Methylenetetrahydrofolate Reductase 677CC Research Articles

Influence of combined methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase enhancer region (TSER) polymorphisms to plasma homocysteine levels in Korean patients with recurrent spontaneous abortion

Objectives Methylenetetrahydrofolate reductase (MTHFR) mutations known to be associated with hyperhomocysteinemia may be a risk factor for recurrent spontaneous abortion. Recently 28-bp tandem repeat polymorphism in thymidylate synthase enhancer region (TSER) was reported to affect plasma homocysteine level. We investigated the association between plasma homocysteine level and MTHFR and TSER genotypes. Methods Plasma homocysteine level was measured by fluorescent polarizing immunoassay. MTHFR mutations (C677T and A1298C) were identified by PCR-restriction fragment length polymorphism assay. TSER mutation was analyzed by PCR method. Results Average homocysteine level was significantly higher in MTHFR 677TT genotype (9.80 ± 3.87 μmol/L) than in MTHFR 677CT (7.04 ± 1.99 μmol/L) in MTHFR 677CC genotype (8.14 ± 1.74 μmol/L) in Korean patients with unexplained recurrent spontaneous abortion ( p = 0.0143). While MTHFR 1298AA showed the highest level, plasma homocysteine levels were not significantly different among MTHFR 1298AA (8.42 ± 2.65 μmol/L), 1298AC (6.98 ± 2.44 μmol/L) and 1298CC (6.09 ± 0.32 μmol/L) ( p = 0.2058). There was no significant difference among TSER genotypes (2R2R, 8.61 ± 1.68 μmol/L; 2R3R, 7.84 ± 2.16 μmol/L; 3R3R, 8.05 ± 2.81 μmol/L; p = 0.9319). Among the combined genotypes of MTHFR C677T and TSER, 677TT-3R3R genotype had the highest homocysteine level (11.47 ± 4.66 μmol/L). 1298AA-3R3R had the highest level (8.54 ± 3.05 μmol/L) among the combined genotypes of MTHFR A1298C and TSER. Conclusion Although there was no significant difference found among combined genotypes, 3R3R showed elevated homocysteine levels in MTHFR 677TT and 1298AA in Korean patients with unexplained recurrent spontaneous abortion. Thus TSER polymorphism may be a genetic determinant of plasma homocysteine level in Korean patients as well as MTHFR C677T polymorphism.

Colorectal Cancer and the Methylenetetrahydrofolate Reductase 677C → T and Methionine Synthase 2756A → G Polymorphisms: A Study of 2,168 Case-Control Pairs from the JANUS Cohort

Abstract Polymorphisms in genes involved in the metabolism of folate and methyl groups have been implicated with risk of colorectal cancer. We evaluated the relation between the polymorphisms 677C → T of the methylenetetrahydrofolate reductase (MTHFR) and 2756A → G of the methionine synthase (MTR) genes and risk of colorectal cancer. From the Norwegian JANUS cohort of 309,000 subjects, 2,179 cases were identified and a similar number of controls were selected. The controls were matched for age, gender, time, and place of serum donation. Genotypes were obtained from 2,168 case-control pairs by real-time PCR of serum samples. Risk of colorectal cancer was estimated with conditional and unconditional logistic regression. Median age at diagnosis was 60 years and mean follow-up 13 years. The odds ratio for MTHFR TT versus CC was 0.73 [95% confidence interval (95% CI), 0.58-0.92] and for MTR GG versus AA was 0.65 (95% CI, 0.47-0.90). No interaction between the polymorphisms was found. Relative risk estimates were similar for men and women, and for young and old age at diagnosis. For the MTR GG genotype, risk reduction was observed at the two most distal sites (sigmoideum and rectum) only (P = 0.003). The folate marker, serum total homocysteine (tHcy), was measured in 1,837 subjects. Odds ratio for the upper versus the lower tertile of tHcy was 1.32 (95% CI, 1.04-1.68). No significant effect modification by tHcy levels was detected for either polymorphism. In summary, we found significantly reduced risk of colorectal cancer in subjects with the MTHFR 677 TT and MTR 2756 GG genotypes. No interaction between the polymorphisms, or of either polymorphism with tHcy, was detected.

Methylenetetrahydrofolate reductase (MTHFR) gene 677C>T and 1298A>C haplotypes: New prognostic factors in chronic lymphocytic leukemia

6524 Background: Methylenetetrahydrofolate reductase (MTHFR) regulates the metabolism of folate and methionine, important components of DNA synthesis and methylation. Two common genetic polymorphisms (677C>T and 1298A>C) are associated with reduced MTHFR activity. We investigated whether MTHFR genotypes are associated with an increased risk for chronic lymphocytic leukaemia (CLL) or might predict disease progression in CLL patients. Methods: We genotyped the two MTHFR polymorphisms using DNA from 111 patients with CLL and 92 healthy controls using PCR amplification followed by restriction analysis. Results: Comparing the CLL patients with the healthy controls we found no significant differences in allele frequencies or genotype distributions for both polymorphisms. Progression-free-survival (PFS), a surrogate marker for disease progression, was not significant different in individuals with CLL, if all disease stages were included. However, in patients with stage A according to Binet PFS was significantly longer in patients displaying the MTHFR 677CC (p= 0.0423) and the MTHFR 1298A/C or CC genotypes (p= 0,0189), respectively. In a multivariate analysis a MTHFR haplotype (677 CC plus 1298 CC or A/C) was the best independent prognostic factor for PFS comparing with other known prognostic factors. In a subgroup analysis of prognostically more favourable, ZAP-70 negative CLL patients the two MTHFR polymorphisms, and especially the MTHFR haplotype, could separate patients into two groups with different PFS. Conclusions: Our data suggest that the MTHFR 677C>T and MTHFR 1298A>C polymorphisms do not affect the risk for B-CLL. However, MTHFR genotypes may be independent prognostic markers, which influence the PFS in patients with B-CLL. No significant financial relationships to disclose.

Methylenetetrahydrofolate reductase (MTHFR) gene 677C>T and 1298A>C haplotypes: New prognostic factors in chronic lymphocytic leukemia

6524 Background: Methylenetetrahydrofolate reductase (MTHFR) regulates the metabolism of folate and methionine, important components of DNA synthesis and methylation. Two common genetic polymorphisms (677C>T and 1298A>C) are associated with reduced MTHFR activity. We investigated whether MTHFR genotypes are associated with an increased risk for chronic lymphocytic leukaemia (CLL) or might predict disease progression in CLL patients. Methods: We genotyped the two MTHFR polymorphisms using DNA from 111 patients with CLL and 92 healthy controls using PCR amplification followed by restriction analysis. Results: Comparing the CLL patients with the healthy controls we found no significant differences in allele frequencies or genotype distributions for both polymorphisms. Progression-free-survival (PFS), a surrogate marker for disease progression, was not significant different in individuals with CLL, if all disease stages were included. However, in patients with stage A according to Binet PFS was significantly longer in patients displaying the MTHFR 677CC (p= 0.0423) and the MTHFR 1298A/C or CC genotypes (p= 0,0189), respectively. In a multivariate analysis a MTHFR haplotype (677 CC plus 1298 CC or A/C) was the best independent prognostic factor for PFS comparing with other known prognostic factors. In a subgroup analysis of prognostically more favourable, ZAP-70 negative CLL patients the two MTHFR polymorphisms, and especially the MTHFR haplotype, could separate patients into two groups with different PFS. Conclusions: Our data suggest that the MTHFR 677C>T and MTHFR 1298A>C polymorphisms do not affect the risk for B-CLL. However, MTHFR genotypes may be independent prognostic markers, which influence the PFS in patients with B-CLL. No significant financial relationships to disclose.

Folate intake, MTHFR C677T polymorphism, alcohol consumption, and risk for sporadic colorectal adenoma (United States).

The purpose of this study was to investigate whether folate intake is associated with risk for incident sporadic colorectal adenoma, and whether the association differs according to methylenetetrahydrofolate reductase (MTHFR) genotypes or is modified by intakes of alcohol or other micronutrients in the folate metabolism pathway. The authors analyzed data from a colonoscopy-based case-control study (n = 177 cases, 228 controls) conducted in North Carolina between 1995 and 1997. The multivariate-adjusted odds ratio (OR) comparing the highest to lowest tertile of total folate intake was 0.61 (95% confidence interval [CI] 0.35-1.05); for MTHFR C677T polymorphism CT and TT genotypes relative to the CC genotype they were, respectively, 1.09 (CI: 0.71-1.66) and 0.68 (CI: 0.29-1.61); and for heavy drinkers (> 3 drinks/week) compared to non-drinkers it was 1.67 (CI: 1.00-2.81). The multivariate-adjusted ORs comparing the highest to lowest tertile of total folate intake according to those with the MTHFR CC, CT, and TT genotypes, were, respectively, 0.65 (CI: 0.30-1.39), 0.57 (CI: 0.23-1.44), and 0.22 (CI: 0.02-3.19). For those in the lowest tertile of folate intake who drank more than three drinks a week compared to those who were in the highest tertile of folate intake and did not drink alcohol the OR was 6.54 (CI: 1.96-21.80). There was no substantial evidence for interactions of folate with intakes of methionine, vitamins B2, B6, or B12. These data are consistent with hypotheses and previous findings that higher folate intake may reduce risk for colorectal neoplasms, perhaps especially among those who consume more alcohol.

The MTHFR 677C > T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis

Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, plays a major role in the provision of methyl groups for DNA methylation and in the production of dTMP for DNA synthesis. Different polymorphisms have been described for this enzyme, the most studied being the C677T, which has been shown to be associated with predisposition to colorectal cancer in patients who consume a high alcohol diet. The aim of this study was to determine whether the MTHFR polymorphism is related to hepatocellular carcinoma (HCC) in patients with alcoholic cirrhosis. MTHFR genotypes were determined in 300 liver transplant patients, 72 of whom had alcoholic cirrhosis with HCC and 122 of whom had alcoholic cirrhosis without HCC. The remaining patients were transplanted for HCC on normal liver (n = 27) or viral cirrhosis with HCC (n = 49) or without HCC (n = 30). We also tested 80 healthy subjects. Among the group of patients transplanted for alcoholic cirrhosis, the frequency of MTHFR variants CC versus CT and TT was significantly higher in patients with HCC than in patients without macroscopic evidence of HCC (P = 0.02). This difference was not observed between patients with and without HCC developed either on viral cirrhosis or on non-cirrhotic liver. If we considered all the patients transplanted for HCC, the MTHFR CC genotype was significantly higher in patients who had developed HCC on alcoholic cirrhosis rather than on viral cirrhosis (P = 0.002) or on non-cirrhotic livers (P = 0.02). The relative risk for HCC in subjects with alcoholic cirrhosis and the CC genotype was 2.03. These results suggest that the MTHFR CC genotype increases the risk to develop HCC in patients who consume a high alcohol diet.

190 E-cadherin and beta catenin immunoexpression in primary ovarian carcinomas: an association with clinicopathological features

Cervical cancer is the third most common cancer among women worldwide. Several factors lead to cervical cancer, among which human papilloma virus (HPV) infection has a prominent role. Methylenetetrahydrofolate reductase (MTHFR) is crucial in folate metabolic pathway and plays an important role in DNA synthesis and DNA methylation. MTHFR gene polymorphisms, including C677T and A1298C, lead to reduced enzyme activity. This case-control study aims to illustrate the association between MTHFR gene polymorphisms and the risk of cervical cancer.This study was conducted on 196 samples, which included 96 cervical biopsy samples compared to 100 Pap smear samples of normal healthy women without HPV infection. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used for the MTHFR polymorphism detection, followed by fluorescent amplification-based specific hybridization PCR method to detect HPV16 and HPV18.The results show that the MTHFR 677TT genotype plays a protective role in cervical cancer (P = 0.0030) (OR = 0.21, 95% confidence interval [CI]: 0.07–0.59). Furthermore, there was a strong significant association between MTHFR 1298CC genotype and the risk of cervical cancer (OR = 10.69; 95% CI: 4.28–26.71, P = 0.0001).It can be concluded that A1298C polymorphism is a genetic risk factor for cervical cancer in the assessed Iranian population group. It seems that MTHFR 1298CC genotype is more susceptible to HPV 16 infection. Combination analysis of MTHFR C677T and A1298C polymorphisms revealed that combined MTHFR 677CC and 1298CC are strongly associated with a risk of cervical cancer.

Methylenetetrahydrofolate reductase (MTHFR) 677C>T and methionine synthase reductase (MTRR) 66A>G polymorphisms: association with serum homocysteine and angiographic coronary artery disease in the era of flour products fortified with folic acid

We analyzed the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T and methionine synthase reductase (MTRR) 66A>G polymorphisms with serum homocysteine and with coronary artery disease (CAD) in 504 patients undergoing clinically-indicated angiography between July 1998 and January 1999. Significant CAD (≥50% stenosis in ≥one artery, blinded to risk factors) was present in 271 patients (54%). Median homocysteine (μmol/l) was 8.8 (interquartile range: 7.5–10.7). The prevalence of the MTHFR TT, CT, and CC genotypes was 11, 44 and 45%, respectively. Median tHcy (with interquartile ranges) for the entire population was 8.8 (7.5–10.7), and for the TT, CT, and CC genotypes was 9.7 (8.2–11.4), 8.8 (7.5–10.7), and 8.6 (7.3–10.6) μmol/l, respectively ( P=0.04). On multiple logistic regression analysis, the MTHFR TT genotype was associated with hyperhomocysteinemia (adjusted OR=3.57; 95% CI, 1.47–8.70), but not with significant CAD. The prevalence of the MTRR AA, AG, GG genotypes was 19, 50 and 31%, respectively. There were no differences in mean homocysteine, prevalence of hyperhomocysteinemia and significant CAD between the three genotypes. On multivariate analysis, the MTRR genotypes were not associated with serum homocysteine or with significant CAD.

Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate?

Periconceptional folic acid supplementation may reduce the risk of cleft lip with or without cleft palate (CL(P)). Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene reduce availability of 5-methyltetrahydrofolate, the predominant circulating form of folate. To determine the effect of MTHFR C677T and MTHFR A1298C genotypes and haplotypes on CL(P) risk and the interaction with maternal periconceptional dietary folate and folic acid supplement intake, the authors conducted a case-control triad study in the Netherlands (1998-2000) among 179 CL(P) and 204 control families. Infant and parental MTHFR C677T and MTHFR A1298C genotypes and haplotypes were not associated with CL(P) risk in the case-control and transmission disequilibrium test analyses. Mothers carrying the MTHFR 677TT genotype and who either did not use folic acid supplements periconceptionally or had a low dietary folate intake, or both, had an increased risk of delivering a CL(P) child (odds ratio (OR) = 5.9, 95% confidence interval (CI): 1.1, 30.9; OR = 2.8, 95% CI: 0.7, 10.5; OR = 10.0, 95% CI: 1.3, 79.1, respectively). No supplement use, low dietary folate intake, and maternal MTHFR 1298CC genotype increased the risk of CL(P) offspring almost sevenfold (OR = 6.5, 95% CI: 1.4, 30.2). Thus, the detrimental effect of low periconceptional folate intake on the risk of giving birth to a CL(P) child was more pronounced in mothers with the MTHFR 677TT or MTHFR 1298CC genotype.

Methylenetetrahydrofolate reductase genotype does not play a role in multiple myeloma pathogenesis.

Methylenetetrahydrofolate reductase (MTHFR) plays an important role in carcinogenesis. A decreased incidence of cancer has been reported in the presence of MTHFR 677TT, 1298AC and 1298CC polymorphic variants. We have analysed the MTHFR genotype in 107 multiple myeloma (MM) patients and 86 controls. The MM and control polymorphisms frequencies were: 34% and 48% for 677CC, 53% and 41% for 677CT, 12% and 11% for 677TT; 36% and 43% for 1298AA, 51% and 44% for 1298AC; and 12% and 13% for 1298CC respectively. No statistically significant differences were observed. In addition, no differences were seen according to MM stage, presence of p16 gene hypermethylation or response to treatment.

Factor V Leiden, prothrombin gene G20210A variant, and methylenetetrahydrofolate reductase C677T genotype in young adults with ischemic stroke.

Ischemic stroke in young adults is a well-known disease, but despite extensive clinical and laboratory investigations, its etiology remains unclear in approximately half of the cases. We examined the prevalence of factor V Leiden, the prothrombin G20210A genotype, and the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in 100 patients (51 males and 49 females) who survived an ischemic stroke without a cardiac embolic source at an age < or = 45 years, and in 238 healthy control subjects from the same geographic area. The patients were selected for study only if the diagnosis of stroke was documented by computed tomography scan or nuclear magnetic resonance (NMR) of the brain, or both. Heterozygosity for the FV Leiden mutation was found in 3 patients (3.0%) and in 10 control subjects (4.2%). Two patients (2.0%) and five control subjects (2.1%) were heterozygous for the prothrombin G20210A mutation. The frequencies of the MTHFR 677TT, CT, and CC genotypes in the patient group were 12%, 37%, and 51%, respectively, and were not significantly different from those in control subjects (11%, 40%, and 49%, respectively). In conclusion, our results indicate that FV Leiden mutation, prothrombin G20210A genotype, and homozygosity for the C677T mutation in the MTHFR gene are not associated with an increased risk for ischemic stroke in young adults.