Dietary Intake of Folate,Vitamin B2, Vitamin B6, Vitamin B12, Genetic Polymorphism of Related Enzymes,and Risk of Breast Cancer: A Case-Control Study in Japan

We investigated associations among intake of folate, vitamin B2, vitamin B6, vitamin B12, and polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) genes and breast cancer risk in a Japanese population. A hospital based, case-control study was conducted in Nagano Prefecture, Japan, in 388 pairs of patients with histologically confirmed invasive breast cancer and age- and area-matched controls selected from medical checkup examinees. Energy-adjusted intakes of folate and other B vitamins were derived from a validated food frequency questionnaire. Genotyping was completed for MTHFR (C677T and A1298T) and MTR (A2756G). Odds ratios and 95% confidence intervals were calculated by the conditional logistical regression model. Median dietary folate intake (μg/day) in the control group was 438.2 (interquartile range: 354.9–542.9). Neither dietary intake of folate, vitamin B2, vitamin B6, or vitamin B12 nor polymorphisms of MTHFR or MTR genes were significantly associated with breast cancer risk. Further, no significant interaction was found among nutrients, polymorphisms, and breast cancer risk. Associations of nutrients with breast cancer risk did not differ by hormone receptors status. We conclude that dietary intake of folate and related B vitamins and genotypes of MTHFR or MTR have no overall association with breast cancer risk in Japanese women.     

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.     

Nutrients and genetic variation involved in one-carbon metabolism and Hodgkin lymphoma risk: a population-based case-control study

Nutritional and genetic determinants of the one-carbon metabolism pathway have been related to risk of malignant lymphomas, but little is known about their associations with Hodgkin lymphoma risk specifically. The authors examined nutrient intake (folate, vitamin B(2), vitamin B(6), vitamin B(12), methionine) and multivitamin use among 497 Hodgkin lymphoma patients and 638 population-based controls (Massachusetts and Connecticut, 1997-2000), and genetic variation (MTHFR 677C>T, MTHFR 1298A>C, MTR 2756A>G, SHMT1 1420C>T, TYMS 1494del6) and gene-diet interactions in a subset. Unconditional logistic regression was used to calculate multivariable odds ratios and 95% confidence intervals. Hodgkin lymphoma risk was not associated with total nutrient intake or intake from food alone (excluding supplements). Multivitamin use (odds ratio (OR) = 1.46, 95% CI: 1.09, 1.96), total vitamin B(6) (OR(quartile 4 vs. 1) = 1.62) (P(trend) = 0.03), and total vitamin B(12) (OR(quartile 4 vs. 1) = 1.75) (P(trend) = 0.02) intakes were positively associated with risk of Epstein-Barr virus-negative, but not -positive, disease. The 5 genetic variants were not significantly associated with Hodgkin lymphoma risk; no significant gene-diet interactions were observed after Bonferroni correction. Study findings do not support a strong role for nutrients and genetic variation in the one-carbon metabolism pathway in susceptibility to Hodgkin lymphoma. Associations between diet and risk of Epstein-Barr virus-negative disease require confirmation in other populations.     

Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank

BACKGROUND: Abnormalities of folate and homocysteine metabolism are associated with a number of pediatric and adult disorders. Folate intake and genetic polymorphisms encoding folate-metabolizing enzymes influence blood folate and homocysteine concentrations, but the effects and interactions of these factors have not been studied on a population-wide basis. OBJECTIVE: The objective was to assess the prevalence of these genetic polymorphisms and their relation to serum folate and homocysteine concentrations. DESIGN: DNA samples from 6793 participants in the third National Health and Nutrition Examination Survey (NHANES III) during 1991-1994 were genotyped for polymorphisms of genes coding for folate pathway enzymes 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C-->T and 1298A-->C, methionine synthase reductase (MTRR) 66A-->G, and cystathionine-beta-synthase 844ins68. The influence of these genetic variants on serum folate and homocysteine concentrations was analyzed by age, sex, and folate intake in 3 race-ethnicity groups. RESULTS: For all race-ethnicity groups, serum folate and homocysteine concentrations were significantly related to the MTHFR 677C-->T genotype but not to the other polymorphisms. Persons with the MTHFR 677 TT genotype had a 22.1% (95% CI: 14.6%, 28.9%) lower serum folate and a 25.7% (95% CI: 18.6%, 33.2%) higher homocysteine concentration than did persons with the CC genotype. Moderate daily folic acid intake (mean: 150 microg/d; 95% CI: 138, 162) significantly reduced the difference in mean homocysteine concentrations between those with the MTHFR 677 CC and TT genotypes. We found a significant interaction between MTHFR 677C-->T and MTRR 66A-->G on serum homocysteine concentrations among non-Hispanic whites. CONCLUSIONS: The MTHFR 677C-->T polymorphism was associated with significant differences in serum folate and homocysteine concentrations in the US population before folic acid fortification. The effect of MTHFR 677C-->T on homocysteine concentrations was reduced by moderate daily folic acid intake.     

亚甲基四氢叶酸还原酶基因多态和叶酸摄取与乳腺癌的发病风险

目的 研究亚甲基四氖叶酸还原酶(5,10-methylenetetrahydrofolate reductase,MTHFR)基因C677T、A1298C多态、饮食叶酸摄取与女性乳腺癌发病风险的关系.方法 采用病例-对照研究,收集江苏省乳腺癌患者669例,选取682名健康人作为埘照,用包括83个饮食项目的 定量问卷表调查研究对象的饮食状况.采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测624例患者和624名对照者的MTHFR C677T和A1298C基因型,用非条件logistic回归进行分析,计算比值比(OR).结果 病例组的MTHFR C677T C/C,C/T和T/T基因型分别为32.37%(202/624)、48.88%(305/624)和18.75%(117/624),对照组分别为37.66%(235/624)、48.24%(301/624)和14.10%(88/624),两组的基因型分布差异有统计学意义(X2=6.616,P=0.037).T/T基因型者的乳腺癌发病风险显著升高[调整OR值为1.62(95%CI值:1.14～2.30)].病例组的MTHFRA1298C A/A、A/C和C/C基因型分别为71.47%(446/624)、27.08%(169/624)和1.44%(9/624),对照组分别为68.11%(425/624)、30.13%(188/624)和1.76%(11/624),两组间的基因型分布差异无统计学意义(X2=1.716,P=0.424).病例组的饮食叶酸摄取量[(263.00±137.38)μg/d]显著低于对照组[(285.12±149.61)μd](t=-2.830,P=0.005).与最低三分位组(≤199.08μg/d)相比,叶酸最高摄取量组(≥315.11μg/d)的OR值为0.70(95%CI值:0.53～0.92).在MTHFR A1298CA/A基因型者中,叶酸中间摄取量组(199.09～315.10μg/d)与最高摄取量组的OR值分别为0.89(95%C/值:0.62～1.27)、1.69(95%C/值:1.20～2.36),其线性趋势检验X2=11.372,P=0.001.结论 本研究结果 显示MTHFR遗传多态、饮食叶酸摄取与乳腺癌的发病风险相关.     

Meta- and pooled analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer risk: a huge-GSEC review

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate, whose role in gastric carcinogenesis is controversial. The authors performed a meta-analysis and individual data pooled analysis of case-control studies that examined the association between C677T and A1298C polymorphisms (the former being associated with low folate serum levels) and gastric cancer (meta-analyses: 16 studies, 2,727 cases and 4,640 controls for C677T and seven studies, 1,223 cases and 2,015 controls for A1298C; pooled analyses: nine studies, 1,540 cases and 2,577 controls for C677T and five studies, 1,146 cases and 1,549 controls for A1298C). An increased risk was found for MTHFR 677 TT in the meta-analysis (odds ratio (OR) = 1.52, 95% confidence interval (CI): 1.31, 1.77) and pooled analysis (OR = 1.49, 95% CI: 1.14, 1.95). No association resulted for MTHFR 1298 CC (meta-OR = 0.94, 95% CI: 0.65, 1.35; pooled OR = 0.90, 95% CI: 0.69, 1.34). Results from the pooled analysis of four studies on C677T stratified according to folate levels showed an increased risk for individuals with low (OR = 2.05, 95% CI: 1.13, 3.72) versus high (OR = 0.95, 95% CI: 0.54, 1.67) folate levels. Overall, these findings support the hypothesis that folate plays a role in gastric carcinogenesis.     

Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study in Mexican, West African, and European populations

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism is heterogeneously distributed worldwide, with the highest and lowest frequencies of the T allele in Mexico and Africa, respectively, and a south-to-north gradient in Europe. Distribution of MTHFR 1298A-->C is less well known. It has been hypothesized that 677T frequency could result in part from gene-nutrient interactions. OBJECTIVE: The objective was to compare the association of 677T and 1298C alleles with plasma concentrations of homocysteine, folate, and vitamin B-12 in geographical areas with contrasting 677T allele frequencies. DESIGN: Healthy young adults (n = 1277) were recruited in Mexico City, the West African countries of Bénin and Togo, France, and Sicily (Italy). Homocysteine, folate, and vitamin B-12 were measured in plasma, and MTHFR polymorphisms were measured in genomic DNA. RESULTS: Mexico City and Sicily reported the highest and Bénin and Togo reported the lowest plasma concentrations of folate. Mexico City had the highest 677T allele prevalence and the lowest influence of 677TT genotype on homocysteine, whereas the opposite was observed in Africa. The prevalence of the 1298C allele was lowest in the Mexicans and Africans and highest in the French. The percentage of the 677T genotype was significantly associated with the folate concentrations in 677CC carriers in a univariate analysis (R = 0.976; 95% CI: 0.797, 0.996; P < 0.0002) and in a multiple regression model that included homocysteine, vitamin B-12, and age (P = 0.0002). CONCLUSION: Our data agree with the hypothesis of a gene-nutrient interaction between MTHFR 677C-->T polymorphism and folate status that may confer a selective advantage of TT-homozygous genotype when dietary intake of folate is adequate, at least in the areas studied.     

Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review

Epidemiologic and mechanistic evidence suggests that folate is involved in colorectal neoplasia. Some polymorphic genes involved in folate metabolism--methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G), cystathionine beta-synthase (CBS exon 8, 68-base-pair insertion), and thymidylate synthase (TS enhancer region and 3' untranslated region)--have been investigated in colorectal neoplasia. For MTHFR C677T and A1298C, the variant allele is associated with reduced enzyme activity in vitro. For the other polymorphisms, functional data are limited and/or inconsistent. Genotype frequencies for all of the polymorphisms show marked ethnic and geographic variation. In most studies, MTHFR 677TT (10 studies, >4,000 cases) and 1298CC (four studies, >1,500 cases) are associated with moderately reduced colorectal cancer risk. In four of five genotype-diet interaction studies, 677TT subjects who had higher folate levels (or a "high-methyl diet") had the lowest cancer risk. In two studies, 677TT homozygote subjects with the highest alcohol intake had the highest cancer risk. Findings from six studies of MTHFR C677T and adenomatous polyps are inconsistent. There have been only one or two studies of the other polymorphisms; replication is needed. Overall, the roles of folate-pathway genes, folate, and related dietary factors in colorectal neoplasia are complex. Research priorities are suggested.     

Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas

BACKGROUND: Folate intake may be related to decreased risk of colorectal cancer and adenomas. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate metabolism. We examined the relation between plasma folate status and colorectal adenomas with reference to effect modification by the genetic polymorphism (C677T) of MTHFR. METHODS: Study subjects were middle-aged Japanese men: 177 cases of colorectal adenomas and 192 controls with normal total colonoscopy. Statistical adjustment was made for hospital, rank in the Self Defense Forces, alcohol use, smoking, and body mass index. RESULTS: Plasma folate levels were slightly lower in adenoma cases than in controls. Adjusted odds ratio (OR) for high (>5.50 ng/ml) versus low plasma folate levels was 0.72 (95% CI: 0.46-1.14). As compared with subjects with the CC or CT genotype having low plasma folate levels, those with the TT genotype showed a decreased risk of colorectal adenomas when they had high levels of plasma folate (adjusted OR = 0.58, 95% CI: 0.21-1.61), and an increased risk when they had low folate levels (adjusted OR = 2.13, 95% CI: 0.82-5.54). There was no clear relation between plasma folate and colorectal adenomas among those with the CC or CT genotype. CONCLUSIONS: The findings suggest an interaction between folate and the MTHFR genotype on colorectal adenomas.     

Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review

The authors performed a meta-analysis of studies examining the association between polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, including MTHFR C677T and A1298C, and common psychiatric disorders, including unipolar depression, anxiety disorders, bipolar disorder, and schizophrenia. The primary comparison was between homozygote variants and the wild type for MTHFR C677T and A1298C. For unipolar depression and the MTHFR C677T polymorphism, the fixed-effects odds ratio for homozygote variants (TT) versus the wild type (CC) was 1.36 (95% confidence interval (CI): 1.11, 1.67), with no residual between-study heterogeneity (I(2) = 0%)--based on 1,280 cases and 10,429 controls. For schizophrenia and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.44 (95% CI: 1.21, 1.70), with low heterogeneity (I(2) = 42%)--based on 2,762 cases and 3,363 controls. For bipolar disorder and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.82 (95% CI: 1.22, 2.70), with low heterogeneity (I(2) = 42%)-based on 550 cases and 1,098 controls. These results were robust to various sensitively analyses. This meta-analysis demonstrates an association between the MTHFR C677T variant and depression, schizophrenia, and bipolar disorder, raising the possibility of the use of folate in treatment and prevention.     

Vitamin B-12 status is inversely associated with plasma homocysteine in young women with C677T and/or A1298C methylenetetrahydrofolate reductase polymorphisms

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms may negatively influence one-carbon metabolism and increase health risks in women of reproductive age. The effect of MTHFR single nucleotide polymorphisms at bp 677 and/or 1298 and differences in folate and vitamin B-12 status on plasma homocysteine concentration in women of reproductive age (20-30 y; n = 186) were investigated. From the multivariate regression model, homozygotes (n = 23) for the C677T MTHFR variant had plasma homocysteine concentrations that were higher (P < 0.05) than those observed in the other 5 genotype groups, including those who were heterozygous for both variants (677CT/1298AC; n = 32). Plasma homocysteine was negatively associated with plasma vitamin B-12 concentration (P = 0.015) and serum folate (P = 0.049), with the degree of correlation between plasma vitamin B-12 and homocysteine concentrations dependent on MTHFR genotype. The C677T and A1298C MTHFR polymorphisms were significant predictors (P < 0.05) of plasma homocysteine when regression analysis was used to model plasma homocysteine concentration as a function of genotype, supplement use, serum folate and plasma vitamin B-12 concentration. Plasma homocysteine decreased as vitamin B-12 concentration increased (P = 0.0005) in individuals who were heterozygous for both the C677T and A1298C variants with nonsignificant trends (P = 0.114-0.128) in individuals homozygous for either the C677T or A1298C variants. In contrast, within the group of individuals with the wild-type genotype for both the C677T and A1298C MTHFR variants, homocysteine was not associated with changes in plasma vitamin B-12 concentrations. These data suggest that enhancing vitamin B-12 status may significantly decrease homocysteine in young women with C677T and/or A1298C MTHFR polymorphisms, even when vitamin B-12 concentrations are within the normal range.     

Dietary and genetic determinants of homocysteine levels among Mexican women of reproductive age

OBJECTIVE: To evaluate the independent and joint effects of dietary folate, vitamin B(12) consumption and methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677C>T and 1298A>C) on the circulating folate and homocysteine (Hcy) levels among Mexican women of reproductive age. DESIGN: A cross-sectional, population-based study. SUBJECTS: The first 130 healthy non-pregnant women (aged 16-34 years) who agreed to participate in a reproductive cohort in Morelos, Mexico. MAIN OUTCOME MEASUREMENTS: Dietary intakes of vitamin B(12) and folate were estimated using a semiquantitative food frequency questionnaire. MTHFR 677C>T and 1298A>C polymorphisms were ascertained using the PCR-based method. Serum levels of Hcy and folate were determined using high-performance liquid chromatography and radioimmunoassay, respectively. RESULTS: Genotype frequencies for the MTHFR 677C>T polymorphism were 21.5% (CC), 52.3% (CT) and 26.2% (TT) among Mexican women. Of the population, 22% had the MTHFR 1298AC genotype, while no individual carried the 1298CC genotype. We observed an increased level of Hcy among carriers of the 677TT genotype, compared to carriers of the 677CC genotype. The highest level of Hcy was observed among MTHFR 677TT carriers with low B(12) intake (<2.0 microg/day), which resulted with a significant interaction (P=0.01). CONCLUSION: Vitamin B(12) is an important determinant of Hcy levels in Mexico. Supplementation of folic acid with vitamin B(12) may be preferable when the MTHFR 677T variant allele is prevalent.     

叶酸、蛋氨酸摄入量,MTHFR多态性与结直肠癌关系的病例对照研究

目的:研究亚甲基四氢叶酸还原酶(MTHFR)基因多态,叶酸、蛋氨酸摄入量与结直肠癌易感性的关系。方法:应用PCR-RFLP法,检测126例结直肠癌患者和343例正常对照者的MTHFRC 677T和A1298C两个位点基因多态,比较不同基因型与结直肠癌风险的关系,以及两个多态位点与叶酸、蛋氨酸的联合作用。结果: MTHFR C677T和A1298C突变基因在对照组中的频率分别为39.7%和17.1%。MTHFR A1298C突变基因携带者与野生型相比,患结直肠癌的风险显著降低(OR=0.51,95% CI:0.27～0.95);在叶酸个别摄入量组,MTHFR C677T多态使结直肠癌的风险显著降低(OR=0.23,95% CI:0.06～0.93)。结论: MTHFR A1298C位点多态性是直肠癌的保护因素 ,在叶酸摄入充足的条件下,MTHFR C677T多态是结肠癌的保护因素。     

胃癌亚甲基四氢叶酸还原酶基因多态性及其与微卫星不稳的关系

目的探讨胃癌亚甲基四氢叶酸还原酶（MTHFR）基因多态性与微卫星不稳的关系。方法采用聚合酶链反应一限制性片段长度多态性技术检测122例胃癌和101名正常对照的MTHFR基因C677T和A1298C多态性；采用PCR为基础的方法检测微卫星不稳定性（MSI）。结果MTHFR C677T多态性可分为677CC、677CT和677TT三种类型。胃癌组3种基因型频率分别为47．5％、39．3％和13．1％；对照组分别为48．5％、42．6％和8．9％，两组相比差异无统计学意义（P〉0．05）。以677CC基因型做为参考，胃贲门癌677CT基因型OR值为0．38，95％CI：0．15～0．98；TT基因型OR值为0．26，95％CI：0．03～2．18；677CT＋TT基因型OR值为0．36，95％CI：0．07～0．98。胃体癌677TT基因型OR值为3．03，95％CI：1．07～8．65。MTHFR A1298C多态性可分为1298AA、1298AC和1298CC3种类型。胃癌组3种基因型频率分别为59．8％、36．1％和4．1％；对照组分别为57．4％，37．6％和5．0％，两组相比差异无统计学意义（P〉0．05）。以1298AA基因型的OR值为1．00，胃窦癌AC基因型的OR值为0．87，95％CI：0．42～1．82，CC基因型的OR值为0．41，95％CI：0．05～3．72。MTHFR 677TT基因型胃癌与微卫星不稳显著相关（P〈0．05），而MTHFR A1298C多态性与微卫星不稳无关（P〉0．05）。结论重庆地区人群中MTHFR C677T多态性是胃贲门癌的保护因素，是胃体癌的危险因素；MTHFR A1298C多态性可能是胃窦癌的保护因素；677TT基因型胃癌的发生可能涉及到MSI途径。     

Folate, vitamin B6, vitamin B12, and vitamin B2 intake, genetic polymorphisms of related enzymes, and risk of colorectal cancer in a hospital-based case-control study in Japan

We conducted a case-control study to investigate the association of nutrient intake involved in the one-carbon pathway of folate for DNA methylation and DNA synthesis and the related enzyme genetic polymorphisms with colorectal cancer. Cases were 107 patients newly diagnosed with colorectal cancer. Controls were 224 subjects matched with cases by sex, age, and residential area. Nutrient intake was assessed by a self-administered, semiquantitative food-frequency questionnaire. Four genetic polymorphisms-MTHFR C677T and A1298C, MTRR A66G, and ALDH2 Glu487Lys-were determined using blood samples. Odds ratios were calculated using conditional logistic regression analysis adjusted for smoking, alcohol consumption, body mass index, and dietary fiber intake. Although folate intake was inversely associated with colorectal cancer, this association was attenuated after further controlling for dietary fiber intake. Neither vitamin B6, vitamin B12, nor vitamin B2, nor any genetic polymorphism was significantly associated with colorectal cancer. MTRR polymorphism interacted with the association of folate (P for interaction = 0.04) or vitamin (P for interaction = 0.02) with colorectal cancer, although the other polymorphisms did not interact with any nutrient intake. In conclusion, the study did not support the existing hypothesis of gene-nutrient interaction in colorectal carcinogenesis.     

亚甲基四氢叶酸还原酶基因单核苷酸多态性与大肠癌风险的关系

目的研究亚甲基四氢叶酸还原酶（MTHFR）基因单核苷酸多态性与我国人大肠癌患病风险的关系.方法以聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）分析方法,检测198 例大肠癌患者和420名健康人MTHFR 基因C677T和A1298C基因型.结果 C677T突变等位基因频率在大肠癌患者和健康人中的分布为51.3% 和44.4%,差异有统计学意义.与携带MTHFR 677CC基因型者比较,携带677TT基因型者罹患大肠癌的相对危险性增加（95% CI为1.05～2.66）,而677CT基因型和MTHFR A1298C遗传变异与大肠癌患病风险无关.未发现MTHFR基因多态性与大肠癌转移程度相关.结论亚甲基四氢叶酸还原酶基因C677T基因多态性可能是我国大肠癌的遗传易感因素.     

5,10-methylenetetrahydrofolate reductase common mutations, folate status and plasma homocysteine in healthy French adults of the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) cohort

The 677cytosine mutation identified in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been frequently associated with an elevated plasma homocysteine concentration. The aim of the present study was to determine the impact of this MTHFR common mutation on plasma and erythrocyte folate (RCF) and plasma total homocysteine (tHcy) concentrations in healthy French adults. A cohort of 291 subjects living in the Paris area and participating in the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study were analysed to assess the impact of MTHFR polymorphism 677C-->T on folate status and plasma tHcy concentration. The frequency of the mutant homozygote for 677C-->T polymorphism (677TT genotype) in the present cohort was 16.8%. There were significant differences in plasma tHcy between 677CC, 677CT and 677TT genotype groups. The RCF concentrations were significantly different between each genotype, the lowest levels being associated with the 677TT genotype. When segregated by gender, no differences in tHcy between homozygous 677TT, heterozygous 677CT and wild-type 677CC genotype groups in women were observed. The fasting tHcy in women was unrelated to the 677C-->T mutation. However, tHcy was significantly increased in men with the homozygous 677TT genotype. We also analysed the possible implication of a second new MTHFR polymorphism (1298A-->C) in subjects with mild hyperhomocysteinaemia (4th quartile of homocysteinaemia; tHcy >11.1 micromol/l). The polymorphism 1298A-->C did not have a notable effect on tHcy or on the RCF levels. Our observations confirm a relatively high frequency of the 677TT genotype in the French population. Women with this genotype did not show the same increase in tHcy observed in men. In the present study dietary folate intake was not measured. Thus, the interaction of dietary folate with the MTHFR genotype in the French population needs further study.     

5,10-Methylenetetrahydrofolate reductase polymorphisms and pharmacogenetics: a new role of single nucleotide polymorphisms in the folate metabolic pathway in human health and disease

Knowledge about the role of folate, a water-soluble B vitamin, and single nucleotide polymorphisms (SNPs) in the folate metabolic pathway in human health and disease has been rapidly expanding. Recently, functionally significant SNPs in 5,10-methylenetetrahydrofolate reductase (MTHFR), a critical enzyme for intracellular folate homeostasis and metabolism, have been identified and characterized. An emerging body of in vitro and clinical evidence suggests that these MTHFR SNPs may be an important pharmacogenetic determinant of predicting response to and toxicity of methotrexate and 5-fluorouracil-based cancer and anti-inflammatory treatments because of their well-defined and highly relevant biochemical effects on intracellular folate composition and one-carbon transfer reactions.     

亚甲基四氢叶酸还原酶基因多态性、饮酒与结直肠癌关系的病例对照研究

目的 研究亚甲基四氢叶酸还原酶(MTHFR)基因多态与结直肠癌(包括结肠癌、直肠癌)易感性的关系。方法 应用聚合酶链反应(PCR)和限制性片段长度多态性方法(RFLP),检测了126例结直肠癌患者和343名正常对照的MTHFR C677T和A1298C两个位点基因多态,并比较不同基因型单独、联合时与结直肠癌风险的关系,以及两个多态位点与饮酒的联合作用。结果MTHFR677T和1298C突变基因在对照组中的频率分别为39.7％和17.1％。1298C突变基因携带者与野生型相比,患结直肠癌的风险均降低;在携带677C和1298C等位基因组合个体中,结直肠癌的风险略有降低(OR=0.718,95％CI:0.367～1.407),同时含677T和1298A等位基因者,结直肠癌的风险降低1倍;同时含有677T和1298C等位基因者,结直肠癌的风险降低4倍,直肠癌的风险降低7倍(OR=0.304,95％CI:0.108～0.852)。在过去饮酒者中,1298A等位基因携带者结直肠癌风险性增加2倍(OR=3.307,95％CI:0.521～17.698)。结论 MTHFR C667T和A1298C位点多态性在结直肠癌发生过程中起着一定作用,携带MTHFR 1298AC基因多态型者过去饮酒是结直肠癌的危险因素。     

5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review

The enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism. The MTHFR gene is located on chromosome 1 (1p36.3), and two common alleles, the C677T (thermolabile) allele and the A1298C allele, have been described. The population frequency of C677T homozygosity ranges from 1% or less among Blacks from Africa and the United States to 20% or more among Italians and US Hispanics. C677T homozygosity in infants is associated with a moderately increased risk for spina bifida (pooled odds ratio = 1.8; 95% confidence interval: 1.4, 2.2). Maternal C677T homozygosity also appears to be a moderate risk factor (pooled odds ratio = 2.0; 95% confidence interval: 1.5, 2.8). The A 1298C allele combined with the C677T allele also could be associated with an increased risk for spina bifida. Some data suggest that the risk for spina bifida associated with C677T homozygosity may depend on nutritional status (e.g., blood folate levels, intake of vitamins) or on the genotype of other folate-related genes (e.g., cystathionine-beta-synthase and methionine synthase reductase). Studies of the C677T allele in relation to oral clefts, Down syndrome, and fetal anticonvulsant syndrome either have yielded conflicting results or have not been yet replicated.