5,10-亚甲基四氢叶酸还原酶基因多态性与肺癌的相关性研究

叶酸代谢在肺癌发生过程中占有重要的地位,因为叶酸的代谢同时影响了DNA与核苷酸的合成。5,10-亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase,MTHFR）是一种非常重要的叶酸还原酶,它不可逆地将5,10-亚甲基四氢叶酸催化生成5-甲基四氢叶酸,而后者正是同型半胱氨酸甲基化生成蛋氨酸反应的甲基供体。MTHFR基因的多态性（C677T,A1298C）会造成酶的活性降低,从而影响疾病的发病率。已有研究表明MTHFR的基因多态性与肺癌的发病率显著相关,文章对MTHFR基因多态性与肺癌的关系作一综述。     

血清叶酸、维生素B12浓度及MTHFR、MS基因多态性与乳腺癌风险相关性研究

目的：分析血清中叶酸和维生素B12的含量以及甲硫氨酸合成酶（Methionine synthase,MS）及亚甲基四氢叶酸还原酶（Methylene tetrahydrofolate reduetase,MTHFR）各基因型在云南籍乳腺癌人群和正常人群中的分布差异,探索MTHFR,MS多态性与乳腺癌易感性之间的关系。方法：应用普通PCR-RFLP技术对95例云南籍乳腺癌患者和90例正常人群MS2756位点、MTHFR677位点和1298位点基因多态与乳腺癌风险关联分析筛查。同时应用全自动免疫分析仪测定血清中叶酸和维生素B12的含量。结果：乳腺癌患者血清维生素B12含量高于正常对照组,而血清叶酸低于正常对照组。云南籍乳腺癌人群和对照人群MS,MTHFR各基因型与分布频率比较无明显差异。结论：血清叶酸和维生素B12含量与乳腺癌发生风险有关,而MS,MTHFR基因多态性与乳腺癌发生风险无明显统计学意义。     

亚甲基四氢叶酸还原酶基因多态性检测在肿瘤患者中的临床价值

摘 要：亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase MTHFR)是叶酸代谢、DNA甲基化的关键酶。MTHFR的单核苷酸多态性(single nucleotide polymorphism,SNP),包括677 C→T和1298A→C突变,可使MTHFR酶活性下降,从而影响细胞内叶酸的正常代谢。全文分析MTHFR 基因多态性对叶酸代谢和DNA合成的影响及其在恶性肿瘤发生、诊治和预后的研究进展,阐述恶性肿瘤患者中检测MTHFR基因多态性的价值及存在争议。     

云南人亚甲基四氢叶酸还原酶基因型多态性与乳腺癌易感性的关联

 目的亚甲基四氢叶酸还原酶(MTHFR)是叶酸代谢的关键性酶,其催化作用决定了DNA甲基化与DNA合成之间的平衡。MTHFR基因多态性可能会影响叶酸代谢结局,从而构成肿瘤风险因子。研究分析了MTHFR各基因型在云南籍乳腺癌人群和正常人群中的分布差异,初步探索了MTH-FR多态性与乳腺癌易感性之间的关系。方法以多重PCR-RFLP技术,对125例云南籍乳腺癌患者和103例正常人群MTHFR677位点1298位点多态性进行筛查。结果未发现MTHFRC677T和A1298C基因型频率在乳腺癌和对照样本之间存在显著差异。结论在目前样本条件下,上述两个MTHFR位点基因型多态性与云南籍人群的乳腺癌易感性之间无明显相关性。     

叶酸及亚甲基四氢叶酸还原酶基因多态性与乳腺癌细胞多药耐药的相关性分析

目的:探讨人乳腺癌亲本细胞株(MCF-7)及耐多柔比星乳腺癌细胞株(MCF-7/ADR)中叶酸受体(FOLR)的表达及亚甲基四氢叶酸还原酶(MTHFR)基因多态性与乳腺癌细胞多药耐药的相关性。方法:流式细胞仪检测不同浓度叶酸对MCF-7细胞及MCF-7/ADR细胞周期的影响;RT-PCR检测MCF-7细胞及MCF-7/ADR细胞中FOLR和mdr-1 mRNA的表达水平;PCR-RFLP方法检测MCF-7细胞及MCF-7/ADR细胞中MTHFR基因C677T及A1298C基因多态性。结果:当叶酸≥270nmol/L时,MCF-7和MCF-7/ADR细胞处于G0/G1期细胞数增加。在MCF-7细胞中S期细胞数在叶酸≥270 nmol/L时显著减少(P<0.001);在MCF-7/ADR细胞中S期细胞数在叶酸≥30nmol/L时开始显著减少,且随着叶酸浓度升高,S期细胞数减少更显著(P<0.001)。在两株细胞中,FOLR和mdr-1基因mRNA表达水平呈负相关,MTHFR的C677T基因多态性及A1298C转录水平无差异;但经限制性核酸内切酶反应后,MCF-7细胞的MTHFR基因有A1298C及C677T两种基因多态性;而MCF-7/ADR细胞MTHFR基因只存在C677T基因多态性。结论:叶酸对MCF-7和MCF-7/ADR细胞的DNA合成均有抑制作用,该抑制作用在MCF-7/ADR细胞中更显著,可能通过阻断细胞从G0/G1期进入S期实现。在MCF-7/ADR细胞MTHFR A1298C基因多态性消失,可能与MCF-7细胞耐药相关。     

血清叶酸、维生素B12浓度及MTHFR、MS基因多态性与乳腺癌风险相关性研究

目的:分析血清中叶酸和维生素B12的含量以及甲硫氨酸合成酶(Methionine synthase,MS)及亚甲基四氢叶酸还原酶(Methylene tetrahydrofolate reduetase,MTHFR)各基因型在云南籍乳腺癌人群和正常人群中的分布差异,探索MTHFR,MS多态性与乳腺癌易感性之间的关系。方法:应用普通PCR-RFLP技术对95例云南籍乳腺癌患者和90例正常人群MS2756位点、MTHFR677位点和1298位点基因多态与乳腺癌风险关联分析筛查。同时应用全自动免疫分析仪测定血清中叶酸和维生素B12的含量。结果:乳腺癌患者血清维生素B12含量高于正常对照组,而血清叶酸低于正常对照组。云南籍乳腺癌人群和对照人群MS,MTHFR各基因型与分布频率比较无明显差异。结论:血清叶酸和维生素B12含量与乳腺癌发生风险有关,而MS,MTHFR基因多态性与乳腺癌发生风险无明显统计学意义。     

亚甲基四氢叶酸还原酶多态性与乳腺癌化疗敏感性的相关研究

目的:观察叶酸代谢的关键酶亚甲基四氢叶酸还原酶(MTHFR)基因C677T、A1298C多态性与乳腺癌FEC方案化疗敏感性的关系。方法:收集经病理学确诊的初治乳腺癌患者104例,所有病例化疗前抽静脉血,提取DNA,用PCR-RFLP技术检测MTHFR基因型,所有患者行FEC方案新辅助或姑息性化疗2~6周期,比较疗效和基因型之间的关系。结果:104例乳腺癌患者中,MTHFR C677T T/T基因型39例(37.5%)、C/C基因型55例(52.9%)、C/T基因型 10例(9.6%);T/T基因型化疗有效率79.5%(31/39)高于C/C基因型52.7%(29/55)和C/T基因型20.0%(2/10)（P＜0.05）。MTHFR A1298C A/A基因型41例(39.4%),A/C基因型56例(53.8%),C/C基因型7例(6.7%);各基因型化疗有效率之间无统计学关系（P＞0.05）。结论:本研究初步显示MTHFR C677T基因多态性对预测乳腺癌化疗效果具有较好的临床应用价值。     

MTHFR基因C667T位点多态性与亚洲人群乳腺癌易感性的Meta分析

目的:采用Meta分析的方法定量评价亚甲基四氢叶酸还原酶（MTHFR）基因C667T位点的多态性与亚洲人群乳腺癌易感性的关系。方法:计算机检索PubMed、Web of Science、中国生物医学文献数据库、CNKI、重庆维普和万方数据库,搜索有关MTHFR基因C667T位点的多态性与亚洲人群乳腺癌易感性的研究,检索时间截止2017年2月。采用Stata 12.0软件进行统计分析。结果:共纳入24篇病例对照研究,共计7 268例乳腺癌患者,9 223例健康对照。Meta分析结果显示:MTHFR基因C667T位点的多态性均与亚洲人群乳腺癌易感性有相关性［CC vs CT:OR=0.70,95%CI（0.60,0.83）,P=0.001;CT vs TT:OR=0.87,95%CI（0.79,0.96）,P=0.05;CC vs TT:OR=0.79,95%CI（0.72,0.88）,P=0.002;CT+TT vs CC:OR=0.81,95%CI（0.76,0.87）,P=0.001;CC+CT vs TT:OR=0.85,95%CI（0.77,0.93）,P=0.003］。结论:MTHFR基因C667T位点的多态性增加了亚洲人群乳腺癌的易感性。     

东北地区亚甲基四氢叶酸还原酶基因C677T单核苷酸多态性与乳腺癌易感性的相关性研究

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乳腺癌易感性的关系.方法:采用以人群为基础的病例对照研究方法,聚合酶链反应-限制性片段长度多态性法检测MTHFR基因型在东北地区乳腺癌患者和正常人群中的分布.结果:MTHFR基因677位点在乳腺癌组和对照组中等位基因频率及基因型分布有显著差异性(P<0.05).进一步分析表明,纯合突变G/G基因型、杂合突变C/G基因型与野生C/C基因型相比,患乳腺癌的危险度分别提高了2.23倍和2.00倍.结论:MTHFR基因C677T突变基因型与乳腺癌的易感性有关.     

叶酸代谢相关酶基因多态性与消化系统肿瘤的关系

叶酸的主要生物学功能是作为甲基供体参与脱氧核糖核酸合成和细胞内甲基化反应.亚甲基四氢叶酸还原酶(methylene tetrahydrofolate reductase,MTHFR)、甲硫氨酸合成酶(methionine synthase,MTR)、甲硫氨酸合成酶还原酶(methionine synthase reductase,MTRR)、胸苷酸合成酶(thymidylate synthase,TS)和亚甲基四氢叶酸脱氢酶(methylenetetrahydrofolate dehydrogenase,MTHFD)等是叶酸代谢通路中重要的酶.叶酸代谢相关酶基因变异、叶酸缺乏或代谢障碍与肿瘤的发生和发展有关.本文就叶酸代谢相关酶基因多态性与消化系统肿瘤间的关系进行简要综述.     

MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study.

Folate plays an important role in DNA methylation, synthesis, and repair; intake has been associated with breast cancer. The folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR) is polymorphic at nucleotides 677 (C-->T) and 1298 (A-->C), resulting in allozymes with decreased activity. We evaluated these two common polymorphisms and their effects on the folate intake and breast cancer risk association in a population-based case-control study of 1144 breast cancer cases and 1236 controls using a PCR-RFLP-based assay. All subjects completed in-person interviews, which included a food frequency questionnaire. Unconditional logistic regression models were used to calculate odds ratios and their 95% confidence intervals, after adjusting for potential confounding factors. Cases and controls were similar in the distribution of MTHFR polymorphisms at codons 677 (41.4% cases and 41.8% controls carried the T allele) and 1298 (17.6% cases and 17.5% controls carried the C allele). An inverse association of breast cancer risk with folate intake was observed in all genotype groups, particularly among subjects with the 677TT genotype. Compared with those with the 677CC genotype and high folate, the adjusted odds ratios (95% confidence intervals) associated with low folate intake were 1.94 (1.15-3.26), 2.17 (1.34-3.51), and 2.51 (1.37-4.60) for subjects who had CC, CT, and TT genotypes (p for interaction, 0.05). No modifying effect of A1298C genotypes on the association of folate intake with breast cancer risk was observed. Results of this study suggest that the MTHFR C677T polymorphisms may modify the association between dietary folate intake and breast cancer risk.     

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.     

The Common 677C>T Gene Polymorphism of Methylenetetrahydrofolate Reductase Gene is not Associated with Breast Cancer Risk

Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and plays a role in DNA biosynthesis, methylation, and repair in actively dividing cells. A common 677C>T polymorphism in the gene for MTHFR, leading to a thermolabile enzyme with decreased activity, has been associated with reduced plasma folate levels and elevated homocysteine levels and could be a risk factor for breast cancer. In the present case-control study, MTHFR genotype was determined in 500 women with clinically verified breast cancer and 500 female age-matched healthy control subjects. The homozygous TT genotype was found in 13.0% patients and 13.1% controls (P = n.s.). The odds ratio of TT homozygotes for breast cancer was 0.99 (95% confidence interval 0.68–1.43). The MTHFR genotype was furthermore not associated with tumor size, histological grading, estrogen or progesterone receptor status and age at diagnosis. In a subgroup of 116 premenopausal patients, no increased frequency of the homozygous 677T genotype was found (13.8%). Therefore, we conclude that the MTHFR 677C>T polymorphism is not associated with individual susceptibility to breast cancer.     

Polymorphisms of methylenetetrahydrofolate reductase and the risk of prostate cancer: a nested case-control study.

It has been proposed that folate and polymorphisms of the enzyme methylenetetrahydrofolate reductase (MTHFR), which regulates influx of folate from DNA synthesis and repair to methylation reactions, are involved in the aetiology of cancer. To relate the MTHFR 677C-->T and 1298A-->C polymorphisms to the risk of prostate cancer, taking into consideration prospective plasma levels of folate, vitamin B12 and homocysteine. The design was a case-control study of 223 prostate cancer cases and 435 matched controls nested within the population-based Northern Sweden Health and Disease Cohort. Neither the MTHFR 677C-->T nor the MTHFR 1298A-->C polymorphism was statistically significantly associated with the risk of prostate cancer in univariate analysis by conditional logistic regression. After adjustment for MTHFR 1298A-->C, plasma folate, vitamin B12, homocysteine, body mass index and smoking, the odds ratios were, for the 677 CT genotype, 1.52 [95% confidence interval (CI) 1.02-2.26], and for TT, 0.91 (95% CI 0.41-2.04). Our previously reported observation of a possible increase in the risk of prostate cancer at high plasma folate levels was attributable in this study to subjects having the MTHFR 677C-->T polymorphism. We found that the MTHFR 677C-->T polymorphism is not likely to have a major role in the development of prostate cancer, although it may possibly increase the risk in combination with high plasma folate levels. Further investigation in larger studies is warranted.     

One-carbon metabolism-related gene polymorphisms and risk of breast cancer

Environmental exposures and/or genetic background in Japanese population, which might contribute to the relatively low breast cancer incidence rates in Japan, have not been clarified in detail. Folate plays an essential role in DNA methylation and synthesis, and thus may be involved in the development of breast cancer. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase (TS), influence folate metabolism, but epidemiological studies have yielded inconsistent findings. We therefore conducted a case-control study to clarify their associations with breast cancer risk. A total of 456 breast cancer cases and 912 age-matched and menopausal status-matched non-cancer controls were genotyped for the polymorphisms. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic models adjusted for potential confounders and gene-environment interactions between the polymorphisms and folate consumption were also evaluated. We observed an increased risk of postmenopausal breast cancer with the MTHFR 677TT genotype (OR = 1.83, 95% CI: 1.08-3.11) with a menopausal status-based analysis. In combination analysis, a significantly elevated OR was found among postmenopausal women with the MTHFR 677TT genotype and lower intake of dietary folate compared with those with 677CC genotype and adequate folate consumption (OR = 2.80, 95% CI: 1.11-7.07). In addition, interaction between the MTRR A66G polymorphism and folate intake for risk of postmenopausal breast cancer was observed (interaction P = 0.008). Our findings indicated that the MTHFR and MTRR polymorphisms were associated with individual susceptibility to breast cancer among postmenopausal women.     

The methylenetetrahydrofolate reductase C677T mutation induces cell‐specific changes in genomic DNA methylation and uracil misincorporation: A possible molecular basis for the site‐specific cancer risk modification

The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with a decreased risk of colon cancer although it may increase the risk of breast cancer. This polymorphism is associated with changes in intracellular folate cofactors, which may affect DNA methylation and synthesis via altered one‐carbon transfer reactions. We investigated the effect of this mutation on DNA methylation and uracil misincorporation and its interaction with exogenous folate in further modulating these biomarkers of one‐carbon transfer reactions in an in vitro model of the MTHFR 677T mutation in HCT116 colon and MDA‐MB‐435 breast adenocarcinoma cells. In HCT116 cells, the MTHFR 677T mutation was associated with significantly increased genomic DNA methylation when folate supply was adequate or high; however, in the setting of folate insufficiency, this mutation was associated with significantly decreased genomic DNA methylation. In contrast, in MDA‐MB‐435 cells, the MTHFR 677T mutation was associated with significantly decreased genomic DNA methylation when folate supply was adequate or high and with no effect when folate supply was low. The MTHFR 677T mutation was associated with a nonsignificant trend toward decreased and increased uracil misincorporation in HCT116 and MDA‐MB‐435 cells, respectively. Our data demonstrate for the first time a functional consequence of changes in intracellular folate cofactors resulting from the MTHFR 677T mutation in cells derived from the target organs of interest, thus providing a plausible cellular mechanism that may partly explain the site‐specific modification of colon and breast cancer risks associated with the MTHFR C677T mutation. © 2008 Wiley‐Liss, Inc.     

Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study

The tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been reported to act as a cancer preventive agent through folate pathway inhibition in experimental studies. We hypothesized that if folate pathway inhibition is the mechanism of cancer preventive activities of EGCG, then the protective effect against breast cancer would be stronger among women with low dietary folate intake and the high-activity methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS) genotypes. In a nested case-control study of 380 women with incident breast cancer and 662 controls within the Singapore Chinese Health Study, we found no association between either green tea intake or gene polymorphisms of MTHFR (C677T and A1298C) and TYMS (1494 ins/del) and breast cancer risk. However, among women with low folate intake (<133.4 microg/day), weekly/daily green tea intake was inversely associated with breast cancer risk compared with less green tea intake [odds ratio (OR) = 0.45, 95% confidence interval (CI) = 0.26-0.79, P for interaction = 0.02]. Among women with high folate intake (>or=133.4 microg/day), green tea intake was not associated with breast cancer. Similarly, among women possessing the high-activity MTHFR/TYMS genotypes (0-1 variant allele), weekly/daily versus less frequent green tea intake was associated with lower breast cancer risk (OR = 0.66, 95% CI = 0.45-0.98), which was observed even more strongly among those who also had low folate intake (OR = 0.44, 95% CI = 0.22-0.89) than high folate intake (OR = 0.92, 95% CI = 0.55-1.54). This association was not observed among women possessing the low-activity genotypes (2-4 variant alleles). Our findings suggest that folate pathway inhibition may be one mechanism through which green tea protects against breast cancer in humans.     

Folate restriction and methylenetetrahydrofolate reductase 677T polymorphism decreases adoMet synthesis via folate-dependent remethylation in human-transformed lymphoblasts.

The homozygous mutation (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene reduces enzyme activity and alters cellular folate composition. Previous epidemiological studies reported a potential protective effect of MTHFR677C --> T against acute lymphocytic leukemia and malignant lymphoma, but the mechanism remains to be determined. We investigated the biochemical impacts of MTHFR677C --> T on cellular S-adenosyl methionine (adoMet) synthesis, global DNA methylation, and de novo purine synthesis, all of which are potential regulatory pathways involved in tumorigenesis. Metabolic fluxes of homocysteine remethylation and de novo purine synthesis were compared between Epstein-Barr virus-transformed lymphoblasts expressing MTHFR 677C and MTHFR 677T using stable isotopic tracers and GCMS. MTHFR TT genotype significantly reduced folate-dependent remethylation under folate restriction, reflecting limited methylated folates under folate restriction. Data also suggested increased formylated folate pool and increased purine synthesis when folate is adequate. The impacts of MTHFR 677T polymorphism appeared closely related to folate status, and such alterations may modulate metabolic pathways involved in cancer onset/progression. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in hematological malignancies. These transformed cells are potential models for studying the consequences of human genetic variation and cancer pathogenesis.     

MTHFR gene polymorphisms in bladder cancer in the Turkish population

Bladder cancer is the 9th most common cancer and is responsible for malignancy related death all on the world. Folate and folate related enzyme polymorphisms related to the cancer risk. The methylene tethrahydrofolate reductase (MTHFR) enzyme is folate related and association of bladder cancer and MTHFR gene. Our purpose was to assess the prevalence of MTHFR gene 677 CT and 1298 AC polymorphisms and Bladder cancer in Turkey. We intended that bladder cancer patients and controls and we used the Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) methods. The MTHFR gene C677T and A1298C polymorphisms were associated with an increased risk of bladder cancer in our population (For the MTHFR gene C677T polymorphism and A1298C polymorphism; p=0.036<0.05; p=0.278>0.05 respectively). Consequently, the MTHFR gene C677T polymorphism augments the risk of bladder cancer in Turkey.     

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.