Risk of colorectal cancer associated with the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in the Kashmiri population

Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, 677 C→T and 1298 A→C, have been shown to impact various diseases, including cancer. The 677 C→T polymorphism has been widely investigated in different cancers and has been implicated as a risk factor for the development of various cancers. We investigated MTHFR C677T genotype frequency in colorectal cancer cases in the Kashmiri population and correlated this information with the known clinicopathological characters of colorectal cancer, in a case-control study. Eighty-six colorectal cancer cases were studied for MTHFR C677T polymorphism, compared to 160 controls taken from the general population, employing the PCR-RFLP technique. We found the frequency of the three different genotypes of MTHFR in our ethnic Kashmir population, i.e., CC, CT and TT, to be 68.6, 20.9 and 10.4% among colorectal cancer cases and 75.6, 16.9 and 7.5% among the general control population, respectively. There was a significant association between the MTHFR TT genotype and colorectal cancer in the higher age group. We conclude that the MTHFR C677T polymorphism slightly increases the risk for colorectal cancer development in our ethnic Kashmir population.     

No association between methylenetetrahydrofolate reductase C677T polymorphism and breast cancer

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme (EC 1.5.1.20), that reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for the homocysteine to methionine conversion. MTHFR is a key enzyme that regulates folate metabolism which has an important role in DNA synthesis, DNA repair and methylation. The association between MTHFR C677T polymorphism and breast cancer has been investigated in several previous studies. Some researchers have shown an association between C677T polymorphism and breast cancer, but not all researchers found this association however. This study was designed to investigate, in the Turkish population, the association of MTHFR C677T polymorphism and breast cancer. Forty women patients with breast cancer and 68 healthy women were included in the study. MTHFR gene polymorphism was determined by the PCR-RFLP method. SPSS 10.0 for windows was used to determine statistical significance. No differences were observed in the distribution of MTHFR genotypes or allele frequencies in the cases versus the controls. It was found that the frequencies of MTHFR polymorphism were 55%, 40%, 5% for CC, CT, TT genotype in patients and 56%, 38%, 6% in healthy controls respectively. Furthermore, association was observed among family history, metastatic risk and MTHFR genotypes in patients. Our data fail to support a relationship between MTHFR C677T and the risk for breast cancer. It may be that there are ethnic differences in terms of this relationship.     

Relationship of the methylenetetrahydrofolate reductase C677T polymorphism with microsatellite instability and promoter hypermethylation in sporadic colorectal cancer

The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with the expression of a thermolabile enzyme with decreased activity that influences the pool of methyl-donor molecules. Several studies have reported an association between C677T polymorphism and susceptibility to colorectal cancer (CRC). Considering that methylation abnormalities appear to be important for the pathogenesis of CRC, we examined the correlation between the genotype of the MTHFR C677T polymorphism, hypermethylation of the promoter region of five relevant genes (DAPK, MGMT, hMLH1, p16(INK4a), and p14(ARF)), and microsatellite instability, in 106 patients with primary CRCs in Brazil. We did not find significant differences in the genotypic frequencies of the MTHFR C677T polymorphism when one or more loci were hypermethylated. However, we did find a significant excess of 677TT individuals among patients with CRC who had microsatellite instability. This strong association was independent of the methylation status of hMLH1 and of the biogeographical genomic ancestry of the patients. Although the mechanism responsible for the link between the C677T polymorphism and microsatellite instability was not apparent, this finding may provide a clue towards a better understanding of the pathogenesis of microsatellite instability in human colorectal cancer.     

亚甲基四氢叶酸还原酶基因C677T、G1793A 单核苷酸多态性 与散发性乳腺癌易感性的关系

目的:研究亚甲基四氢叶酸还原酶(MTHFR)基因C677T、G1793A位点单核苷酸多态性与散发性乳腺癌易感性关系。方法:采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,对200例乳腺癌患者及200例正常对照者MTHFR基因C677T、G1793A位点单核苷酸多态性进行分析,logistic回归分析不同基因型与乳腺癌风险的关系。结果:乳腺癌组MTHFR 677TT基因型频率为25.00%显著高于正常对照组的10.50%(X2=14.401,P=0.001),CT基因型频率为44.50%低于正常对照组的54.50%,CC基因型频率在乳腺癌组和正常对照组中无差别;MTHFR 1793GA基因型频率为18.50%显著高于正常对照者的8.50%(X2=8.563,P=0.003)。乳腺癌患者MTHFR 677T和1793A等位基因频率分别为47.25%、9.25%,显著高于对照组中的37.75%、4.25%。MTHFR 677TT基因型携带者罹患乳腺癌的风险是677CC基因型携带者的2.732倍(95%CI=1.418～5.051,P=0.001),MTHFR1793GA基因型携带者罹患乳腺癌的风险是1793GG基因型携带者的2.444倍(95%CI=1.325～4.505,P=0.003)。另外,乳腺癌组中MTHFR C677T基因多态性与肿瘤大小相关(x2=7.431,P=0.024,MTHFR G1793A基因多态性与淋巴结转移情况(x2=8.939,P=0.011)、癌组织学分级(x2=9.983,P=0.007)相关。结论:MTHFR C677T、G1793A基因多态性与散发性乳腺癌的易感性相关。     

Methylenetetrahydrofolate reductase genotypes and haplotypes associated with susceptibility to colorectal cancer in an eastern Chinese Han population

Methylenetetrahydrofolate reductase (MTHFR) plays an important role in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, C677T and A1298C have been associated with several diseases, including cancer. We made a case-control study to analyze a possible association of MTHFR gene polymorphisms C677T and A1298C with risk for colorectal cancer in an eastern Chinese Han population of 137 patients with a confirmed histopathological diagnosis of CRC and 145 age- and gender-matched controls with no history of cancer. DNA was isolated from peripheral blood samples and the genotypes were determined by PCR-RFLP. The concentrations of folate in plasma were measured by chemiluminescence immunoassay. The MTHFR 677TT genotype had a protective effect against colorectal cancer, with an odds ratio (OR) = 0.467 (95% confidence interval (CI) = 0.225-0.966). The 1298CC genotype was significantly correlated with a reduced risk of colorectal cancer (OR = 0.192; 95%CI = 0.040-0.916). Compared with the MTHFR 677CC and MTHFR 1298 AA genotypes, for individuals who carried both MTHFR 677CC and 1298CC genotypes, the OR of colorectal cancer was 0.103 (95%CI = 0.012-0.900); among individuals who carried both MTHFR 677TT and 1298AC genotypes, the OR for risk of colorectal cancer was 0.169 (95%CI = 0.044-0.654). MTHFR 677TT+CT genotypes had a significantly lower plasma folate concentration than those with the MTHFR 677CC genotype. MTHFR 1298AC+CC genotypes had a lower plasma folate concentration than those with the MTHFR 1298AA genotype (P < 0.05). In conclusion, subjects with the MTHFR 677TT and MTHFR 1298CC genotypes appeared to have a significantly lower risk for colorectal cancer. MTHFR haplotypes 677CC/1298CC and 677TT/1298AC were less common in cases than in controls. These haplotypes, when compared to the most common haplotype 677CC/1298AA, were associated with a decreased risk for colorectal cancer. We conclude that plasma folate level is influenced by MTHFR genotypes.     

Interaction of MTHFR 1298C with ACE D allele augments the risk of diabetic nephropathy in Western Iran

The aim of the current study was to examine the influence of interaction between polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C with angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism on the risk of diabetic nephropathy (DN). In a case control study using polymerase chain reaction (PCR)- and PCR-restriction fragment length polymorphism (RFLP), the presence of three polymorphisms in 140 patients with type 2 diabetes mellitus (T2DM) with nephropathy including patients with micro- and macro-albuminuria and 72 patients with normoalbuminuria from Western Iran were investigated. In the presence of both MTHFR 677 T and ACE D alleles, there was a trend toward increased risk of DN 2.68-fold (p=0.054). The possession of both MTHFR 677 T and ACE D alleles increased the risk of macro-albuminuria four times (p=0.035). The concomitant presence of both MTHFR 1298 C and ACE D alleles increased the risk of macro-albuminuria 7.8-fold (p=0.012). In addition, the risk of progression from micro- to macro-albuminuria in the presence of both alleles tended to be increased (4.1-fold, p=0.09). Our study for the first time demonstrated a synergistic effect between ACE I/D with either MTHFR C677T or A1298C polymorphism on the increased risk of DN among patients with T2DM. We found that MTHFR 1298 C strongly interacts with the ACE D allele and augments the risk of DN in our population.     

Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer

This study was designed to investigate, in the Turkish population, an association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer. Our study was carried out in 35 patients with gastric cancer (20 men, 15 women) and 144 controls (75 men, 69 women) and 52 colorectal cancer (31 men, 21 women). MTHFR C677T genotypes were determined by polymerase chain reaction, restriction fragment length polymorphism techniques. No differences were observed in the distribution of MTHFR genotypes or allele frequencies in cases versus controls. The homozygous mutation (T/T) in the MTHFR gene was identified in 14.3% of gastric cancer versus 10.4% of controls. MTHFR C677T frequencies of the CC, CT and TT genotypes among colorectal cancer patients were 34.6%, 51.9% and 13.5%, respectively. MTHFR C677T polymorphism may not be important in an individual's susceptibility to gastric and colorectal cancer in Turkey and may not be a useful marker for identifying patients at high risk of developing gastric and colorectal cancer.     

Methylene tetrahydrofolate reductase C677T mutation and left ventricular hypertrophy in Turkish patients with type II diabetes mellitus

This study was designed to investigate, in the Turkish population, the association of methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism and left ventricular hypertrophy (LVH) in patients with type II diabetes mellitus. Our study included 249 patients with type II diabetes mellitus (102 men, 147 women) and 214 healthy volunteers as controls (91 men, 123 women). MTHFR C677T genotypes were determined by polymerase chain reaction, restriction fragment length polymorphism techniques. No differences were observed in the distribution of MTHFR genotypes or allele frequencies in the cases versus the controls. The frequency of the MTHFR-mutated allele (T) was 31.7% in the type II diabetes mellitus versus 31.1% of the controls. The homozygous mutation (T/T) in the MTHFR gene was identified in 12% of the type II diabetes mellitus versus 9.3% of the controls. Patients with the TT genotype showed a higher prevalence of LVH when compared to patients with the CC and CT genotypes (p = 0.01). The MTHFR gene C677T mutation may be a possible risk factor for the development of LVH in the type II diabetic patients.     

The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk

This study aimed to determine the relation between methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism and lung cancer risk and the frequency of this polymorphism. The study involved 64 lung cancer patients (the study group) with definitive diagnosis and 61 noncancerous subjects (the control group). MTHFR C677T and A1298C mutation analysis was made using DNA isolated from peripheric blood and multiplex PCR and reverse hybridization strip test. Eighty-four percent of the patients were male. The age, gender, and history of alcohol use of the patients and control group were statistically similar. While MTHFR 677T and 677C allele frequency was 0.33 and 0.67 in the patients respectively, it was 0.29 and 0.71 in the control group. The frequencies of MTHFR 1298C and 1298A were 0.33 and 0.67 in the patients, and it was 0.31 and 0.69 in the control group respectively. When MTHFR 677TT and 677CT genotypes were compared with 677CC genotype, lung cancer risk was 2.4 times higher in the 677TT genotype. When MTHFR 1298AC and 1298CC genotypes were compared with 1298AA genotype, lung cancer risk was 1.5 times higher in 1298CC genotype. According to the results, allele frequency of homozygote T and C was high in lung cancer patients. It was 3.05 and 1.29 times higher in smokers than in non-smokers, and 3.05 and 1.64 times higher in males than in females; 3.0 and 2.44 times higher in those with non-small cell lung cancer than in those with small-cell lung cancer.     

Polymorphisms in xenobiotic-metabolizing genes in the pathogenesis of glucocorticoid-induced osteoporosis in patients with bronchial asthma

Search for and study of risk factors for glucocorticoid-induced (GI) osteoporosis, as one of the most frequent and serious complications of long-term systemic glucocorticoid (SGC) therapy for bronchial asthma are an important problem of prevention medicine. In the present work to determine the frequencies of genotypes and alleles of eight candidate genes of GI osteoporosis in 137 patients with bronchial asthma receiving long-term SGC therapy, using allele-specific hybridization on the biochip. In the analysis of gene polymorphism MTHFR 677C>T showed a statistically significant association between genotypes for this gene and proximal femur mineral density (BMD) for the Z-criterion in patients treated with SGC (non-parametric ANOVA Kruskal-Wallis p = 0.0013). In addition, the analysis of insertion-deletion polymorphism of GSTM1 found that carriers of GSTM1 "null" genotype have lower values of BMD Z-criterion, than carriers of at least one functional allele of GSTM1 gene (Mann-Whitney U-test with Bonferroni correction, p = 0.034). Analysis of gene-gene interactions revealed that carriers of MTHFR genotype 677C/C in combination with GSTM1 "null" genotype characterized by a statistically significant lower values of BMD Z-criterion, than carriers of other variants of genotypes (ANOVA Kruskal-Wallis, p = 0.0012). Thus, the alleles of MTHFR and GSTM1 genes may modulate the risk of GI osteoporosis in patients with bronchial asthma, which is very important to identify group of patients with high risk for osteoporosis among individuals receiving SGC as well as inhaled glucocorticoids.     

No association of Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in susceptibility to gallbladder cancer

Gallbladder carcinoma (GBC) is a leading cause of cancer deaths in north India. Evidence has highlighted the role of abnormal DNA methylation patterns on inappropriate gene expression in development and progression of various cancers. 5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a major role in provision of methyl groups for DNA methylation. A C/T substitution in MTHFR at nucleotide 677 results in replacement of ala222-to-val in the N-terminal catalytic domain of protein, and causes considerable decrease in enzymatic activity. Thus, MTHFR C677T polymorphism may influence genetic susceptibility to GBC. The present study aimed to examine the role of C677T MTHFR polymorphism in conferring genetic susceptibility to GBC. The present study included 146 proven GBC patients and 210 healthy controls. Genotyping was done by PCR-RFLP method. The MTHFR C677T genotypes in control population were in Hardy-Weinberg equilibrium (p = ns). No statistically significant difference was observed in frequency of variant TT genotype in GBC patients in comparison to healthy controls (4.1% and 2.9%). Stratification of GBC patients on the basis of presence or absence of gallstones showed no significant association with the disease. Further, gender and age of onset of the disease did not show any significant association. In conclusion, the present study indicates that the genetic risk for GBC is not modulated by MTHFR C677T polymorphism.     

Polymorphisms of 5,10-methylenetetralydrofolate reductase (MTHFR), fruit and vegetable intake, and the risk of stomach cancer

Stomach cancer is a serious public health problem in China. 5,10-Methylenetetralydrofolate reductase (MTHFR) may be involved in both DNA methylation and DNA synthesis. Folate deficiency is associated with cancer risk that may be modulated by a genetic variation in the MTHFR gene in folate metabolism. The main goal of this study was to evaluate the association between polymorphisms of the MTHFR gene and the risk of stomach cancer. This study also explored the modification effects of fruit and vegetable intake (one of the main constituents is folate) on the risk of this disease. A population-based case-control study was conducted in Taixing, China, consisting of 206 newly diagnosed cases with primary stomach cancer and 415 healthy population controls. Polymorphisms of MTHFR C677T and A1298C were assayed by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) techniques. The data were analysed using the logistic regression model. No obvious association between the MTHFR A1298C polymorphism and the risk of stomach cancer was observed in this study. The frequencies of 677 C/C, C/T, and T/T were 34.5, 50.9, and 14.6%, respectively, in controls. The frequency of the MTHFR 677 wild homozygotic genotype was 25.8% in cases, which was lower than that in controls (34.5%). The adjusted odds ratio (OR) for the MTHFR 677 any T genotype was 2.05 (95% confidence interval (CI), 1.26-3.34) when compared with the C/C genotype. In the low fruit and vegetable intake group an increasing trend was observed with the T allele exposure, p=0.0056. The adjusted ORs were 1.68 (95% CI = 0.86-3.29) for the C/T genotype and 3.58 (95% CI = 1.46-8.75) for the T/T genotype, respectively. The MTHFR 677 any T genotype was associated with an increased risk of primary stomach cancer among the Chinese population. Folate deficiency might modify the MTHFR gene polymorphism and influence the risk of stomach cancer.     

亚甲基四氢叶酸还原酶基因C677T、G1793A单核苷酸多态性与散发性乳腺癌易感性的关系

目的：研究亚甲基四氢叶酸还原酶（MTHFR）基因C677T、G1793A位点单核苷酸多态性与散发性乳腺癌易感性关系。方法：采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法,对200例乳腺癌患者及200例正常对照者MTHFR基因C677T、G1793A位点单核苷酸多态性进行分析,logistic回归分析不同基因型与乳腺癌风险的关系。结果：乳腺癌组MTHFR 677TT基因型频率为25.00%显著高于正常对照组的10.50%（X2=14.401,P=0.001）,CT基因型频率为44.50%低于正常对照组的54.50%,CC基因型频率在乳腺癌组和正常对照组中无差别;MTHFR 1793GA基因型频率为18.50%显著高于正常对照者的8.50%（X2=8.563,P=0.003）。乳腺癌患者MTHFR 677T和1793A等位基因频率分别为47.25%、9.25%,显著高于对照组中的37.75%、4.25%。MTHFR 677TT基因型携带者罹患乳腺癌的风险是677CC基因型携带者的2.732倍（95%CI=1.418～5.051,P=0.001）,MTHFR1793GA基因型携带者罹患乳腺癌的风险是1793GG基因型携带者的2.444倍（95%CI=1.325～4.505,P=0.003）。另外,乳腺癌组中MTHFR C677T基因多态性与肿瘤大小相关（x2=7.431,P=0.024,MTHFR G1793A基因多态性与淋巴结转移情况（x2=8.939,P=0.011）、癌组织学分级（x2=9.983,P=0.007）相关。结论：MTHFR C677T、G1793A基因多态性与散发性乳腺癌的易感性相关。     

Modulator effects of the methylenetetrahydrofolate reductase C677T polymorphism on response to vitamin B12 therapy and homocysteine metabolism

In this study, our aim was to investigate the association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on the vitamin B12 therapy response in 95 patients with vitamin B12 deficiency and 92 healthy control subjects using vitamin B12, plasma total homocysteine (tHcy), and folate as the main measure of outcome. MTHFR C677T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism techniques. There were no differences in the distribution of MTHFR genotypes in the cases versus the controls. Mean concentrations of plasma tHcy and B12 vitamin were 18.84 μM and 142.47 pg/mL in patients with TT (10.5%) genotypes. Furthermore, mean concentrations of B12 vitamin after cobalamin therapy were 697.62, 656.64, and 488.76 pg/mL in patients with the CC, CT, and TT genotypes, respectively. The MTHFR 677 TT genotype has decreasing effect in B12 vitamin and increasing effect in tHcy. In comparison with the patients having CC and CT genotypes, patients with the TT genotype had a lower response to vitamin B12 therapy.     

MTHFR C677T polymorphism in chronic pancreatitis and pancreatic adenocarcinoma

Chronic pancreatitis and pancreatic adenocarcinoma are extensively studied as common and potentially lethal disorders. However, their causes and genetic background in most cases remain unclear. The C677T polymorphism in 5',10'-methylenetetrahydrofolate reductase (MTHFR) gene may modulate the risk of pancreatic disorders. In this study, we tested whether MTHFR C677T polymorphism is associated with chronic pancreatitis and pancreatic adenocarcinoma in the Serbian population. DNA was extracted from blood samples of 51 chronic pancreatitis patients, 21 pancreatic adenocarcinoma patients, and a control group consisting of 50 healthy smokers. The MTHFR C677T polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Although, no statistically significant differences were observed in the distribution of MTHFR genotype or allele frequencies between patients and control groups, the results showed an increased frequency of homozygotes for MTHFR C677T polymorphism in chronic pancreatitis patients (14%) and a decreased frequency in pancreatic adenocarcinoma patients (5%) in comparison to the control group (8%). We speculate that the MTHFR C677T polymorphism could act as a possible risk factor for chronic pancreatitis and a possible protective factor in pancreatic adenocarcinoma. This observation needs further investigation in prospective studies on a larger number of patients, in which the effect of other genetic and environmental factors should also be taken into consideration.     

Methylenetetrahydrofolate reductase gene polymorphisms in patients with nonalcoholic steatohepatitis (NASH)

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal hepatic steatosis in the absence of a history of alcohol use. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. Hyperhomocysteinemia causes steatosis, and the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms result in hyperhomocysteinemia. To examine whether the C677T and A1298C polymorphisms of the MTHFR gene were associated with NASH, we analysed the allele and genotype distribution of the MTHFR C677T and A1298C polymorphisms in 57 well-diagnosed NASH patients, 324 healthy controls in a case-control study of Turkish subjects of Caucasian origin. The diagnosis of the NASH patients was based on liver biopsy. The method used in the analysis of genotypes was PCR-RFLP. The MTHFR A1298C polymorphism was significantly associated with NASH (chi(2) = 8.439; p = 0.015) in the total NASH patients compared with healthy controls. The MTHFR 1298C allele (odds ratio (OR) = 2.480; 95%CI = 1.286-4.782; chi(2) = 7.703; df = 1; p = 0.006) was significantly associated with NASH in the total NASH patients. The MTHFR C677C/A1298C compound genotype (OR = 2.218; 95%CI = 1.003-4.906; chi(2) = 3.998; df = 1; p = 0.046) in men patients was also significantly associated with NASH. Likewise the MTHFR C1298C genotype was significantly associated with NASH in women patients with NASH (OR = 2.979; 95%CI = 1.027-8.641; chi(2) = 4.343; df = 1; p = 0.037). In conclusion, the MTHFR 1298C allele in all NASH patients, C1298C genotype, C677C/C1298C compound genotype in women NASH patients and C677C/A1298C compound genotype in men NASH patients were genetic risk factors for NASH.     

Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats

The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been shown to be associated with cardiovascular disease and in patients with end-stage renal disease (ESRD). However, the relationship between MTHFR polymorphisms and cardiovascular disease (CVD) in patients on hemodialysis has not been examined. The aim of this study was to assess the association of polymorphisms of MTHFR gene with homocysteine (Hcy) and intimal medial thickness (IMT) in patients on hemodialysis. We performed case-control study involving107 patients with ESRD and 103 healthy controls. Plasma Hcy was measured in all the subjects and these subjects were genotyped for three MTHFR polymorphisms (C677T, A1298C, and G1793A). We observed significantly higher Hcy levels in patients as compared to controls. The frequency of MTHFR 1298CC genotype was significantly higher in ESRD patients than in controls (21.4% vs. 2.9%); the frequency of the MTHFR C677T genotypes did not differ between groups (26.1% vs. 17.4%). Compound heterozygous MTHFR 677CT/1298AC genotypes showed maximum association with the risk of ESRD (OR: 12.8; 5%CI: 1.64–10.01, P < 0.05). Concurrent occurrence of MTHFR 677CC wild genotype with either 1298CC or 1793GA significantly increased the risk of disease (OR: 7.20; 95%CI: 2.06–2.51, P < 0.001 and OR: 7.60; 95%CI: 1.68–34.35; P < 0.05, respectively). MTHFR 1298CC genotype was associated with higher Hcy levels. IMT was also significantly higher in patients with the 1298CC genotype (P < 0.05). Thus, A1298C polymorphism of MTHFR gene appears to be associated with the severity of carotid atherosclerosis and co-occurrence of MTHFR polymorphisms may be a risk factor for CVD in patients on hemodialysis.     

不明原因复发性自然流产夫妇MTHFR C677T位点多态性分析

目的：分析不明原因复发性自然流产（URSA）夫妇与亚甲基四氢叶酸还原酶基因C677T（MTHFR C677T）位点多态性的关 联性研究。方法：采用聚合酶链式反应- 限制性片段长度多态性( PCR-RFLP)对URSA 组和对照组各50 对夫妇的外周血进行 MTHFR C677T 的位点多态性进行检测分析。结果：URSA 组MTHFR 基因677 位点的T/T、C/T+T/T 基因型的发生频率显著高于 对照组,差异具有统计学意义(P<0.05),而对照组MTHFR 基因677 位点的C/C 基因型发生频率显著高于URSA 组（P<0.05）,两 组MTHFR 基因677 位点的C/T 基因型比较无明显差异（P>0.05)。另外URSA 组等位基因T 明显高于C 的频率,且URSA 组等 位基因T 发生频率显著高于对照组,对照组等位基因C 发生频率显著高于USRA 组,差异均具有统计学意义（P<0.05）。结论： MTHFR C677T 位点的多态性与URSA 的发生密切相关,是该病的重要遗传风险因素。     

MTHFR C677T polymorphism contributes to colorectal cancer susceptibility: evidence from 61 case–control studies

Methylenetetrahydrofolate reductase (MTHFR) is believed to be involved in folate metabolism which plays a critical role in carcinogenesis. To date, many case-control studies have investigated the association between MTHFR C677T polymorphism and colorectal cancer risk. However, the results were inconsistent. In order to derive a more precise estimation of the association, we conducted this meta-analysis. This meta-analysis recruited 61 published studies which were selected by a search of PubMed up to 31st September 2011, including 16,111 colorectal cancer cases and 23,192 controls. We used crude odds ratios (ORs) with 95?% confidence intervals (CIs) to assess the association between MTHFR C677T polymorphism and colorectal cancer susceptibility. Our results showed that MTHFR C667T polymorphism contributed to the decreased colorectal cancer risk in overall population (for TT vs. CC: OR?=?0.89, 95?% CI?=?0.82-0.97; for TT vs. CT/CC: OR?=?0.88, 95?% CI?=?0.83-0.92). In subgroup analysis by ethnicity, the results also indicated a correlation between the T allele of MTHFR C667T and the colorectal cancer risk in Asian population (for TT vs. CC: OR?=?0.82, 95?% CI?=?0.69-0.97; for TT vs. CT/CC: OR?=?0.81, 95?% CI?=?0.74-0.90). Additionally, the correlation was also observed in male subgroup in sub-analysis by gender (for TT vs. CC: OR?=?0.82, 95?% CI?=?0.71-0.93; for TT vs. CT/CC: OR?=?0.81, 95?% CI?=?0.71-0.92). In summary, our meta-analysis strongly indicated the MTHFR C667T polymorphism was associated with a reduced risk of CRC.     

Combination of polymorphisms between MTHFR and TS gene modulates survival after 5-fluorouracil-based therapy in colorectal cancer patients

The major targets of 5-fluorouracil (5-FU) are thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR). Therefore, we hypothesized that the variable number of tandem repeat (VNTR) of the thymidylate synthase enhancer region (TSER) together with methylenetetrahydrofolate reductase (MTHFR 677C>T) polymorphism could alter drug activity and predict drug toxicity or efficacy. This study was designed to investigate the influence of TSER and MTHFR polymorphisms on the clinical outcomes of patients with colorectal cancer receiving 5-FU-based chemotherapy. Genomic DNA was isolated from 103 samples of colorectal cancer patients. The genotypes of two common polymorphisms (TSER and MTHFR 677C>T) were determined by polymerase chain reaction-restriction fragment length polymorphism. Patient prognoses were compared with genotype groups and analyzed according to tumor location and gender. There were no differences in prognosis between genotypes or functional groups when the TSER and MTHFR groups were considered separately. However, analysis of combined genotypes of the TSER and the MTHFR 677C>T polymorphisms were associated with the survival rate of colorectal cancer patients who received 5-FU-based chemotherapy (P=0.028). Prognosis of colorectal cancer patients was significantly different between proximal colon and distal colon cancers (P=0.002). However, prognosis did not receive any effect of the combined genotype when analyzed according to tumor location, such as proximal and distal colon cancer. The male group also showed a significant difference between low and high risk types of TSER and MTHFR combined genotypes when stratified according to gender (P=0.019). In conclusion, the combined TSER and MTHFR 677C>T genotypes can be potential prognostic factors in colorectal cancer with 5-FU-based chemotherapy, especially in male gender in Koreans.