The A1298C Mutation in Methylenetetrahydrofolate Reductase Gene and Its Association With Idiopathic Venous Thrombosis in an Iranian Population (original) (raw)
Related papers
Vascular specialist international, 2015
Deep venous thrombosis (DVT) is a common but elusive condition characterized by a high morbidity and mortality rate. The aim of the present study was to investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with plasma total homocysteine (tHcy) levels and DVT risk in an Iranian population. Materials and Methods: Our study population consisted of 67 patients with a diagnosis of DVT and 67 healthy subjects as controls. Genotyping of MTHFR C677T polymorphism was performed by the polymerase chain reaction technique combined with restriction enzyme fragment length polymorphism (PCR-RFLP) and measurement of tHcy levels was done by enzyme immunoassay method. Results: Plasma tHcy levels were significantly higher in DVT patients than controls (18.09±7.6 vs. 10.5±4.3, P=0.001). Also, plasma tHcy levels were significantly higher in MTHFR 677TT genotypes compared to 677CC genotypes in both DVT patients (P=0.016) and controls (P=0.03). Neither heterozygote nor homozygote genotypes of MTHFR C677T polymorphism was significantly correlated with DVT (P>0.05). The distribution of MTHFR C677T genotypes was similar between men and women in both DVT patients and controls (P>0.05). Moreover, the frequency of mutant 677T allele did not differ significantly between the two groups (28.3% vs. 21.6%, P=0.15). Conclusion: Based on this study, we propose that hyperhomocysteinemia but not homozygosity for MTHFR C677T polymorphism is a significant risk factor for DVT in the Iranian population. Also, MTHFR 677TT genotype is a determinant of elevated plasma tHcy levels.
Labmedicine, 2008
Venous thrombosis, including deep-vein thrombosis and pulmonary embolism, is a common cause of morbidity and mortality, particularly in older people. 1 Venous thrombosis (VT) is multifactorial, and its exact pathogenesis has not been fully elucidated. Most cases of venous thrombosis arise due to prolonged immobilization, major surgery, trauma, or cancer, but genetic or acquired hemostatic abnormalities, including elevated plasma homocysteine (Hcy) levels, have also been implicated. 2 Elevated concentrations of total homocysteine have been associated with an increased risk of arterial and venous thrombosis. 3-5 A point mutation, C to T substitution at the nucleotide 677, in the coding sequence of the gene for methylenetetrahydrofolate reductase (MTHFR) is the most common enzyme defect associated with moderately-raised homocysteine concentrations, particularly in the presence of a suboptimal folate intake. 6 Genetic analyses studying the prevalence of the 677 C to T mutation in the MTHFR gene have recently shown divergent results in patients with venous thrombotic disease from different geographic regions. Several studies in patients with venous thrombosis failed to demonstrate an association between MTHFR C677T polymorphism and increased risk of venous thrombotic disease, 7,8,19-22 whereas other studies have reported a positive association. 9,17,18 In view of this controversy, our study was conducted with the purpose of evaluating the potential association of the C677T mutation of the MTHFR gene with venous thrombosis in adult patients. Materials and Methods Patients and Controls The present case control study included 200 patients with VT and 100 healthy controls. Cases and controls were recruited simultaneously from the same geographic area. Diagnosis of VT was made by ultrasonography, radioisotope venography, and magnetic resonance imaging angiography. 22 Patients who had an acquired disorder that predisposed them to VT were excluded from the study. These acquired disorders included malignancy, myeloproliferative disorder, nephrotic syndrome, liver disease, antiphospholipid syndrome, or pregnancy. The inclusion criteria for controls were: routine biochemical values within the normal range, nonsmokers, and no history of metabolic, renal, malignant, or vascular pathology. The exclusion criteria also included history of thrombosis and supplementary intake of vitamins. Homocysteine assay was carried out by ELISA method using Axis Homocysteine kit (Axis-Shield, Dundee, Scotland). Genetic Analysis Genomic DNA was extracted from the peripheral blood leukocytes by a previously described method. 10 The C677T mutation in the MTHFR gene was analyzed by PCR-RFLP using forward primer 5'-TGAAGGAGAAGGTGTCTGCGGGA-3' and reverse primer 5'-AGGACGGTGCGGTGAGAGTG-3'. PCR was carried out in a total volume of 40 µL containing 0.5 µmol/L of each primer, 200 µmol/L of all 4 dNTPs, 10 mmol/L Tris-HCl (pH 8.9), 2.2 mmol/L MgCl 2 , 10% glycerol, 50 mmol/L KCl, 1.
Circulation, 1998
Background-The results of retrospective and prospective case-control studies have clearly established that mild elevations of the plasma homocysteine level are associated with increased risk of coronary, cerebral, and peripheral vascular disease. Recently, a mutation (677C3 T) was identified in the methylenetetrahydrofolate reductase (MTHFR) gene that results in reduced folate-dependent enzyme activity and reduced remethylation of homocysteine to methionine. Mutant homozygotes (TT genotype) constitute Ϸ12% of the white population and frequently have mildly elevated circulating homocysteine. Therefore, it seems likely that they would also be at increased risk of vascular disease. A number of studies have investigated this during the past 3 years, and the present article evaluates the results in a meta-analysis. Methods and Results-We identified 13 studies in which there were measurements of plasma homocysteine in relation to the 3 genotypes (TT, CT, and CC) and 23 case-control studies comprising 5869 genotyped cardiovascular disease patients (mostly coronary artery disease) and 6644 genotyped control subjects. Those bearing the TT genotype had plasma homocysteine concentrations 2.6 mol/L (25%) higher than those with the CC genotype. However, there was no difference between patients and control subjects either in the frequency of mutant alleles (T) (34.3% versus 33.8%) or the TT genotype (11.9% versus 11.7%). In the analysis of the 23 studies, the relative risk (OR) of vascular disease associated with the TT genotype was 1.12 (95% CI, 0.92 to 1.37). Conclusions-We conclude that although the C677T/MTHFR mutation is a major cause of mild hyperhomocysteinemia, the mutation does not increase cardiovascular risk. Our findings suggest that the mild hyperhomocysteinemia found frequently in vascular disease patients is not causally related to the pathogenesis of the vascular disease. (Circulation.
Vascular specialist international, 2016
Portal vein thrombosis (PVT) is a rare and life-threatening vascular disorder characterized by obstruction or narrowing of the portal vein. Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism has been studied in PVT patients with conflicting results. In the present study the association of hyperhomocysteinemia and MTHFR C677T polymorphism with PVT risk was investigated in Iranians. Materials and Methods: Our study population consisted of 10 idiopathic PVT patients and 80 healthy control subjects matched for age and sex. MTHFR C677T polymorphism was genotyped by the polymerase chain reaction technique combined with restriction enzyme fragment length polymorphism (PCR-RFLP) technique and plasma total homocysteine (tHcy) levels were determined by enzyme immunoassay method. Results: Mean plasma tHcy levels were significantly higher in PVT patients (20.2±6.8) than control subjects (10.9±4.7) (P=0.001). Moreover, plasma tHcy levels were significantly higher in 677T allele carriers relative to 677C allele carriers in both PVT patients (P=0.01) and control subjects (P=0.03). Neither homozygote nor heterozygote genotypes of MTHFR C677T polymorphism correlated significantly with PVT risk (P>0.05). Moreover, MTHFR C677T polymorphism didn't increase the risk of PVT under dominant (CT+TT vs. CC) or recessive (TT vs. CC+CT) genetic models analyzed (P>0.05). The difference in frequency of minor 677T allele between PVT patients and control subjects was not statistically significant (P>0.05). Conclusion: Based on the current study, we suggest that hyperhomocysteinemia constitutes a significant and common risk factor for PVT. Also, MTHFR C677T polymorphism is not a risk factor for PVT but is a contributing factor for elevated plasma tHcy levels.
Balkan Medical Journal, 2013
Background: Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have recently raised the interest as a possible thrombophilic factors. Aims: We aimed to assess the frequency of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in idiopathic venous thromboembolism (VTE) in a Romanian population and the associated risk of VTE. Study Design: We performed a case-control transversal study including 90 patients diagnosed with VTE and 75 sex-and age-matched controls. Methods: MTHFR C677T and A1298C polymorphisms were detected using PCR-RFLP method. Results: The homozygous MTHFR 677TT genotype, present in 18.8% of patients with VTE versus 6.6% of controls, was significantly associated with VTE (p= 0.021, OR= 3.26, 95%CI (1.141-9.313)). The heterozygous MTHFR A1298C genotype, presenting the highest prevalence in the VTE group (34.4%) as well as in controls (37.3%), was not associated with VTE (p=0.7). No associations were found for heterozygous MTHFR C677T (with a frequency of 32.2% in VTE and 37.3% in controls, p=0.492), respective homozygous MTHFR A1298C genotype (with a frequency of 1.1% in VTE and 2.6% in controls, p=0.456). Conclusion: Among MTHFR polymorphisms, only homozygosity for MTHFR 677TT may be considered a risk factor for VTE; the MTHFR A1298C polymorphism is not significantly associated with an increased risk of VTE.
Arteriosclerosis, Thrombosis, and Vascular Biology, 1997
Hyperhomocysteinemia is a frequent risk factor for deep-vein thrombosis. A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) is responsible, in the homozygous state, for decreased enzyme activity and mild hyperhomocysteinemia and is associated with increased risk for cardiovascular disease. We studied the prevalence of C677T MTHFR in 77 patients with deep-vein thrombosis and in 154 age-and sex-matched healthy control subjects. In the same individuals, we also evaluated the frequency of the coexistence of C677T MTHFR with mutant factor V:Q 506 , a common risk factor for deep-vein thrombosis. Sixteen patients (20.8%) and 35 control subjects (22.7%) were homozygous for the C677T MTHFR mutation (odds ratio [OR]=0.8, 95% confidence interval [CI]=0.4-2.0). Sixteen patients (20.8%) and 4 control subjects (2.6%) had factor V:Q 506 ; of them, 10 patients and 3 control subjects had isolated factor V:Q 506 (adjusted OR=6.3, 95% CI=1.6-25.3) and 6 patients and 1 control subject also had C677T MTHFR (adjusted OR=17.3, 95% CI=2.0-152.9). The OR for the coexistence of the two mutations was 65% to 75% higher than the expected joint effect calculated by either an additive (OR=6.0) or multiplicative(OR=4.4) model . The homozygous C677T mutation of MTHFR per se is not a risk factor for deep-vein thrombosis but increases the risk associated with factor V:Q 506 . Due to the high prevalence of C677T MTHFR, it is likely that previous studies, which did not look for this mutation, overestimated the relative risk of thrombosis associated with factor V:Q 506 alone.