ 55years (LCAD). RESULTS: We found a statistically significant association of the ACE D allele, as homozygous or ACE ID plus DD genotypes (ID+DD), only in the ECAD subjects OR=1.35, p=0.015, OR=3.27, p=0.014, and OR=2.8, p=0.013, respectively. In addition, there was a significant association after adjustment for the absence of history of diabetes, presence of normolipidemia and absence of history of blood pressure [OR 1.38, p=0.017 and 2.35, p=0.02]. Our results indicated that the ACE D allele is a risk factor for early onset of CAD even after correcting for conventional risk factors. The incidence of triple vessel disease was significantly higher in individuals carrying ACE(D/D) genotype in ECAD patients compared to those who carried ACE(I/I) genotype (OR 3.38; p=0.019; 57.5% vs. 42.5%; p=0.013). CONCLUSION: The presence of D allele of ACE can be important independent risk factor in the onset of CAD patients less than 55 years old in a west population of Iran. Larger collaborative studies are needed to confirm these results.

Factor V G1691A, prothrombin G20210A and methylenetetrahydrofolate reductase polymorphism C677T are not associated with coronary artery disease and type 2 diabetes mellitus in western Iran.

There are controversial results related to the contribution of factor V Leiden G1691A, prothrombin gene G20210A and methylentetrahydrofolate reductase (MTHFR) C677T mutations in the development of coronary artery disease (CAD) and their association with diabetes. To assess the distribution of these thrombophilic mutations in CAD patients with and without type 2 diabetes mellitus (T2DM), we studied 117 CAD patients [65 CAD patients with diabetes (CAD/T2DM) and 52 CAD patients without diabetes (CAD/ND)] and 59 age-matched and sex-matched healthy individuals without CAD from population of western Iran. Genotyping was done by polymerase chain reaction (PCR)-restriction fragment length polymorphism using Mnl I, Hind III and Hinf I for factor V Leiden, prothrombin G20210A and MTHFR C677T, respectively. The prevalence of prothrombin G20210A variant in CAD/T2DM, CAD/ND and control individuals was 3.1, 1.9 and 0%, respectively. Factor V Leiden G1691A was found in 4.6% of patients with CAD/T2DM, 3.8% of patients with CAD/ND and 3.4% of healthy individuals. The prevalence of MTHFR C677T was found to be 49.2, 32.7 and 44.1% in CAD/T2DM, CAD/ND and control group, respectively. Our results indicate that there is no significant difference between the prevalence of thrombophilic mutations of factor V Leiden, prothrombin G20210A variant and MTHFR C677T in CAD patients with or without diabetes compared with controls. Although a higher prevalence of these thrombophilic mutations was observed in CAD patients, especially in those patients with diabetes, it seems that these variants may not be considered as independent risk factors for CAD or diabetes in our sample. These findings are discussed in relation to available literature.

The presence of apolipoprotein epsilon4 and epsilon2 alleles augments the risk of coronary artery disease in type 2 diabetic patients.

OBJECTIVE: It has been suggested that there is a relationship between apolipoprotein E polymorphism and the severity of coronary artery disease in type II diabetes mellitus (T2DM). The current study specifically aimed to examine whether APOE polymorphism in association with serum lipids-lipoproteins level is a risk factor for developing coronary artery disease (CAD) in diabetic patients living in western of Iran. METHODS: The APOE genotypes were detected by PCR-RFLP in 152 angiographically documented diabetic CAD patients, 262 non-diabetic (ND) individuals with CAD and 300 unrelated controls (normal coronary artery cases without diabetes) and serum lipid level was measured enzymatically. RESULTS: The APOE-epsilon4 and epsilon2 allele frequencies were significantly higher in the CAD/T2DM and CAD/ND patients than in the control group (p<0.001). Our study demonstrated a significant association between APOE polymorphism and the level of plasma lipids with CAD/T2DM (p=0.001) and CAD/ND (p=0.026) patients. The CAD subjects with T2DM and ND patients carrying APOE-epsilon4 allele had lower plasma HDL-C level (p<0.001), (p=0.008) but had higher plasma LDL-C (p=0.01), total cholesterol (p=0.002), (p=0.03) and TG (p<0.001), (p=0.042) than that of the APOE-epsilon3 carriers, respectively. However, carriers of APOE-epsilon2 had significantly higher levels of plasma TG only. OR of APOE-epsilon4 and epsilon2 alleles in CAD/T2DM and CAD/ND patients were found to be 2.98 (p=0.001),1.86 (p=0.001), 2 (p=0.001), and 1.65 (p=0.001), respectively. CONCLUSIONS: The major finding of the present case-control study is that T2DM patients carrying APOE-epsilon2 and epsilon4 alleles have a higher risk of developing CAD than ND patients in the western population of Iran, with APOE-epsilon4 being more closely associated with CAD than the APOE-epsilon2 allele. These results indicated that carriers of APOE-epsilon4 allele have a distinct plasma lipids profile and carrier of this allele with low levels of HDL-C and with high levels of LDL-C may be susceptible to CAD and myocardial infarction specially in diabetic patients. This suggests that a therapeutic modality should be considered for these patients.

Glutathione S-transferases activity in patients with colorectal cancer.

OBJECTIVES: The glutathione S-transferases (GSTs) play a critical role in protecting the colorectal mucosa. We investigated the efficacy of using the GSTs activity of plasma as a biomarker of risk for colorectal cancer. METHODS: GSTs activity was measured in the plasma of control individuals (n=39) and in the plasma, tumor tissue and normal tissue adjacent to a tumor of patients with colorectal cancer taken at colonoscopy (n=60). RESULTS: Mean GSTs activity was significantly (P< 0.01) higher in tumors (242+/- 45 nmol/min mg protein) as compared to normal tissues adjacent to a tumor (84+/- 49 nmol/min mg protein). A significant correlation between normal tissues adjacent to a tumor GSTs with those in malignant tissues was observed (r=0.61). Plasma GSTs activity was significantly (P<0.0001) higher in colorectal cancer patients (164+/-11 nmol/min mL) than those obtained from normal individuals (92+/- 23 nmol/min mL). CONCLUSIONS: GSTs measurement may be useful as a colorectal cancer marker in colorectal cancer, and biopsies obtained at colonoscopy can be used to measure tumor markers.