The relationship of the methylenetetrahydrofolate reductase C677T gene polymorphism in Turkish type 2 diabetic patients with and without nephropathy

BACKGROUND: Poor glycaemic control, hypertension and duration of diabetes are risk factors for the development of diabetic nephropathy, but there may be genetic factors. Recently, a common C to T mutation at nucleotide position 677 of the MTHFR gene (MTHFR677C > T) has been reported to be correlated with hyperhomocysteinemia and the severity of coronary artery disease as macroangiopathy. We aim to investigate Turkish type 2 diabetic patients with/without diabetic nephropathy and healthy group and examine the contribution of the MTHFR gene polymorphism to the development of diabetic nephropathy. METHODS: DNA was extracted from peripheral leukocytes of the subjects. Genotyping of the MTHFR C677T polymorphism for all individuals was performed by melting curve analysis of the generated amplicons after real-time online PCR. RESULTS: This genotype distribution did not differ between control subjects and type 2 diabetic patients in which 6.8% were TT, 43.7% were CT and 49.5% were CC (chi2 = 0.201, p > 0.05). The frequency of the mutant T allele was 23.4% in diabetic patients with nephropathy versus 33.0% in those without nephropathy. The genotype frequencies were TT, 2.1%; CT, 46.6%; CC, 55.3% in diabetic patients with nephropathy versus TT, 10.7%; CT, 44.6%; CC, 44.6% in those without nephropathy. CONCLUSIONS: The MTHFR genotype and allele frequencies were not different between diabetic patients with and without nephropathy (chi2 = 3, 386, p > 0.005; chi2 = 2.320, p > 0.005, respectively). Therefore, we conclude that the MTHFR gene polymorphism is not associated with the development of diabetic nephropathy in Turkish type 2 diabetic patients.     

The VITA Project: C677T mutation in the methylene-tetrahydrofolate reductase gene and risk of venous thromboembolism

We evaluated the hypothesis that a common polymorphism of the methylenetetrahydrofolate reductase gene (C677T), which results in increased levels of plasma homocysteine, may be a putative risk factor for venous thromboembolism (VT). Sixty-five cases of VT and 130 controls, both identified within the framework of an epidemiologic survey on thrombophilia, the Vicenza Thrombophilia and Arteriosclerosis (VITA) Project, were genotyped for the mutation. No increased risk of VT was found in carriers of the mutation. We conclude that screening for the C677T mutation of the methylenetetrahydrofolate reductase gene should not be recommended in unselected patients with VT.     

Prevalence of the C677T methylenetetra- hydrofolate reductase mutation in Thai patients with deep vein thrombosis

We investigated the prevalence of a genetic variation in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) using polymerase chain reaction techniques in a sample of 500 general Thai population and among 40 unselected Thai patients with an objectively confirmed history of deep vein thrombosis (DVT). The prevalence of the mutated homozygous and heterozygous C677T MTHFR genotype in the group of 500 healthy Thai population was 1.4 and 25.6%, respectively (allele frequency of 14.2%). Of the 40 patients studied, none were homozygotes and 15% were heterozygotes for the C677T MTHFR gene mutation (allele frequency of 7.5%). There was no significant difference in genotype frequency between patients and control groups (p = 0.09). Odds ratios for the probability of the C677T MTHFR gene mutation in the patient versus control group were 0.49 (95% CI 0. 21-1.12). These data indicated that the C677T MTHF gene mutation was not associated with DVT in the Thai population. The lower frequency of the C677T MTHFR gene mutation in our Thai population compared with reports from other studies suggests a wide heterogeneity in the 677T MTHFR genotype frequencies of the different ethnic populations even among Asians.     

Hyperhomocysteinemia and the methylene tetrahydrofolate reductase C677T mutation in splanchnic vein thrombosis

Introduction: The role that hyperhomocysteinemia (HH) and the C677T mutation in 5,10‐methylenetetrahydrofolate reductase (MTHFR) play in splanchnic vein thrombosis (SVT) remains unclear due to this unusual thrombotic location. Objective: To analyse the possible association of HH with the C677T mutation in the MTHFR gene in SVT. Material and methods: We determined homocysteine levels and the C677T MTHFR mutation, along with classical cardiovascular risk factors, in 48 patients with SVT (18 Budd‐Chiari syndrome, 11 mesenteric vein thrombosis, 19 portal vein thrombosis) and 84 controls. Results: In the univariate analysis, patients with SVT showed statistically higher homocysteine levels (P = 0.044). After adjusting for total cholesterol, differences disappeared (P = 0.256). However, no differences in homocysteine levels were observed when comparing the three SVT types (P = 0.199), even after adjusting for age and total cholesterol (P = 0.095). In addition, the prevalence of the TT genotype was no different when controls were compared with patients with SVT (P = 0.253) or with SVT subtypes (P = 0.885). No association was found between HH (>15 μm ) and the TT genotype in cases (P = 0.404), controls (P = 0.178), or in the different SVT subtypes (P = 0.495). Conclusions: Our results suggest that HH and the homozygous genotype in the MTHFR C677T mutation do not seem to play a role in SVT development.     

Portal vein thrombosis in Egyptian patients with liver cirrhosis: Role of methylenetetrahydrofolate reductase C677T gene mutation

Aim: The pathogenesis of non‐malignant portal vein thrombosis (PVT) in cirrhotic patients is not clearly defined. This case‐control study aimed to investigate the role of methylenetetrahydrofolate reductase (MTHFR) C677T gene mutation in the pathogenesis of PVT in Egyptian cirrhotic patients. Methods: Plasma homocysteine was measured and MTHFR C677T gene mutation was detected in 76 cirrhotic patients (21 with PVT, 55 without PVT) and 20 healthy controls. Results: The frequency of CC genotype (wide type) in cirrhotic patients with PVT was lower than controls and cirrhotics without PVT. However, the frequency of TT genotype (homozygous mutation) was elevated in cirrhotic patients with PVT as compared to controls and those without PVT. Cirrhotic patients with PVT had significantly higher homocysteine than those without PVT. Cirrhotic patients with TT genotype are at a significant risk for PVT (odds ratio = 7.7, 95% confidence interval, 1.50–42.81) when compared with CC genotype. Moreover, subjects carrying TT genotype had a higher homocysteine than those carrying CC genotype. Conclusions: The TT genotype of MTHFR is associated with an increased risk of PVT in Egyptian cirrhotic patients. Hyperhomocysteinemia could be considered as a relatively new risk factor for PVT in cirrhotic patients and plasma homocysteine should be investigated particularly in patients with PVT of unexplained etiology. The important clinical implication is that the readily available therapy of folate, vitamin B6 and B12 supplementation may reduce homocysteine and prevent further thrombotic complications in cirrhotic patients carrying the TT genotype.     

An updated meta-analysis of methylenetetrahydrofolate reductase gene 677C/T polymorphism with diabetic nephropathy and diabetic retinopathy

Studies investigating the association of methylenetetrahydrofolate reductase (MTHFR) gene 677C/T polymorphism with diabetic nephropathy and diabetic retinopathy have so far reported inconclusive results. We therefore aim to address this inconclusiveness by conducting a meta-analysis. Random-effects model was applied irrespective of between-study heterogeneity. Data and study quality were assessed in duplicate. A total of 7807 and 1599 subjects from 21 and 8 studies were analyzed for diabetic nephropathy and diabetic retinopathy, respectively. Carriers of 677TT genotype were 1.71 (95% confidence interval [95% CI]: 1.02-2.88; P = 0.042) and 2.89 (95% CI: 1.51-5.53; P = 0.001) times more likely to develop diabetic nephropathy separately relative to diabetic patients without nephropathy and nondiabetic controls. Likewise, this association was preserved for diabetic patients with retinopathy referring to those without (odds ratio [OR] = 1.86; 95% CI: 1.21-2.86; P = 0.004). Subgroup analyses showed that ethnicity was a possible confounder, especially in West Asians and Africans, and so were gender and duration of diabetes mellitus in diabetic nephropathy studies. Probability of publication bias was low across all comparisons as reflected by the funnel plot and corresponding test. Taken together, our results demonstrate that MTHFR gene 677TT genotype might confer a moderately augmented risk for diabetic nephropathy and diabetic retinopathy.     

亚甲基四氢叶酸还原酶基因C677T突变与高尿酸血症的相关性研究

目的探讨高尿酸血症（HUM）与亚甲基四氢叶酸还原酶（MTHFR）基因C677T突变及高血糖、肥胖和高血压等的相关性。方法从青岛地区糖尿病流行病学调查数据库中，随机选取HUM＋T2DM患者79例、HUM无T2DM患者（HUM组）90例、并选取T2DM无HUA患者（DM组）90例和健康对照（NC）91例。采用聚合酶链反应-限制性片段长度多态性技术检测MTHFR基因突变。结果HUM组和HUM＋T2DM组MTHFR677T等位基因频率分别为46．7％和51．3％，TT基因型频率分别为23．3％和26．6％，两组差异无统计学意义（P〉0．05）；T等位基因和TT基因型频率在NC组和DM组间差异无统计学意义（P〉0．05）；而HUM组和HUM＋T2DM组MTHFR677T等位基因型频率和TT基因型频率均分别高于NC组和DM组（P〈0．005）。CT和TT基因型患者平均血尿酸水平（分别为394．2μmol／L和465．8μmol／L）明显高于CC基因型者（347．3μmol／L）（P〈0．05）。多因素logistic回归分析表明，调整BMI、SBP、TG、TC及饮酒等因素后显示，MTHFR基因型是HUM患病的独立危险因素。结论MTHFR基因C677T突变是青岛地区人群发生HUM的独立危险因素。     

Methylenetetrahydrofolate reductase C677T polymorphism and liver fibrosis progression in patients with recurrent hepatitis C

Background/Aims: Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, being a putative steatogenic factor, may promote liver fibrosis progression in patients with chronic hepatitis C. This study aimed to verify the role of recipient MTHFR polymorphism in favouring graft fibrosis progression in patients with recurrent HCV after orthotopic liver transplantation (OLT). Methods: We studied 63 such patients, followed for >1 year. MTHFR allelic variants were determined by a polymerase chain reaction/restriction fragment length polymorphism method. Results: Recipients carrying the TT genotype had more frequently, 1‐year post‐OLT, homocysteine serum levels >23 μmol/L (P<0.05), serum triglycerides >180 mg/dL (P<0.02) and de novo diabetes mellitus (P<0.05) but not a higher frequency of graft steatosis. Time‐to‐event analysis in reaching an Ishak staging score >2 was performed by stratifying the recipients as follows: (a) patients with donor age ≤45 years, (b) patients with donor age >45 and C/^* genotype, and (c) patients with donor age >45 years and TT genotype. A significant linear trend was observed, with increasing frequencies as follows: (a) 8/37, (b) 10/19 and (c) 6/7 (P=0.0005). Conclusion: The MTHFR C677T polymorphism may play a role in influencing liver fibrosis progression in patients with recurrent hepatitis C, in conjunction with donor age, but not via steatosis promotion.     

Methylenetetrahydrofolate reductase C677T gene polymorphism in Turkish patients with polycystic ovary syndrome

Higher Levels of Hcy are associated with several clinical conditions, among them non-insulin-dependent diabetes mellitus, endometrial dysplasia and hypertension with insulin resistance, and polycystic ovary syndrome. The purpose of this study was to investigate the serum homocystein levels and other metabolic parameters in relationship with the MTHFR C677T gene polymorphism in patients with PCOS. Our study included 86 young women with PCOS constituting the study group and 70 healthy women constituting the control group. Homocystein levels, metabolic, and hormonal parameters were measured, and genetic analysis of the MTHFR C677T gene polymorphism was performed in all the subjects. A statistically significant difference was observed in mean homocystein levels between patients with PCOS when compared to the control group. The MTHFR 677 CC genotypes had significantly higher proportions in the control group compared to the PCOS patients (χ(2) = 21.381, P < 0.001). Our data show that homocystein levels were higher than normal subjects in patients with PCOS and that the MTHFR C677T gene polymorphism does not influence homocystein levels of patients with PCOS.     

Total plasma homocysteine and methylenetetrahydrofolate reductase C677T polymorphism in patients with colorectal carcinoma

INTRODUCTION Homocysteine, a sulfur-containing amino acid produced by the adenylation and subsequent demethylation of dietary methionine, is an essential intermediate in folate metabolism. Two enzymes and three vitamins play a key role in the regulation o…     

The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular dementia

OBJECTIVE: To determine the association between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and vascular dementia in Ashkenazi and non-Ashkenazi Jews. DESIGN: A case-control study. SETTING: Nursing homes in Jerusalem, Israel. PARTICIPANTS: Two hundred fifty nine Jewish people of Ashkenazi and non-Ashkenazi origin, older than age 70, who have vascular dementia (VD) (n = 85), Alzheimer's disease (AD) (n = 92), and who are cognitively intact (n = 82) with no clinical evidence of atherosclerotic vascular disease. MEASUREMENTS: The frequencies of the mutant allele (T allele) and homozygotes for the C677T MTHFR mutation (T/T genotype). The total plasma homocysteine (tHCT) level in 75 subjects. RESULTS: There were no significant differences in the frequencies of the T/T genotype or T allele among VD, AD, and cognitively intact older people of the same ethnic origin (0.15, 0.19, 0.25 T/T genotype and 0.42, 0.46, 0.47 T allele in Ashkenazi; 0.08, 0.06, 0.10 T/T genotype and 0.28, 0.32, 0.33 T allele in non-Ashkenazi with VD and AD, and in cognitively intact older people, respectively). The relative risk of VD associated with the T/T genotype versus the C/C genotype was 0.62 (95% CI, 0.19-1.19) in Ashkenazi and 0.65 (95% CI, 0.11-3.7) in non-Ashkenazi, respectively. The relative risk of AD associated with the T/T genotype was 0.85 (95% CI, 0.29-2.45) in Ashkenazi and 0.62 (95% CI, 0.1-4.3) in non-Ashkenazi, respectively. The frequencies of mutant homozygotes and allele were significantly higher in Ashkenazi than in non-Ashkenazi Jews (19.9% vs 7.5% T/T genotype, chi2 = 6.2, P = .01, 0.45 vs 0.31 T allele, chi2 = 9.77, P = .002 in Ashkenazi vs non-Ashkenazi, respectively). There were no differences in mean tHCT concentration among VD, AD, and cognitively intact older people. CONCLUSIONS: The MTHFR C677T is not associated with an increased risk of vascular dementia or Alzheimer's disease. The frequency of the mutation is significantly higher in Ashkenazi compared with non-Ashkenazi Jews.     

亚甲基四氢叶酸还原酶基因677C/T多态性与上海地区2型糖尿病合并大血管并发症的关系

目的 研究亚甲基四氢叶酸还原酶（MTHFR）基因677C／T多态性与糖尿病大血管并发症（脑梗死和冠心病）之间的关系。方法 在416例中国人受试者中：大血管病变患者（AS组，即脑梗死亚组和冠心病亚组总和）216例，其中脑梗死亚组（CI）111例，该亚组中伴及不伴糖尿病患者分别为50例及61例；冠心病亚组（CHD）105例，该亚组中伴及不伴糖尿病患者分别为48例及57例。糖尿病无大血管病变者（DM）100例，正常对照（C）100例。研究方法采用PCR／酶解鉴定基因变异及群体关联分析。结果 大血管病变组中MTHFR基因的677C／T的TT基因型和T等位基因频率显著增高。Logistic回归分析表明MTHFR基因参与大血管病变（AS）的致病过程。大血管病变各组内糖尿病和非糖尿病两亚组间相互比较基因型频率差异没有显著性。大血管病变不同亚组按有无糖尿病及性别分层后可见高密度脂蛋白胆固醇及舒张压水平随基因型不同而差异有显著性。结论 在中国人中，不论有无糖尿病，MTHFR基因均参与大血管病变（脑梗死或冠心病）的致病过程。     

MTHFR C677T and A1298C gene polymorphisms and hyperhomocysteinemia as risk factors of diabetic nephropathy in type 2 diabetes patients

Point mutations in methylenetetrahydrofolate reductase (MTHFR) and hyperhomocysteinemia were implicated in the pathogenesis of diabetic nephropathy (DN) in many ethnic groups. This study addressed the association of C677T and A1298C single nucleotide polymorphisms (SNPs) of MTHFR gene with DN in Tunisian type 2 diabetes (T2DM) patients. Study subjects comprised 93 DN patients, 267 patients with normoalbuminuria, and 400 control subjects. C677T and A1298C genotypes were determined by PCR-RFLP analysis, and homocysteine levels were measured by ELISA. A1298C and C677T were highly prevalent among T2DM patients, with allele frequencies of 0.26 and 0.36, respectively. Higher mutant 677T allele and 677C/T and 677T/T genotypes of C677T SNP, but not A1298C SNP, together with 677C/1298A, 677C/1298C, and 677T/1298A haplotypes were seen in DN patients compared to normoalbuminuric patients, (p<0.001). Plasma homocysteine was positively associated with MTHFR 677T/T genotype among the three groups, and was significantly elevated in double heterozygous DN patients but not in normoalbuminuric patients or controls. Logistic regression analysis with DN as dependent variable showed that homocysteine (OR, 1.153) and MTHFR 677T/T (OR, 9.799) were the only variables associated with DN, after adjusting for possible confounding variables. C677T, but not A1298C, SNP, is a risk factor for DN, presumably acting by elevating homocysteine levels.     

Methylenetetrahydrofolate reductase C677T variant and hyperhomocysteinemia in subarachnoid hemorrhage patients from India

Metabolic Brain Disease - Methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T, A1298C) has been implicated in increased plasma homocysteine (Hcy) levels. The present study was designed...