Polymorphisms in the MTHFR gene are associated with breast cancer.

The methylenetetrahydrofolate reductase (MTHFR) gene is a polymorphic gene involved in folate metabolism, DNA biosynthesis, methylation and genomic integrity in actively dividing cells. The MTHFR C677T and A1298C polymorphisms are likely to play an important role in the susceptibility to breast cancer. In this case-control study, we examined the role of MTHFR C677T and A1298C polymorphisms in breast cancer patients. We genotyped 118 premenopausal women with sporadic breast cancer and 193 controls, using a PCR-RFLP method. The allele frequencies of the MTHFR 677T were 31.36% in the breast cancer cases and 28.76% in the controls. The allele frequencies of the MTHFR 1298C were 37.29% in the breast cancer subjects and 31.35% in the controls. Frequencies of MTHFR C677C, C677T and T677T were 50.8, 33.9 and 14.4% in the breast cancer patients and 48.7, 45.1 and 6.2% in the controls, respectively. The results of a chi(2) analysis indicated that the MTHFR 677T allele was significantly distributed (chi(2) = 7.234; p = 0.027). Likewise, the MTHFR T677T genotype showed a 2.5-fold increased risk for breast cancer and the C1298C genotype showed a 1.9-fold increased risk for breast cancer. In the compound genotypes, T677T/A1298A and C677C/C1298C showed a 4.472- and a 2.301-fold increased risk for breast cancer (OR = 4.472, p = 0.001, and OR = 2.301, p = 0.024), respectively. In conclusion, our data suggest that the MTHFR 677T, 1298C alleles, T677T, C1298C genotypes, and C677C/C1298C and T677T/A1298A compound genotypes are genetic risk factors for premenopausal women with sporadic breast cancer.     

Association of polymorphisms in one-carbon metabolizing genes with breast cancer risk in Syrian women

Dietary folate status as well as polymorphisms in one-carbon metabolism genes may affect the risk of breast cancer through aberrant DNA methylation and altered nucleotide synthesis and DNA repair. A large number of studies investigated the role of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms in breast cancer with inconsistent results. Association between multiple polymorphisms in one-carbon metabolism genes and breast cancer was not studied before in an Arab population. The purpose of the present study is to test the hypothesis that polymorphisms in one-carbon metabolism genes are associated with breast cancer susceptibility in Syrian breast cancer women patients. A total of 245 subjects (119 breast cancer women patients and 126 healthy controls) were genotyped for MTHFR C677T and A1298C and MTRR A66G polymorphisms. Association was tested for under numerous genetic models. A statistically significant association was found for MTHFR A1298C polymorphism especially under the allele contrast model (odds ratio (OR) = 1.68, 95% confidence interval (CI) (1.16-2.45), P = 0.006). On the other hand, no significant association was found for MTHFR C677T or MTRR A66G under any of the genetic models tested. The effects of the compound genotypes were also examined. The 66GG genotype was found to be protective against breast cancer when combined with the 677CT or 1298AC genotype (OR = 0.18, 95% CI (0.04-0.82), P = 0.014; OR = 0.3, 95% CI (0.08-1.11), P = 0.058). In conclusion, our study supports the hypothesis that polymorphisms in one-carbon gene metabolisms modulate the risk for breast cancer, particularly the A1298C polymorphism of the MTHFR gene.     

Diets, polymorphisms of methylenetetrahydrofolate reductase, and the susceptibility of colon cancer and rectal cancer

The aim of this study was to investigate the association of environmental factors (dietary folate, methionine and drinking status) and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) gene, as well as the combination of these factors, with the risk of colon cancer and rectal cancer. A case-control study of 53 colon cancer patients, 73 rectal cancer patients and 343 healthy controls was conducted. Genotypes of C677T and A1298C polymorphisms were analyzed by PCR-RFLP. The dietary folate and methionine intakes were assessed using food-frequency questionnaires and food consumption tables. Unconditional logistic regression was applied to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs). The frequency of MTHFR 677T and 1298C alleles in healthy population were 39.4 and 17.2%, respectively. After adjustment for specific variants, the MTHFR 677TT genotype showed a significantly reduced risk of colon cancer compared with the wild type (OR=0.22, 95% CI: 0.50-0.98), and 1298C allele-carrier showed an inverse association with the risk of rectal cancer compared to the wild type (OR=0.52, 95% CI: 0.28-0.98). Adequate intake of folate was a protective factor from colon cancer (OR=0.32, 95% CI: 0.12-0.88) and MTHFR C677T polymorphism showed a statistically significant effect (OR=0.25, 95% CI: 0.06-0.93), reducing the risk of colon cancer in groups that have an intake of folate exceeding 115.64ng per 1000kcal per day. This study suggests that MTHFR C677T and A1298C polymorphisms are associated with the reduced risk of colon and rectal cancers, respectively. Adequate folate intake shows an inverse association with the risk of colon cancer. There is a significant interaction between MTHFR C677T polymorphism and folate intake in reducing the risk of colon cancer.     

Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan

Methylenetetrahydrofolate reductase (MTHFR) balances the pool of folate coenzymes in one-carbon metabolism for DNA synthesis and methylation, both are implicated in carcinogenesis. Two common variants in the MTHFR gene (C677T and A1298C) have been associated with reduced enzyme activity, thereby making MTHFR polymorphisms a potential candidate cancer-predisposing factor. To evaluate the C677T and A1298C functional polymorphisms in the MTHFR gene and their associations with breast cancer risk, as well as the potential modifying effect by plasma folate status on the MTHFR-associated risk, a hospital-based case-control study was conducted on a Taiwanese population consisting of 146 histologically confirmed incident breast cancer cases and their 285 age-matched controls without a history of cancer. A PCR-RFLP method was used for MTHFR polymorphism genotyping and RIA was used to measure the plasma folate. Statistical evaluations were performed using logistic regression analysis. The plasma folate level was inversely associated with breast cancer risk with an adjusted odds ratio (OR) of 0.52 [95% confidence interval (CI): 0.26-1.05] observed among women who were in the highest plasma folate tertile. The MTHFR 677T and 1298C variant alleles were associated with decreased risk for breast cancer [adjusted ORs were 0.81 (95% CI: 0.54-1.21) and 0.57 (95% CI: 0.36-0.89) for 677CT + TT genotypes and 1298AC + CC genotypes, respectively]. Furthermore, compound heterozygote and homozygote variants (677CT + TT and 1298AC + CC) had greater reduced risk (adjusted OR: 0.11, 95% CI: 0.03-0.43) among women with lower plasma folate levels. These results provide support for the important role of folate metabolism in breast tumorigenesis. Further mechanistic studies are warranted to investigate how MTHFR combined genotypes exert their effect on cancer susceptibility.     

Interactions between MTHFR C677T-A1298C variants and folic acid deficiency affect breast cancer risk in a Chinese population

Background: Our objective was to evaluate the MTHFR C677T-A1298C polymorphisms in patients withbreast cancer and in individuals with no history of cancer, to compare the levels of genetic damage and apoptosisunder folic acid (FA) deficiency between patients and controls, and to assess associations with breast cancer.Methods: Genetic damage was marked by micronucleated binucleated cells (MNBN) and apoptosis was estimatedby cytokinesis-block micronucleus assay (CBMN). PCR-RFLP molecular analysis was carried out. Results: Theresults showed significant associations between the MTHFR 677TT or the combined MTHFR C677T-A1298Cand breast cancer risk (OR = 2.51, CI = 0.85 to 7.37, p = 0.08; OR = 4.11, CI = 0.78 to 21.8, p < 0.001). TheMNBN from the combined MTHFR C677T-A1298C was higher and the apoptosis was lower than that of thesingle variants (p < 0.05). At 15 to 60 nmol /L FA, the MNBN in cases with the TTAC genotype was higher thancontrols (p < 0.05), whereas no significant difference in apoptosis was found between the cases and controls afterexcluding the genetic background. Conclusions: Associations between the combined MTHFR C677T-A1298Cpolymorphism and breast cancer are possible from this study. A dose of 120 nmol/L FA could enhance apoptosisin cases with MTHFR C677T-A1298C. Breast cancer individuals with the TTAC genotype may be more sensitiveto the genotoxic effects of FA deficiency than controls.     

Methylenetetrahydrofolate reductase polymorphisms increase risk of esophageal squamous cell carcinoma in a Chinese population

Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism that affects DNA methylation and synthesis. Because germ-line mutations at nucleotides 677 (C-->T) and 1298 (A-->C) in the MTHFR gene cause diminished enzyme activity, and aberrant DNA methylation is oncogenic, we examined the relationship between these two MTHFR polymorphisms and susceptibility to esophageal squamous cell carcinoma (ESCC) in 240 ESCC cases and 360 age- and sex-matched controls in northern CHINA: We found that the allele frequency of MTHFR 677T was significantly higher among cases than among controls (63% versus 41%, P < 0.001). Subjects with the 677TT genotype had a more than 6-fold increased risk of developing ESCC [adjusted odds ratio (OR), 6.18; 95% confidence interval (CI), 3.32-11.51] compared with those who had the 677CC genotype. Furthermore, the elevated ESCC risk associated with the 677 polymorphism was in an allele-dose relationship (trend test, P = 0.0001) with ORs of 1.00, 3.14 (95% CI, 1.94-5.08), and 6.18 (95% CI, 3.32-11.51) for the CC, CT, and TT genotype, respectively, after adjustment for age, sex, smoking status, and the MTHFR 1298 polymorphism. The allele frequency for the MTHFR 1298C was 14% among cases and 17% among controls. The 1298CC genotype was extremely rare in both controls (1.4%) and cases (2.9%) and was also associated with an elevated risk of ESCC (adjusted OR, 4.43; 95% CI, 1.23-16.02) compared with the 1298AA genotype, whereas the 1298AC genotype had no effect on the risk of ESCC. Thus, our findings support the hypothesis that genetic polymorphisms in the MTHFR gene may contribute to susceptibility to carcinogenesis of the esophagus in the at-risk Chinese population.     

Sex differences in risk of lung cancer associated with methylene-tetrahydrofolate reductase polymorphisms.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the metabolism of folate and nucleotides needed for DNA synthesis and repair. Variations in MTHFR functions likely play roles in the etiology of lung cancer. The MTHFR gene has three nonsynonymous single nucleotide polymorphisms (i.e., C677T, A1298C, and G1793A) that have a minor allele frequency of >5%. We investigated the associations between the frequencies of MTHFR variant genotypes and risk of lung cancer in a hospital-based case-control study of 1,051 lung cancer patients and 1,141 cancer-free controls in a non-Hispanic White population. We found that compared with the MTHFR 1298AA genotype, the 1298CC genotype was associated with a significantly increased risk of lung cancer in women [(odds ratio (OR), 2.09; 95% confidence interval (95% CI), 1.32-3.29)] but not in men (OR, 0.95; 95% CI, 0.62-1.45). The MTHFR 677TT genotype was associated with a significantly decreased risk of lung cancer in women (OR, 0.60; 95% CI, 0.40-0.92) but not in men. No association was found between the MTHFR G1793A polymorphism and risk of lung cancer. Further analysis suggested evidence of gene-dietary interactions between the MTHFR C677T polymorphism and dietary intake of vitamin B6, vitamin B12, and methionine in women and evidence of gene-environment interactions between the MTHFR C677T and A1298C polymorphisms and tobacco smoking in men. In conclusion, the polymorphisms of MTHFR may contribute to the risk of lung cancer in non-Hispanic Whites and modify the risk associated with the dietary and environmental exposure in a sex-specific manner.     

One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer

Accumulating evidence from epidemiologic studies suggests that risk of breast cancer is reduced in relation to increased consumption of folate and related B vitamins. We investigated independent and joint effects of B vitamin intake as well as two polymorphisms of a key one-carbon metabolizing gene [i.e., methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C] on breast cancer risk. The study uses the resources of a population-based case-control study, which includes 1,481 cases and 1,518 controls. Significant inverse associations between B vitamin intake and breast cancer risk were observed among non-supplement users. The greatest reduction in breast cancer risk was observed among non-supplement users in the highest quintile of dietary folate intake [odds ratio (OR), 0.61; 95% confidence interval (95% CI), 0.41-0.93] as compared with non-supplement users in the lowest quintile of dietary folate intake (high-risk individuals). The MTHFR 677T variant allele was associated with increased risk of breast cancer (P, trend = 0.03) with a multivariate-adjusted OR of 1.37 (95% CI, 1.06-1.78) for the 677TT genotype. The 1298C variant allele was inversely associated with breast cancer risk (P, trend = 0.03), and was likely due to the linkage of this allele to the low-risk allele of 677C. The MTHFR-breast cancer associations were more prominent among women who did not use multivitamin supplements. Compared with 677CC individuals with high folate intake, elevation of breast cancer risk was most pronounced among 677TT women who consumed the lowest levels of dietary folate (OR, 1.83; 95% CI, 1.13-2.96) or total folate intake (OR, 1.71; 95% CI, 1.08-2.71). From a public heath perspective, it is important to identify risk factors, such as low B vitamin consumption, that may guide an effective prevention strategy against the disease.     

Folate metabolism-related gene polymorphisms and susceptibility to primary liver cancer in North China

Genetic factors may contribute to individual differences in cancer susceptibility. This study was designed to investigate the effects of the polymorphisms of methylenetetrahydrofolate reductase 677 C → T (MTHFR 677 C → T), methylenetetrahydrofolate reductase 1298 A → C (MTHFR 1298A → C), thymidylate synthase (TYMS 3R → 2R), and methionine synthase 2756 A → G (MTR 2756 A → G) on the risk of primary liver cancer (PLC). We conducted a case-control study involving 356 PLC cases and 641 healthy controls in North China. Compared with the MTHFR 677CC genotype, the MTHFR 677TT genotype showed an increased risk for PLC (TT vs. CC: adjusted odds ratio (OR) = 1.56; 95% confidence interval (CI): 1.02-2.40; P = 0.043) after adjusting for gender and age, whereas the MTHFR 1298CC genotype showed a significantly decreased risk for PLC (CC vs. AA: adjusted OR = 0.23; 95% CI: 0.08-0.70; P = 0.010). However, no significant association was found between the TYMS 3R → 2R or the MTR 2756 A → G polymorphism and the risk of PLC. Our results suggest that the MTHFR 677 C → T and the MTHFR 1298A → C genetic polymorphisms might play important role in hepatic carcinogenesis. Further studies with larger sample sizes are required to validate this association.     

Strong Correlation of MTHFR Gene Polymorphisms with Breast Cancer and its Prognostic Clinical Factors among Egyptian Females

Introduction: Globally, Breast cancer (BC) is considered the second most common type of cancer and the principal cause of death among affected women. Aim: In this study, we targeted to demonstrate the association of MTHFR single gene polymorphisms (SNPs) with the susceptibility of breast cancer, in addition to its correlation with the clinical patient features. Patients and Methods: This work was conducted on 100 Egyptian females with breast cancer and 60 healthy matched controls. Clinical examinations and pathological investigations were recorded. Genotyping of MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) by using Restriction Fragment length Polymorphisms (RFLP) and Sequencing assays were performed. Univariate, Multivariate and Haplotype analysis for the allelic frequencies and the association with clinicopathological features of BC were assessed. Results: The present data showed a strong significant association between the CT and TT of MTHFR (C677T), and AC and CC of (A1289C) with the susceptibility of BC showing highly statistical P- value (0.001). It was also demonstrated that the most frequent haplotype of the two loci of MTHFR (rs1801133-rs1801131) was TC. The latter was strongly associated with the aggressive clinical features of each of tumor size, advanced stage, involvement of cancer in lymph nodes, overexpression of HER2neu and dual negativity of both ER and PR hormones. Conclusions: SNPs within the MTHFR gene (C677T) and (A1289C) have strong correlation with BC among Egyptian females; These SNPs should be considered as important prognostic markers for identifying the individuals at high risk of developing BC and its progression.     

5,10-Methylenetetrahydrofolate reductase polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis.

There is evidence supporting a role for 5-10 methylenetetrahydrofolate reductase (MTHFR) gene variants in acute lymphoblastic leukemia (ALL). To provide a more robust estimate of the effect of MTHFR polymorphisms on the risk of ALL, we did a meta-analysis to reevaluate the association between the two most commonly studied MTHFR polymorphisms (C677T and A1298C) and ALL risk. All case-control studies investigating an association between the C677T or A1298C polymorphisms and risk of ALL were included. We applied both fixed-effects and random-effects models to combine odds ratio (OR) and 95% confidence intervals (95% CI). Q-statistic was used to evaluate the homogeneity and both Egger and Begg-Mazumdar tests were used to assess publication bias. The meta-analysis of the C677T polymorphism and risk of childhood ALL included 13 studies with a total of 4,894 individuals. Under a fixed-effects model, the TT genotype failed to be associated with a statistically significant reduction of childhood ALL risk (TT versus CT + CC: OR, 0.88; 95% CI, 0.73-1.06; P = 0.18). However, individuals homozygous for the 677T allele exhibited a 2.2-fold decrease in risk of adult ALL (TT versus CT + CC: OR, 0.45; 95% CI, 0.26-0.77; P = 0.004). In both cases, no evidence of heterogeneity was observed. No association between the A1298C variant and susceptibility to both adult and childhood ALL was disclosed. Our findings support the proposal that the common genetic C677T polymorphism in the MTHFR contributes to the risk of adult ALL, but not to the childhood ALL susceptibility.     

Genetic polymorphisms of methylenetetrahydrofolate reductase and susceptibility to colorectal cancer

Objectives: To study the relation between genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T or A1298C and the susceptibility of colorectal cancer. Methods: We conducted a case-control study with 315 cases of colorectal cancer and 371 population-based controls in Jiangsu province, China. The epidemiological data were collected, and DNA of peripheral blood leukocytes was obtained from all of the subjects. MTHFR C677T and A1298C genotypes were detected by the PCR-RFLP method. Results: (1) When men and women were assessed together, the frequencies of the MTHFR C677T and A1298 genotypes or their alleles were not significantly different between controls and colon cancer or rectal cancer cases. No significant relation was observed between MTHFR C677T or A1298C polymorphisms and colon or rectal cancer susceptibility. (2) Among males, individuals who had MTHFR C677T T/T genotype were at a significantly higher risk of developing colon cancer (age-, residence-, smoking-, alcohol drinking-, tea consumption-adjusted OR=2.15, 95%CI: 1.07-4.33) compared with those who had C677T C allele. Individuals who had C677T T/T and A1298C A/A genotypes were at an increased risk of developing colon cancer (adjusted OR=2.64, 95%CI: 1.20-5.81) compared with those with C677T C allele and A1298C A/A genotypes among males. On the contrary, individuals who had C677T T/T and A1298C A/A genotypes were at an decreased risk of developing rectal cancer (adjusted OR=0.47, 95%CI: 0.22-1.03). Conclusions: These results in the present study suggested that polymorphisms of the MTHFR C677T could influence susceptibility to colon or rectal cancer and that there was a coordinated effect between MTHFR A1298C A/A and C677T T/T genotypes among males.     

亚甲基四氢叶酸还原酶基因多态性与结直肠癌易感性的关系

目的:研究亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因C677T、A1298C多态性与结直肠癌易感性的关系。方法:在江苏省进行了一个病例-对照研究(结直肠癌患者315例,人群对照371例),调查研究对象的生活习惯,抽取静脉血,提取白细胞DNA,采用PCR-RFLP检测研究对象的MTHFR C677T、A1298C基因型。结果:1)男女合计的结直肠癌组、结肠癌组和直肠癌组与对照组之间的MTHFR C677T、A1298C基因型分布频度和等位基因频度差异无统计学意义,MTHFR C677T、A1298C基因多态与结直肠癌、结肠癌和直肠癌的易感性无显著相关。2)在男性中,结肠癌组MTHFR C677T T/T基因型的频度为24.6%,明显高于对照组的14.8%,但差异无统计学意义,χ2=3.42,P=0.064。与C677T C等位基因携带者相比,T/T基因型者发生结肠癌的危险性显著升高,其性别、年龄、居住地区及吸烟、饮酒和饮茶习惯调整后的OR为2.15(95%CI:1.07~4.33)。与同时携带MTHFR C677T C等位基因和A1298C A/A基因型者相比,男性的MTHFR C677T T/T和A1298C A/A基因型携带者发生结肠癌的危险性显著升高,其调整OR为2.64(95%CI:1.20~5.81),而他们发生直肠癌的危险性则明显降低,(调整OR=0.47,95%CI:0.22~1.03)。结论:MTHFR C677T基因多态可以影响男性结、直肠癌的易感性,MTHFR A1298C多态与C677T多态在对男性结、直肠癌易感性的影响中有协同作用。     

Methylenetetrahydrofolate Reductase Gene Germ-Line C677T and A1298C SNPs are Associated with Colorectal Cancer Risk in the Turkish Population

Colorectal cancer (CRC) is the third most common cause of death due to cancer in the worldwide and theincidence is also increasing in Turkey. Our present aim was to investigate any association between germ-linemethylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and CRC risk in Turkey.A total of 86 CRC cases and 212 control individuals of the same ethnicity were included in the current study.Peripheral blood-DNA samples were used for genotyping by StripAssay technique, based on the reversehybridizationprinciple and real-time PCR methods. Results were compared in Pearson Chi-square and multiplelogistic regression models. The MTHFR 677TT (homozygous) genotype was found in 20.9% and the T allelefrequency 4.2-fold increased in CRC when compared with the control group.The second SNP MTHFR 1298CC(homozygous) genotype was found in 14.0% and the C allele frequency 1.4-fold elevated in the CRC group.The current data suggest strong associations between both SNPs of germ-line MTHFR 677 C>T and 1298 A>Cgenotypes and CRC susceptibility in the Turkish population. Now the results need to be confirmed with a largersample size.     

Allele and Genotype Frequencies of the Polymorphic Methylenetetrahydrofolate Reductase and Lung Cancer in ther Jordanian Population: a Case Control Study

Background: Methylenetetrahydrofolate reductase (MTHFR) is involved in amino acid synthesis and DNAfunction. Two common polymorphisms are reported, C677T and A1298C, that are implicated in a number ofhuman diseases, including cancer. Objective: The association between MTHFR C677T and A1298C genotype andhaplotype frequencies in risk for lung cancer (LC) was investigated in the Jordanian population. Materials andMethods: A total of 98 LC cases were studied for MTHFR C677T and A1298C polymorphisms, compared to 89controls taken from the general population, employing the PCR-RFLP technique. Results: The frequency of thegenotypes of MTHFR C677T among Jordanians was: CC, 59.6%, CT, 33%; and TT, 7.4% among LC cases and49.4%, 40.2% and 10.3% among controls. No significant association was detected between genetic polymorphismat this site and LC. At MTHFR A12987C, the genotype distribution was AA, 29.5%; AC, 45.3%, and CC 25.3%among LC cases and 36.8%, 50.6% and 12.6% among controls. Carriers of the CC genotype were more likelyto have LC (OR=2.5; 95%CI: 1.04-6; p=0.039) as compared to AA carriers. Smokers and males with the CCgenotype were 9.9 and 6.7 times more likely to have LC, respectively (ORsmokers=9.9; 95%CI: 1.2-84.5, p=0.018;ORmen=6.6; 95%CI: 1.7-26.2, p=0.005). Haplotype analysis of MTHFR polymorphism at the two loci showeddifferential distribution of the CC haplotype (677C-1298C) between cases and controls. The CC haplotypewas associated with an increased risk for lung cancer (OR=1.6; 95% CI: 1.03-2.4, p=0.037). Conclusions: Thegenetic polymorphism of MTHFR at 1298 and the CC haplotype (risk is apparently lower with the C allele atposition 677) may modulate the risk for LC development among the Jordanian population. Risk associated withthe 1298C allele is increased in smokers and in males. The results indicate that a critical gene involved in folatemetabolism plays a modifying role in lung cancer risk, at least in the Jordanian population.     

MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer.

5,10-methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism, diverting metabolites toward methylation reactions or nucleotide synthesis. Using data from an incident case-control study (1608 cases and 1972 controls) we investigated two polymorphisms in the MTHFR gene, C677T and A1298C, and their associations with risk of colon cancer. All of the combined genotypes were evaluated separately, and the 1298AA/677CC (wild-type/wild-type) group was considered the reference group. Among both men and women, the 677TT/1298AA (variant/wild-type) genotype was associated with a small reduction in risk [men: odds ratio (OR), 0.7, 95% confidence interval (CI), 0.5-1.0; women: OR, 0.8, 95% CI, 0.5-1.2]. However, the 677CC/1298CC (wild-type/variant) genotype was associated with a statistically significant lower risk among women (OR, 0.6; 95% CI, 0.4-0.9) but not men. When the polymorphisms were considered individually, for A1298C a significant risk reduction associated with the homozygous variant CC genotype was seen among women only (OR, 0.6; 95% CI, 0.5-0.9), and nonstatistically significant reduced risks were observed for the variant 677 TT genotypes among both men and women. Stratification by nutrient intakes showed inverse associations with higher intakes of folate, vitamin B(2), B(6), B(12), and methionine among women with the MTHFR 677CC/1298AA genotypes, but not those with 677TT/1298AA. We observed opposite risk trends for both MTHFR variants, depending on whether women used hormone-replacement therapy or not (P for interaction = <.01). In summary, this study supports recent findings that the MTHFR A1298C polymorphism may be a predictor of colon cancer risk and have functional relevance. The possible interaction with hormone-replacement therapy warrants additional investigation.     

亚甲基四氢叶酸还原酶基因单核苷酸多态性与儿童急性淋巴细胞白血病的相关性

 【摘要】　目的　探讨亚甲基四氢叶酸还原酶基因（MTHFR）单核甘酸多态性与儿童急性淋巴细胞白血病（ALL）发病风险的关系。方法　分别收集45例ALL患儿（ALL组）及45名健康儿童（对照组）外周血各2 ml,提取基因组DNA,应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）法,检测MTHFR C677T和A1298C基因型,比较不同基因型对儿童ALL发病风险的影响。采用Logistic回归模型计算比值比（OR）和95 %可信区间（95 % CI）。结果　对照组MTHFR 677CC、CT和TT基因型基因分布频率分别为31.1 %（14／45）、51.1 %（23／45）和17.7 %（8／45）,ALL组3种基因型分布频率分别为51.1 %（23／45）、40.0 %（18／45）和8.9 %（4／45）,两者比较差异有统计学意义（χ2＝7.48,P＝0.04）;MTHFR 677 T等位基因在ALL组中的检出率为48.8 %（22／45）,在对照组中的检出率为69.9 %（31／45）;T等位基因携带者发生ALL的风险是CC基因型的0.4倍（95 % CI 0.21～0.83）。对照组MTHFR 1298AA、AC和CC基因型基因分布频率分别为57.8 %、40.0 %和2.2 %,ALL组中3种基因型分布频率分别为18.8 %、44.4 %和6.8 %,两者比较差异无统计学意义（χ2＝11.23,P＝0.23）;MTHFR 1298 C等位基因ALL组中的检出率为42.2 %（19／45）,对照组中的检出率为51.1 %（23／45）;C等位基因的存在并不会提高儿童ALL发生的风险（OR＝1.3,95 % CI 0.21～0.83）。结论　MTHFR 677 T等位基因的存在会显著降低儿童发生ALL的风险,而MTHFR 1298各基因型与儿童ALL的发生均无明显相关性。     

亚甲基四氢叶酸还原酶基因单核苷酸多态与乳腺癌风险

目的 内研究亚甲基四氢叶酸还原酶(MTHFR)基因单核苷酸多态与女性乳腺癌风险的关系。方法 以聚合酶链反应(PCR)和限制性片段长度多态性(RFLF)分析方法,检测了217例乳腺癌患者和218例配对的正常对照者MTHFR因C677T和A1298C基因型,并比较不同基因型与乳腺癌风险的关系。结果 677TT基因型频率在乳腺癌患者和正常对照中的分布差异有显著性(32．7％比24．8％,P=0．02)。携带MTHFR 677TT基因犁者与携带MTHFR 677CC基因型者比较,前者罹患乳腺癌的风险增加1,84倍(95％ C：1．09～3．14)。MTHFR 677CT基因型以及MTHFR A1298C多态与乳腺癌风险不相关。结论 MTHFR基因677C→T突变是女性乳腺癌的遗传易感因素。     

The role of methylenetetrahydrofolate reductase in acute lymphoblastic leukemia in a Brazilian mixed population

The polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene are associated with leukemogenesis. In order to investigate the influence of two polymorphisms in the MTHFR gene, 677C>T and 1298A>C, on the risk of acute lymphoblastic leukemia (ALL) we performed a case-control study in children from different Brazilians' regions. Genotyping of 176 ALL and 199 unselected healthy subjects was performed using PCR-RFLP assay. There was no association between the 677C>T or 1298A>C and risk of ALL in total case-control sample. However, 677T allele was linked to a decrease risk of ALL [odds ratio (OR), 0.43; 95% confidence interval (CI), 0.22-0.86], whereas the 1298A>C polymorphism presents an elevated risk factor [OR, 2.01; 95% CI, 1.01-3.99] in non-White children. Our investigation provides interesting data concerning the opposite effect of A1298C polymorphisms, particularly in the light of relatively scarce data regarding the MTHFR role in leukemia susceptibility in different populations.     

Associations between 5,10-methylenetetrahydrofolate reductase codon 677 and 1298 genetic polymorphisms and environmental factors with reference to susceptibility to colorectal cancer: a case-control study in an Indian population

Although the incidence rate of colorectal cancer is very low, and rectal cancer remains more common in India, a significant increase in its incidence has been reported for both men and women over the last 2 decades. We evaluated MTHFR genetic susceptibility and common environmental risk factors in the development of colon and rectal cancer, and assessed the interactions between gene and environmental factors with colorectal cancer in a case-control study in the Indian population. The study included 59 colon cancer cases, 243 rectal cancer cases and 291 controls. The variant MTHFR 677T allele is rare, while the 1298C allele is common among Indians. MTHFR 677T showed no association with colon cancer (OR = 0.82; 95% CI 0.28-2.05) and a nonstatistically significantly elevated risk with rectal cancer (OR = 1.51; 95% CI 0.86-2.68), and MTHFR 1298 CC genotype was found to be associated with a significantly decreased risk for both colon cancer (OR = 0.30, 95% CI 0.09-0.81) and rectal cancer (OR = 0.43, 95% CI 0.23-0.80). High intake of nonfried vegetables or fruits was inversely associated with both colon and rectal cancer risk. Especially, the combination of a high intake of nonfried vegetables and MTHFR 1298CC genotype was associated with the lowest rectal cancer risk (OR = 0.22, 95% CI 0.09-0.52). Regarding alcohol consumption, indigenous Indian alcohol drinkers (OR = 2.26, 95% CI 0.86-6.36), and those consuming alcohol for duration more than 20 years (OR = 1.55, 95% CI 0.73-3.33), were at a somewhat higher rectal cancer risk. Moreover, the consumed alcohol amount (gram-years) may be also associated with colon or rectal cancer risk.