Methylenetetrahydrofolate reductase polymorphism (C677T), hyperhomocysteinemia, and risk of ischemic cardiovascular disease and venous thromboembolism: … (original) (raw)
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A Methylenetetrahydrofolate Reductase Polymorphism and the Risk of Colorectal Cancer
MTHFR3 is a critical enzyme regulating the metabolism of folate and methionine , both of which are important factors in DNA methylation and synthesis. MTHFR irreversibly converts 5,10-meth ylenetetrahydrofolate to 5.methyltetrahydrofolate, the primary methyl donor for the remethylation of homocysteine to methionine. A com mon 677Câ€"*T (Alaâ€"*Val) mutation of the gene was found to enhance the thermolability of the enzyme , and the variant homozygous genotype is associated with elevation in plasma homocysteine levels (7), decrease in plasma 5-methyltetrahydrofolate levels (8), as well as risk of spina bifida (9).
1998
We examined the relationship between a functional polymorphism ( 667 C→T, ala→val) of the methylenetetrahydrofolate reductase gene (MTHFR) and the risk of colorectal adenomas in the prospective Nurses' Health Study. Among 257 incident polyp cases and 713 controls, the MTHFR val/val polymorphism [relative risk (RR) ⍧ 1.35, 95% confidence interval (CI) 0.84-2.17] was not significantly associated with risk of adenomas. This lack of association was observed for both small (RR ⍧ 1.36, 95% CI 0.76-2.45) and large (RR ⍧ 1.32, 95% CI 0.66-2.66) adenomas. Furthermore, there was no significant interaction between this polymorphism and consumption of either folate, methionine or alcohol. We also examined the relationship of a newly identified polymorphism (asp919gly) of the methionine synthase gene (MS) with the risk of colorectal adenomas in the same population. The MS gly/gly polymorphism was also not significantly associated with risk of colorectal adenomas (RR ⍧ 0.66, 95% CI 0.26-1.70). These results, which need to be confirmed in other studies, suggest that the MTHFR val/val polymorphism, which has been previously inversely associated with risk of colorectal cancer, plays a role only in a late stage (adenoma→carcinoma) of colorectal tumorigenesis, and/or may protect against malignant transformation in the subset of benign adenomas, which may progress to malignancy.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2004
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. Re...
Methylenetetrahydrofolate reductase polymorphism (C-677T) and coronary artery disease
Clinical Science, 1998
MTHFR3 is a critical enzyme regulating the metabolism of folate and methionine , both of which are important factors in DNA methylation and synthesis. MTHFR irreversibly converts 5,10-meth ylenetetrahydrofolate to 5.methyltetrahydrofolate, the primary methyl donor for the remethylation of homocysteine to methionine. A com mon 677Câ€"*T (Alaâ€"*Val) mutation of the gene was found to enhance the thermolability of the enzyme , and the variant homozygous genotype is associated with elevation in plasma homocysteine levels (7), decrease in plasma 5-methyltetrahydrofolate levels (8), as well as risk of spina bifida (9).
Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 2011
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / g e n t o x C o m m u n i t y a d d r e s s : w w w . e l s e v i e r . c o m / l o c a t e / m u t r e s MTHFR and MTRR genotype and haplotype analysis and colorectal cancer susceptibility in a case-control study from the Czech Republic a b s t r a c t Polymorphic variants in genes involved in one-carbon metabolism, in particular of dietary folate, may modulate the risk for colorectal cancer through aberrant DNA-methylation and altered nucleotide synthesis and repair. In the present study, we have assessed the association of six polymorphisms and relative haplotypes in the MTHFR gene (rs1801133 and rs1801131) and in the MTRR gene (rs1801394, rs1532268, rs162036, and rs10380) with the risk for colorectal cancer in 666 patients and 1377 controls from the Czech Republic.
Cancer science, 2004
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated the relation of MTHFR C677T and A1298C polymorphisms to colorectal cancer in a case-control study in Fukuoka, Japan. The subjects comprised 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly in the study area. The genotype was determined by the PCR-RFLP method using genomic DNA extracted from buffy coat. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for gender, age class, area, and alcohol use. The MTHFR 677TT genotype was associated with a statistically significant decrease in the risk with an adjusted odds ratio of 0.69 (95% confidence interval 0.51-0.93) compared with the 677CC and 677CT combined, and the decrease was most evident in individuals with no alcohol consumption. While the A1298C polymorphism showed no measur...
2008
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA methylation and synthesis. One of the most important polymorphisms identified in the MTHFR gene is C677T. MTHFR activity is lowered in individuals with 677TT genotype. Using pyrosequencing, we analyzed the MTHFR genotypes in 118 colorectal cancer patients and 189 normal matched controls. Whereas the CC, CT and TT genotypes of MTHFR among the colorectal cancer patients were 51.7%, 28.0 % and 20.3% respectively, we were able to find 47.1% of 677CC, 27.0% of 677CT and 25.9% of 677TT in normal controls. An inverse association was observed between the risk of colorectal cancer and TT genotype with the odds ratios (OR) of 1, 0.94 and 0.71 for CC, CT, and TT genotypes, respectively. This association was similar in both sexes, but in patients with high levels of folate intake. Our study corroborates previous findings of an inverse association between MTHFR 677TT genotype and colorectal cancer, especially at high levels of folate.
Reverse association between MTHFR polymorphism (C677T) with sporadic colorectal cancer
… and Hepatology from …, 2009
Aim: To investigate association between MTHFR gene polymorphism with colorectal cancer. Background: The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) is linked to DNA methylation, synthesis and repair. One of the most important polymorphisms that has been identified in the MTHFR gene is C677T. The single nucleotide polymorphism C677T has been found to be associated with decreased enzyme activity and decreased plasma folate. Thus it might play an important role in the etiology of colorectal neoplasia. Patients and methods: Using pyrosequencing, we analyzed the MTHFR genotypes in 234 colorectal cancer patients and 257 normal matched controls. Results: Whereas the CC, CT and TT genotypes of MTHFR among the colorectal cancer patients were 50%, 29% and 21% respectively, we found 36.6% of 677CC, 31.1% of 677CT and 32.3% of 677TT in the normal controls. We observed a decreased risk of colon cancer when folate intake was high for participants with wild type genotype. This association was stronger at higher levels of folate intake. Conclusion: Our study corroborates previous findings of an inverse association of the MTHFR 677TT genotype with colorectal cancer, especially at high levels of folate.
American Journal of Clinical Nutrition, 2008
Background: Polymorphisms located in genes involved in the metabolism of folate and some methyl-related nutrients are implicated in colorectal cancer (CRC). Objective: We evaluated the association of 3 genetic polymorphisms [C677T MTHFR (methylene tetrahydrofolate reductase), A2756G MTR (methionine synthase), and C1420T SHMT (serine hydroxymethyltransferase)] with the intake of methyl-donor nutrients in CRC risk. Design: Patients with CRC (n ҃ 196) and healthy controls (n ҃ 200) matched for age and sex were evaluated for intake of methyl-donor nutrients and the 3 polymorphisms. Results: Except for folate intake, which was significantly lower in patients (P ҃ 0.02), no differences were observed in the dietary intake of other methyl-donor nutrients between groups. High intake of folate (406.7 g/d) was associated with a significantly lower risk of CRC (odds ratio: 0.67; 95% CI: 0.45, 0.99). The A2756G MTR polymorphism was not associated with the risk of developing CRC. In contrast, homozygosity for the C677T MTHFR variant (TT) presented a 3.0-fold increased risk of CRC (95% CI: 1.3, 6.7). Similarly, homozygosity for the C1420T SHMT polymorphism also had a 2.6-fold increased risk (95% CI: 1.1, 5.9) of developing CRC. When interactions between variables were studied, low intake of all methyl-donor nutrients was associated with an increased risk of CRC in homozygous participants for the C677T MTHFR polymorphism, but a statistically significant interaction was only observed for folate (odds ratio: 14.0; 95% CI: 1.8, 108.5). No significant associations were seen for MTR or SHMT polymorphisms. Conclusion: These results show an association between the C677T MTHFR variant and different folate intakes on risk of CRC.