Gene Summary

Gene:MTRR; 5-methyltetrahydrofolate-homocysteine methyltransferase reductase
Aliases: MSR, cblE
Summary:This gene encodes a member of the ferredoxin-NADP(+) reductase (FNR) family of electron transferases. This protein functions in the synthesis of methionine by regenerating methionine synthase to a functional state. Because methionine synthesis requires methyl-group transfer by a folate donor, activity of the encoded enzyme is important for folate metabolism and cellular methylation. Mutations in this gene can cause homocystinuria-megaloblastic anemia, cbl E type. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:methionine synthase reductase
Source:NCBIAccessed: 16 March, 2017


What does this gene/protein do?
Show (15)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Adolescents
  • Genotype
  • Sex Distribution
  • Chromosome 5
  • Stomach Cancer
  • Carbon
  • Haplotypes
  • SEER Program
  • DNA Methylation
  • Vitamin B 12 Deficiency
  • Single Nucleotide Polymorphism
  • Thymidylate Synthase
  • Romania
  • Colorectal Cancer
  • Spain
  • Cervical Cancer
  • Alleles
  • Transfection
  • Folic Acid
  • Childhood Cancer
  • Breast Cancer
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Survival Rate
  • Texas
  • Vascular Diseases
  • Case-Control Studies
  • Alcohol Drinking
  • Vegetables
  • Polymerase Chain Reaction
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Pregnancy Complications
  • Risk Factors
  • Odds Ratio
  • Polymorphism
  • Ferredoxin-NADP Reductase
  • Surveys and Questionnaires
  • Genetic Predisposition
  • Syria
  • Risk Assessment
  • Bladder Cancer
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MTRR (cancer-related)

Nakao H, Wakai K, Ishii N, et al.
Associations between polymorphisms in folate-metabolizing genes and pancreatic cancer risk in Japanese subjects.
BMC Gastroenterol. 2016; 16(1):83 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects.
METHODS: Our case-control study involved 360 newly diagnosed pancreatic cancer cases and 400 frequency-matched, non-cancer control subjects. We genotyped four folate metabolizing gene polymorphisms, including two polymorphisms (rs1801133 and rs1801131) in the methylenetetrahydrofolate (MTHFR) gene, one polymorphism (rs1801394) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene and one polymorphism (rs1805087) in the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between folate metabolizing gene variants and pancreatic cancer risk.
RESULTS: Overall we did not observe a significant association between these four genotypes and pancreatic cancer risk. For rs1801133, compared with individuals with the CC genotype of MTHFR C677T, the OR for those with the CT genotype and TT genotype was 0.87 (0.62-1.22) and 0.99 (0.65-1.51), respectively. For rs1801131, individuals with the CC genotype had approximately 1.2-fold increased risk compared with those with the AA genotype, but the association was not statistically significant. In analyses stratified by smoking and drinking status, no significant associations were noted for C677T genotypes. No significant interactions were observed with smoking and drinking with respect to pancreatic cancer risk.
CONCLUSIONS: Our data did not support the hypothesis that MTHFR polymorphisms or other polymorphisms in the folate metabolizing pathway are associated with pancreatic cancer risk.

Wu X, Xu W, Zhou T, et al.
The Role of Genetic Polymorphisms as Related to One-Carbon Metabolism, Vitamin B6, and Gene-Nutrient Interactions in Maintaining Genomic Stability and Cell Viability in Chinese Breast Cancer Patients.
Int J Mol Sci. 2016; 17(7) [PubMed] Free Access to Full Article Related Publications
Folate-mediated one-carbon metabolism (FMOCM) is linked to DNA synthesis, methylation, and cell proliferation. Vitamin B6 (B6) is a cofactor, and genetic polymorphisms of related key enzymes, such as serine hydroxymethyltransferase (SHMT), methionine synthase reductase (MTRR), and methionine synthase (MS), in FMOCM may govern the bioavailability of metabolites and play important roles in the maintenance of genomic stability and cell viability (GSACV). To evaluate the influences of B6, genetic polymorphisms of these enzymes, and gene-nutrient interactions on GSACV, we utilized the cytokinesis-block micronucleus assay (CBMN) and PCR-restriction fragment length polymorphism (PCR-RFLP) techniques in the lymphocytes from female breast cancer cases and controls. GSACV showed a significantly positive correlation with B6 concentration, and 48 nmol/L of B6 was the most suitable concentration for maintaining GSACV in vitro. The GSACV indexes showed significantly different sensitivity to B6 deficiency between cases and controls; the B6 effect on the GSACV variance contribution of each index was significantly higher than that of genetic polymorphisms and the sample state (tumor state). SHMT C1420T mutations may reduce breast cancer susceptibility, whereas MTRR A66G and MS A2756G mutations may increase breast cancer susceptibility. The role of SHMT, MS, and MTRR genotype polymorphisms in GSACV is reduced compared with that of B6. The results appear to suggest that the long-term lack of B6 under these conditions may increase genetic damage and cell injury and that individuals with various genotypes have different sensitivities to B6 deficiency. FMOCM metabolic enzyme gene polymorphism may be related to breast cancer susceptibility to a certain extent due to the effect of other factors such as stress, hormones, cancer therapies, psychological conditions, and diet. Adequate B6 intake may be good for maintaining genome health and preventing breast cancer.

Kim W, Woo HD, Lee J, et al.
Dietary folate, one-carbon metabolism-related genes, and gastric cancer risk in Korea.
Mol Nutr Food Res. 2016; 60(2):337-45 [PubMed] Related Publications
SCOPE: We evaluated the interactions between polymorphisms involved in one-carbon metabolism-related genes and dietary folate intake in gastric cancer risk within the Korean population through a hospital-based case-control study.
METHODS AND RESULTS: A total of 542 controls and 271 cases were included. Genotype data were selected from data produced by the Affymetrix Axiom(®) Exome 319 Array. We considered seven single nucleotide polymorphisms (SNPs) of five genes whose SNPs are located in the coding region with a minor allele frequency > 5%: MTHFR (G1793A, A1298C, C677T), MTR A2756G, MTRR A66G, SHMT1 C1420T, and SLC19A1 G80A. Our study found that MTR A2756G was associated with a decreased gastric cancer risk. MTHFR G1793A showed a statistically significant interaction between dietary folate intake and gastric cancer.
CONCLUSION: Our results suggest that MTR A2756G is significantly associated with gastric cancer risk, and that MTHFR G1793A statistically interacts with dietary folate intake. Our findings indicate that gene-folate interactions may contribute to gastric cancer risk.

Wu PP, Tang RN, An L
A meta-analysis of MTRR A66G polymorphism and colorectal cancer susceptibility.
J BUON. 2015 May-Jun; 20(3):918-22 [PubMed] Related Publications
PURPOSE: A meta-analysis was performed to determine the association between MTRR A66G polymorphism and colorectal cancer (CRC) susceptibility.
METHODS: Based on comprehensive searches of the MEDLINE, EMBASE and ISI Web of knowledge, China National Knowledge Infrastructure (CNKI) and Wanfang Database, we identified eligible studies about the association between MTRR A66G polymorphism and CRC susceptibility.
RESULTS: A total of 6020 cases and 8317 controls in 15 studies were pooled together for evaluation of the overall association between MTRR A66G polymorphism and susceptibility of CRC. The allele model (G vs A: p=0.01; OR=1.07, 95% CI=1.02-1.12), and homozygous model (GG vs AA: p=0.006; OR=1.15, 95% CI=1.04-1.28) showed increased risk for CRC development. Similarly, the dominant model (GG+GA vs AA: p=0.04; OR=1.11, 95% CI=1.01-1.22) and the recessive model (GG vs GA+AA: p=0.04; OR=1.08, 95% CI=1.00-1.17) showed increased risk for CRC development. In the analysis stratified by ethnicity (Caucasian and East Asian), significant associations were found between MTRR A66G polymorphism and susceptibility to CRC among Caucasians.
CONCLUSION: Our pooled data suggest an association between MTRR A66G polymorphism and CRC susceptibility among Caucasians.

Cheng TY, Makar KW, Neuhouser ML, et al.
Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study.
Cancer. 2015; 121(20):3684-91 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations.
METHODS: Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations.
RESULTS: Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P < .05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-β-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3β (DNMT3B), methionine adenosyltransferase I α (MAT1A), MTHFD1, and MTRR (nominal P < .05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS).
CONCLUSIONS: Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk.

Llanos AA, Marian C, Brasky TM, et al.
Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues.
Epigenetics. 2015; 10(8):727-35 [PubMed] Free Access to Full Article Related Publications
Genome-wide DNA hypomethylation is an early event in the carcinogenic process. Percent methylation of long interspersed nucleotide element-1 (LINE-1) is a biomarker of genome-wide methylation and is a potential biomarker for breast cancer. Understanding factors associated with percent LINE-1 DNA methylation in histologically normal tissues could provide insight into early stages of carcinogenesis. In a cross-sectional study of 121 healthy women with no prior history of cancer who underwent reduction mammoplasty, we examined associations between plasma and breast folate, genetic variation in one-carbon metabolism, and percent LINE-1 methylation using multivariable regression models (adjusting for race, oral contraceptive use, and alcohol use). Results are expressed as the ratio of LINE-1 methylation relative to that of the referent group, with the corresponding 95% confidence intervals (CI). We found no significant associations between plasma or breast folate and percent LINE-1 methylation. Variation in MTHFR, MTR, and MTRR were significantly associated with percent LINE-1 methylation. Variant allele carriers of MTHFR A1289C had 4% lower LINE-1 methylation (Ratio 0.96, 95% CI 0.93-0.98), while variant allele carriers of MTR A2756G (Ratio 1.03, 95% CI 1.01-1.06) and MTRR A66G (Ratio 1.03, 95% CI 1.01-1.06) had 3% higher LINE-1 methylation, compared to those carrying the more common genotypes of these SNPs. DNA methylation of LINE-1 elements in histologically normal breast tissues is influenced by polymorphisms in genes in the one-carbon metabolism pathway. Future studies are needed to investigate the sociodemographic, environmental and additional genetic determinants of DNA methylation in breast tissues and the impact on breast cancer susceptibility.

Zhao T, Gu D, Xu Z, et al.
Polymorphism in one-carbon metabolism pathway affects survival of gastric cancer patients: Large and comprehensive study.
Oncotarget. 2015; 6(11):9564-76 [PubMed] Free Access to Full Article Related Publications
Although it has been shown that polymorphisms in one-carbon metabolism (OCM) pathway are associated with gastric cancer (GC), their interactions and contributions for patients' survival are elusive. In this study, we investigated the effects of polymorphisms and their interactions on the survival of GC patients, including genes of Methylenetetrahydrofolate reductase (MTHFR 677C > T, 1298A > C), Methionine synthase reductase (MTRR 66A > G), Methionine synthase (MTR 2756A > G), and Thymidylate synthase (TS 3'-UTR ins6 > del6, 5'-UTR 2R > 3R). We recruited 919 GC patients from 1998 to 2006. The Kaplan-Meier plots, Cox regression analyses and the log-rank tests were carried out in this study. MTHFR 1298CC genotype showed protective effect (HR = 0.444, 95% CI = 0.210-0.940). MTRR 66 GA + GG genotypes decreased the risk of death (HR = 0.793, 95% CI = 0.651-0.967) in general, and in subgroups with more pronounced diffuse type, greater depth of invasion (T2/T3/T4), higher level lymph node metastasis (N1/N2/N3), advanced TNM stages (II/III level) and 5-Fu treatment. However, the improved survival disappeared when GC patients simultaneously had MTR 2756 GA + GG genotypes (HR = 1.063, 95% CI = 0.750-1.507). Although MTRR 66GA genotype was not associated with the survival of GC patients, patients with simultaneous MTRR 66GA and MTR 2756AA genotypes exhibited significant risk reduction of death (HR = 0.773, 95% CI = 0.609-0.981). MTHFR 1298 CA + CC combined with TS 5-UTR 2R3R + 3R3R genotypes (HR = 0.536, 95% CI = 0.315-0.913) also increased patient survival rates. Our results suggest that the MTRR 66A > G and MTHFR 1298A > C polymorphisms may be useful prognostic biomarkers for GC patients.

van Huis-Tanja LH, Ewing E, van der Straaten RJ, et al.
Clinical validation study of genetic markers for capecitabine efficacy in metastatic colorectal cancer patients.
Pharmacogenet Genomics. 2015; 25(6):279-88 [PubMed] Related Publications
BACKGROUND AND AIM: Pharmacogenetic studies continue to search for pretreatment predictors of chemotherapeutic efficacy and toxicity in metastatic colorectal cancer. Both genome-wide association studies and candidate gene studies have yielded potential genetic markers for chemosensitivity. We conducted a clinical association study, validating the effect of specific genetic markers cited in recently published papers on the efficacy of the oral 5-fluoro-uracil prodrug capecitabine.
PATIENTS AND METHODS: Germline DNA was collected for 268 metastatic colorectal cancer patients from the CAIRO trial, a multicenter phase III trial, randomizing between combined or sequential first-line treatment with capecitabine, irinotecan, and oxaliplatin. Genotyping was performed for eight single-nucleotide polymorphisms (SNPs), using high-resolution melting curves. Four SNPs are located in the MTRR gene, and another four SNPs showed significant association with 5-fluoro-uracil cytotoxicity in a recent in-vitro genome-wide association study. The primary endpoint was progression-free survival (PFS); secondary endpoints were objective response and overall survival.
RESULTS: In patients receiving capecitabine monotherapy, rs4702484, located in ADCY2 and close to MTRR, was associated with slightly reduced PFS for homozygous wild-type patients (CC 6.2 vs. CT 8.0 months; P=0.018). For the other selected genetic markers, we found no association with PFS, overall survival, or radiologic response upon treatment with capecitabine, either in the total study population or in the capecitabine monotherapy subgroup.
CONCLUSION: With the exception of rs4702484, we found no evidence of an effect on capecitabine chemosensitivity for any of the studied SNPs. More specifically, variants in methionine synthase reductase (MTRR) are not likely associated with capecitabine efficacy.

Greenop KR, Scott RJ, Attia J, et al.
Folate pathway gene polymorphisms and risk of childhood brain tumors: results from an Australian case-control study.
Cancer Epidemiol Biomarkers Prev. 2015; 24(6):931-7 [PubMed] Related Publications
BACKGROUND: Recent research suggests that maternal folic acid supplementation is associated with a reduced risk of childhood brain tumors (CBT); polymorphisms in folate pathway genes could modify this association or directly influence CBT risk.
METHODS: Associations between risk of CBT and folate pathway polymorphisms were investigated in a population-based case-control study in Australia (2005-2010). Cases were recruited through all Australian pediatric oncology centers and controls by national random digit dialing. Data were available from 321 cases and 552 controls. Six polymorphisms were genotyped in children and parents (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756A>G, MTR 5049C>A, and CBS 2199 T>C). Maternal folic acid use was ascertained via questionnaire. ORs were estimated using unconditional logistic regression. Case-parent trio analyses were also undertaken.
RESULTS: There was weak evidence of a reduced risk of CBT for the MTRR 66GG genotype in the child or father: ORs 0.71 [95% confidence interval (CI), 0.48-1.07]; 0.54 (95% CI, 0.34-0.87), respectively. Maternal prepregnancy folic acid supplementation showed a stronger negative association with CBT risk where the child, mother, or father had the MTRR 66GG genotype (Pinteraction = 0.07, 0.10, and 0.18, respectively).
CONCLUSIONS: Evidence for an association between folate pathway genotypes and CBT is limited in this study. There was possible protection by the MTRR 66GG genotype, particularly when combined with maternal prepregnancy folic acid supplementation; these results are novel and require replication.
IMPACT: The possible interaction between folic acid supplementation and MTRR 66A>G, if confirmed, would strengthen evidence for prepregnancy folate protection against CBT.

López-Cortés A, Echeverría C, Oña-Cisneros F, et al.
Breast cancer risk associated with gene expression and genotype polymorphisms of the folate-metabolizing MTHFR gene: a case-control study in a high altitude Ecuadorian mestizo population.
Tumour Biol. 2015; 36(8):6451-61 [PubMed] Related Publications
Breast cancer (BC) is the leading cause of cancer-related death among women in 2014. Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and MTR reductase (MTRR) are enzymes that play an important role in folate metabolism. The single nucleotide polymorphisms, MTHFR C677T, A1298C, MTR A2756G, and MTRR A66G, alter plasmatic folate and homocysteine concentrations, causing problems during the repairment, synthesis, and methylation of the genetic material. Therefore, it is essential to know how BC risk is associated with histopathological and immunohistochemical characteristics, genotype polymorphisms, and gene expression in a high altitude Ecuadorian mestizo population. DNA was extracted from 195 healthy and 114 affected women. Genotypes were determined by restriction enzymes and genomic sequencing. mRNA was extracted from 26 glandular breast tissue samples, both from cancerous tissue and healthy tissue adjacent to the tumor. Relative gene expression was determined with the comparative Livak method (2(-ΔΔCT)). We found significant association between the rs1801133 (A222V) genotypes and an increased risk of BC development: C/T (odds ratio [OR] = 1.8; 95 % confidence interval [CI] = 1.1-3.2; P = 0.039), T/T (OR = 2.9; 95 % CI = 1.2-7.2; P = 0.025), and C/T + T/T (OR = 1.9; 95 % CI = 1.1-3.3; P = 0.019). Regarding relative gene expression, we found significant mRNA subexpression between the combined genotypes C/T + T/T (rs1801133) and triple negative breast cancer (TNBC) (P = 0.034). In brief, the MTHFR gene and its protein could act as potential predictive biomarkers of BC, especially TNBC among the high altitude Ecuadorian mestizo population.

Naushad SM, Vijayalakshmi SV, Rupasree Y, et al.
Multifactor dimensionality reduction analysis to elucidate the cross-talk between one-carbon and xenobiotic metabolic pathways in multi-disease models.
Mol Biol Rep. 2015; 42(7):1211-24 [PubMed] Related Publications
Putatively functional polymorphisms of one-carbon and xenobiotic metabolic pathways influence susceptibility for wide spectrum of diseases. The current study was aimed to explore gene-gene interactions among these two metabolic pathways in four diseases i.e. breast cancer, systemic lupus erythematosus (SLE), coronary artery disease (CAD) and Parkinson's disease (PD). Multifactor dimensionality reduction analysis was carried out on four case-control datasets. Cross-talk was observed between one-carbon and xenobiotic pathways in breast cancer (RFC 80 G>A, COMT H108L and TYMS 5'-UTR 28 bp tandem repeat) and SLE (CYP1A1 m1, MTRR 66 A>G and GSTT1). Gene-gene interactions within one-carbon metabolic pathway were observed in CAD (GCPII 1561 C>T, SHMT 1420 C>T and MTHFR 677 C>T) and PD (cSHMT 1420 C>T, MTRR 66 A>G and RFC1 80 G>A). These interaction models showed good predictability of risk for PD (The area under the receiver operating characteristic curve (C) = 0.83) and SLE (C = 0.73); and moderate predictability of risk for breast cancer (C = 0.64) and CAD (C = 0.63). Cross-talk between one-carbon and xenobiotic pathways was observed in diseases with female preponderance. Gene-gene interactions within one-carbon metabolic pathway were observed in diseases with male preponderance.

Gong Z, Yao S, Zirpoli G, et al.
Genetic variants in one-carbon metabolism genes and breast cancer risk in European American and African American women.
Int J Cancer. 2015; 137(3):666-77 [PubMed] Free Access to Full Article Related Publications
Folate-mediated one-carbon metabolism plays critical roles in DNA synthesis, repair and DNA methylation. The impact of single nucleotide polymorphisms (SNPs) in folate-metabolizing enzymes has been investigated in risk of breast cancer among European or Asian populations, but not among women of African ancestry. We conducted a comprehensive analysis of SNPs in eleven genes involved in one-carbon metabolism and risk of breast cancer in 1,275 European-American (EA) and 1,299 African-American (AA) women who participated in the Women's Circle of Health Study. Allele frequencies varied significantly between EA and AA populations. A number of these SNPs, specifically in genes including MTR, MTRR, SHMT1, TYMS and SLC19A1, were associated with overall breast cancer risk, as well as risk by estrogen receptor (ER) status, in either EA or AA women. Associations appeared to be modified by dietary folate intake. Although single-SNP associations were not statistically significant after correcting for multiple comparisons, polygenetic score analyses revealed significant associations with breast cancer risk. Per unit increase of the risk score was associated with a modest 19 to 50% increase in risk of breast cancer overall, ER positive or ER negative cancer (all p < 0.0005) in EAs or AAs. In summary, our data suggest that one-carbon metabolizing gene polymorphisms could play a role in breast cancer and that may differ between EA and AA women.

Milne E, Greenop KR, Scott RJ, et al.
Folate pathway gene polymorphisms, maternal folic acid use, and risk of childhood acute lymphoblastic leukemia.
Cancer Epidemiol Biomarkers Prev. 2015; 24(1):48-56 [PubMed] Related Publications
BACKGROUND: Several studies suggest that maternal folic acid supplementation before or during pregnancy protects against childhood acute lymphoblastic leukemia (ALL). We investigated associations between ALL risk and folate pathway gene polymorphisms, and their modification by maternal folic acid supplements, in a population-based case-control study (2003-2007).
METHODS: All Australian pediatric oncology centers provided cases; controls were recruited by national random digit dialing. Data from 392 cases and 535 controls were included. Seven folate pathway gene polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756 A>G, MTR 5049 C>A, CBS 844 Ins68, and CBS 2199 T>C) were genotyped in children and their parents. Information on prepregnancy maternal folic acid supplement use was collected. ORs were estimated with unconditional logistic regression adjusted for frequency-matched variables and potential confounders. Case-parent trios were also analyzed.
RESULTS: There was some evidence of a reduced risk of ALL among children who had, or whose father had, the MTRR 66GG genotype: ORs 0.60 [95% confidence interval (CI) 0.39-0.91] and 0.64 (95% CI, 0.40-1.03), respectively. The ORs for paternal MTHFR 677CT and TT genotypes were 1.41 (95% CI, 1.02-1.93) and 1.81 (95% CI, 1.06-3.07). ORs varied little by maternal folic acid supplementation.
CONCLUSIONS: Some folate pathway gene polymorphisms in the child or a parent may influence ALL risk. While biologically plausible, underlying mechanisms for these associations need further elucidation.
IMPACT: Folate pathway polymorphisms may be related to risk of childhood ALL, but larger studies are needed for conclusive results.

Suthandiram S, Gan GG, Mohd Zain S, et al.
Genetic polymorphisms in the one-carbon metabolism pathway genes and susceptibility to non-Hodgkin lymphoma.
Tumour Biol. 2015; 36(3):1819-34 [PubMed] Related Publications
Corroborating evidence related to the role of aberrations on one-carbon metabolism (OCM) genes has been inconsistent. We evaluated the association between polymorphisms in 12 single nucleotide polymorphisms (SNPs) in 8 OCM genes (CBS, FPGS, FTHFD, MTRR, SHMT1, SLC19A1, TCN1, and TYMS), and non-Hodgkin lymphoma (NHL) risk in a multi-ethnic population which includes Malay, Chinese and Indian ethnic subgroups. Cases (N = 372) and controls (N = 722) were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects showed a significantly enhanced NHL risk for CBS Ex9 + 33C > T (T versus C: OR 1.55, 95% CI 1.22-1.96, P = 0.0003), CBS Ex18-319G > A (A versus G: OR 1.15, 95% CI 1.14-1.83; P = 0.002), SHMT1 Ex12 + 236 T > C (T versus C: OR 1.44, 95% CI 1.15-1.81, P = 0.002), and TYMS Ex8 + 157C > T (T versus C: OR 1.29, 95% CI 1.06-1.57, P = 0.01). Haplotype analysis for CBS SNPs showed a significantly decreased risk of NHL in subjects with haplotype CG (OR 0.69, 95% CI 0.56-0.86, P = <0.001). The GG haplotype for the FTHFD SNPs showed a significant increased risk of NHL (OR 1.40, 95% CI 1.12-1.76, P = 0.002). For the TYMS gene, haplotype CAT at TYMS (OR 0.67, 95% CI 0.49-0.90, P = 0.007) was associated with decreased risk of NHL, while haplotype TAC (OR 1.29, 95% CI 1.05-1.58, P = 0.01) was found to confer increased risk of NHL. Our study suggests that variation in several OCM genes (CBS, FTHFD, SHMT1, TCN1, and TYMS) may influence susceptibility to NHL.

Chang SC, Chang PY, Butler B, et al.
Single nucleotide polymorphisms of one-carbon metabolism and cancers of the esophagus, stomach, and liver in a Chinese population.
PLoS One. 2014; 9(10):e109235 [PubMed] Free Access to Full Article Related Publications
One-carbon metabolism (folate metabolism) is considered important in carcinogenesis because of its involvement in DNA synthesis and biological methylation reactions. We investigated the associations of single nucleotide polymorphisms (SNPs) in folate metabolic pathway and the risk of three GI cancers in a population-based case-control study in Taixing City, China, with 218 esophageal cancer cases, 206 stomach cancer cases, 204 liver cancer cases, and 415 healthy population controls. Study participants were interviewed with a standardized questionnaire, and blood samples were collected after the interviews. We genotyped SNPs of the MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes, using PCR-RFLP, SNPlex, or TaqMan assays. To account for multiple comparisons and reduce the chances of false reports, we employed semi-Bayes (SB) shrinkage analysis. After shrinkage and adjusting for potential confounding factors, we found positive associations between MTHFR rs1801133 and stomach cancer (any T versus C/C, SB odds-ratio [SBOR]: 1.79, 95% posterior limits: 1.18, 2.71) and liver cancer (SBOR: 1.51, 95% posterior limits: 0.98, 2.32). There was an inverse association between DNMT1 rs2228612 and esophageal cancer (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94). In addition, we detected potential heterogeneity across alcohol drinking status for ORs relating MTRR rs1801394 to esophageal (posterior homogeneity P = 0.005) and stomach cancer (posterior homogeneity P = 0.004), and ORs relating MTR rs1805087 to liver cancer (posterior homogeneity P = 0.021). Among non-alcohol drinkers, the variant allele (allele G) of these two SNPs was inversely associated with the risk of these cancers; while a positive association was observed among ever-alcohol drinkers. Our results suggest that genetic polymorphisms related to one-carbon metabolism may be associated with cancers of the esophagus, stomach, and liver. Heterogeneity across alcohol consumption status of the associations between MTR/MTRR polymorphisms and these cancers indicates potential interactions between alcohol drinking and one-carbon metabolic pathway.

Zhang H, Liu C, Han YC, et al.
Genetic variations in the one-carbon metabolism pathway genes and susceptibility to hepatocellular carcinoma risk: a case-control study.
Tumour Biol. 2015; 36(2):997-1002 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the sixth common cancer and the third common cause of cancer mortality worldwide. However, the exact molecular mechanism of HCC remains uncertain. Many enzymes are involved in one-carbon metabolism (OCM), and single nucleotide polymorphisms (SNPs) in the corresponding genes may play a role in liver carcinogenesis. In this study, we enrolled 1500 HCC patients and 1500 cancer-free controls, which were frequency-matched by age, gender, and HBV infection status. Then eight SNPs from seven OCM genes (MTHFR, MTR, MTRR, FTHFD, GART, SHMT, and CBS) were evaluated. Results showed that six SNPs (MTHFR rs1801133, MTRR rs2287780, MTRR rs10380, FTHFD rs1127717, GART rs8971, and SHMT rs1979277) were significantly associated with HCC risk in Chinese population, with P values range from 2.26 × 10(-4) to 0.035). The most significant association was detected for GART rs8971. Compared with individuals with the TT genotype, the age- and sex-adjusted odds ratio (OR) for developing HCC was 1.44 (95% confidence interval (CI): 1.03-2.02) among those with the CC genotype and 1.30 (95% CI: 1.10-1.53) for those with CT genotype. Under the log-additive model, each additional copy of minor allele C was associated with a 1.28-fold increased risk of HCC (OR = 1.28, 95% CI: 1.12-1.45). These findings indicated that genetic variants in OCM genes might contribute to HCC susceptibility.

Reimers MS, Kuppen PJ, Lee M, et al.
Validation of the 12-gene colon cancer recurrence score as a predictor of recurrence risk in stage II and III rectal cancer patients.
J Natl Cancer Inst. 2014; 106(11) [PubMed] Related Publications
BACKGROUND: The 12-gene Recurrence Score assay is a validated predictor of recurrence risk in stage II and III colon cancer patients. We conducted a prospectively designed study to validate this assay for prediction of recurrence risk in stage II and III rectal cancer patients from the Dutch Total Mesorectal Excision (TME) trial.
METHODS: RNA was extracted from fixed paraffin-embedded primary rectal tumor tissue from stage II and III patients randomized to TME surgery alone, without (neo)adjuvant treatment. Recurrence Score was assessed by quantitative real time-polymerase chain reaction using previously validated colon cancer genes and algorithm. Data were analysed by Cox proportional hazards regression, adjusting for stage and resection margin status. All statistical tests were two-sided.
RESULTS: Recurrence Score predicted risk of recurrence (hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.11 to 2.21, P = .01), risk of distant recurrence (HR = 1.50, 95% CI = 1.04 to 2.17, P = .03), and rectal cancer-specific survival (HR = 1.64, 95% CI = 1.15 to 2.34, P = .007). The effect of Recurrence Score was most prominent in stage II patients and attenuated with more advanced stage (P(interaction) ≤ .007 for each endpoint). In stage II, five-year cumulative incidence of recurrence ranged from 11.1% in the predefined low Recurrence Score group (48.5% of patients) to 43.3% in the high Recurrence Score group (23.1% of patients).
CONCLUSION: The 12-gene Recurrence Score is a predictor of recurrence risk and cancer-specific survival in rectal cancer patients treated with surgery alone, suggesting a similar underlying biology in colon and rectal cancers.

Hu S, Liu HC, Xi SM
Methionine synthase reductase A66G polymorphism is not associated with breast cancer susceptibility - a meta-analysis.
Asian Pac J Cancer Prev. 2014; 15(7):3267-71 [PubMed] Related Publications
BACKGROUND: Several studies have investigated the association between methionine synthase reductase (MTRR) A66G polymorphism and breast cancer risk, but controversial results were yielded. Therefore, we performed a meta-analysis to provide a more robust estimate of the effect of this polymorphism on susceptibility to breast cancer.
MATERIALS AND METHODS: Case-control studies investigating the relationship between MTRR A66G polymorphism and breast cancer risk were included by searching PubMed, EMBASE, China National Knowledge Infrastructure and Wanfang Database. Either fixed-effects or random-effects models were applied to calculate odds ratios(ORs) and 95% confidence intervals (CIs) by RevMan5.2 software.
RESULTS: A total of 9 studies bearing 7,097 cases and 7,710 controls were included in the meta-analysis. The results were that the combined ORs and 95%CIs of MTRR 66AG, GG, (AG+GG) genotypes were 0.98(0.91-1.05), 1.06(0.97-1.16) and 1.02(0.94-1.10), respectively with p=0.52, 0.19 and 0.65. We also performed subgroup analysis by specific ethnicity. The results of the combined analysis of MTRR 66AG, GG, (AG+GG) genotypes and breast cancer in Asian descent were Z=0.50, 0.53 and 0.21, with p all>0.05; for breast cancer in Caucasian descent, the results were Z=1.14, 1.65 and 0.43, with p all>0.05.
CONCLUSIONS: Our findings suggested that MTRR A66G polymorphism was not associated with breast cancer susceptibility.

Cheng C, Lingyan W, Yi H, et al.
Association between TLR2, MTR, MTRR, XPC, TP73, TP53 genetic polymorphisms and gastric cancer: a meta-analysis.
Clin Res Hepatol Gastroenterol. 2014; 38(3):346-59 [PubMed] Related Publications
OBJECTIVE: The aim of our meta-analyses is to test the association between six genetic polymorphisms and gastric cancer.
METHODS: A systematic search was performed for all the available candidate genes and gastric cancer among several online databases including PubMed, Embase, Web of Science, the Cochrane Library, CNKI and Wanfang online libraries. After a comprehensive screening, a total of six genes were harvested for the current meta-analyses. These genes include TLR2 (-196 to -174 ins>del), MTR (rs1805087), MTRR (rs1801394), XPC (rs2228001), TP73 (G4C14-A4T14), and TP53 (rs1042522).
RESULTS: Altogether 49 comparative studies among 11 776 cases and 18 633 controls were involved in our meta-analyses. TP53 rs1042522 polymorphism was shown to be associated with gastric cancer risk under the dominant model (P=0.02, OR=1.03, 95% CI=1.00-1.05). A subgroup meta-analysis indicated a significant association under dominant model between TP53 rs1042522 and gastric cancer in the Eastern Asians (P=0.03, OR=1.17, 95%=1.02-1.34).
CONCLUSIONS: These results suggest that TP53 rs1042522 polymorphism might contribute to the susceptibility of gastric cancer under the dominant model, especially in Eastern Asians.

Coppedè F, Migheli F, Lopomo A, et al.
Gene promoter methylation in colorectal cancer and healthy adjacent mucosa specimens: correlation with physiological and pathological characteristics, and with biomarkers of one-carbon metabolism.
Epigenetics. 2014; 9(4):621-33 [PubMed] Free Access to Full Article Related Publications
We evaluated the promoter methylation levels of the APC, MGMT, hMLH1, RASSF1A and CDKN2A genes in 107 colorectal cancer (CRC) samples and 80 healthy adjacent tissues. We searched for correlation with both physical and pathological features, polymorphisms of folate metabolism pathway genes (MTHFR, MTRR, MTR, RFC1, TYMS, and DNMT3B), and data on circulating folate, vitamin B12 and homocysteine, which were available in a subgroup of the CRC patients. An increased number of methylated samples were found in CRC respect to adjacent healthy tissues, with the exception of APC, which was also frequently methylated in healthy colonic mucosa. Statistically significant associations were found between RASSF1A promoter methylation and tumor stage, and between hMLH1 promoter methylation and tumor location. Increasing age positively correlated with both hMLH1 and MGMT methylation levels in CRC tissues, and with APC methylation levels in the adjacent healthy mucosa. Concerning gender, females showed higher hMLH1 promoter methylation levels with respect to males. In CRC samples, the MTR 2756AG genotype correlated with higher methylation levels of RASSF1A, and the TYMS 1494 6bp ins/del polymorphism correlated with the methylation levels of both APC and hMLH1. In adjacent healthy tissues, MTR 2756AG and TYMS 1494 6bp del/del genotypes correlated with APC and MGMT promoter methylation, respectively. Low folate levels were associated with hMLH1 hypermethylation. Present results support the hypothesis that DNA methylation in CRC depends from both physiological and environmental factors, with one-carbon metabolism largely involved in this process.

Morita M, Yin G, Yoshimitsu S, et al.
Folate-related nutrients, genetic polymorphisms, and colorectal cancer risk: the fukuoka colorectal cancer study.
Asian Pac J Cancer Prev. 2013; 14(11):6249-56 [PubMed] Related Publications
One-carbon metabolism plays an important role in colorectal carcinogenesis. Meta-analyses have suggested protective associations of folate and vitamin B6 intakes with colorectal cancer primarily based on studies in Caucasians, and genetic polymorphisms pertaining to the folate metabolism have been a matter of interest. Less investigated are the roles of methionine synthase (MTR) and thymidylate synthetase (TS) polymorphisms in colorectal carcinogenesis. In a study of 816 cases and 815 community controls in Japan, we investigated associations of dietary intakes of folate, methionine, vitamin B2, vitamin B6, and vitamin B12 with colorectal cancer risk. The associations with MTR 2756A>G, MTRR 66A>G, and TSER repeat polymorphism were examined in 685 cases and 778 controls. Methionine and vitamin B12 intakes were inversely associated with colorectal cancer risk, but the associations were totally confounded by dietary calcium and n-3 fatty acids. The other nutrients showed no association with the risk even without adjustment for calcium and n-3 fatty acids. The TSER 2R allele was dose-dependently associated with an increased risk. The MTR and MTRR polymorphisms were unrelated to colorectal cancer risk. There was no measurable gene-gene or gene-nutrient interaction, but increased risk associated with the TSER 2R allele seemed to be confined to individuals with high folate status. This study does not support protective associations for folate and vitamin B6. The TSER 2R allele may confer an increased risk of colorectal cancer. The role of the TSER polymorphism in colorectal carcinogenesis may differ by ethnicity.

Dixon SC, Ibiebele TI, Protani MM, et al.
Dietary folate and related micronutrients, folate-metabolising genes, and ovarian cancer survival.
Gynecol Oncol. 2014; 132(3):566-72 [PubMed] Related Publications
OBJECTIVE: Folate is essential for DNA synthesis and methylation and is implicated in tumour progression. Few studies have examined its role in ovarian cancer survival. Our objective was to determine relationships between intake of folate, related one-carbon nutrients, single nucleotide polymorphisms (SNPs) in folate-metabolising genes and survival following ovarian cancer diagnosis.
METHODS: This analysis included 1270 women with invasive epithelial ovarian cancer diagnosed in 2002-2006. Pre-diagnostic and some post-diagnostic lifestyle, dietary, and sociodemographic information was collected via self-administered questionnaires. DNA samples were genotyped for SNPs in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR) genes. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox regression.
RESULTS: Multivariate analyses did not identify associations between higher pre-diagnostic intake of folate, folic acid, vitamins B2, B6, and B12, methionine, betaine or choline and survival overall. In stratified analyses, higher folic acid and folate intake was associated with significantly worse survival among women with mucinous tumours (HRs per 100 μg 1.30 and 1.43, respectively) and smokers (HRs per 100 μg 1.23 and 1.16 respectively). There was also a suggestion that higher supplemental folic acid use post-diagnosis was associated with worse survival (HR per 100 μg 1.03, 95%CI 1.00-1.05). MTHFR SNP rs2066470 was significantly associated with survival (per allele HR 0.81, 95%CI 0.67-0.98).
CONCLUSIONS: Our data provide little evidence that folate intake affects ovarian cancer survival. However, combined effects with smoking, and findings within the mucinous subtype and for post-diagnosis folic acid, warrant further investigation.

Zhang L, Meng X, Ju X, et al.
One-carbon metabolism pathway gene variants and risk of clear cell renal cell carcinoma in a Chinese population.
PLoS One. 2013; 8(11):e81129 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: One-carbon metabolism is the basement of nucleotide synthesis and the methylation of DNA linked to cancer risk. Variations in one-carbon metabolism genes are reported to affect the risk of many cancers, including renal cancer, but little knowledge about this mechanism is known in Chinese population.
METHODS: Each subject donated 5 mL venous blood after signing the agreement. The study was approved by the Institutional Review Board of the Nanjing Medical University, Nanjing, China. 18 SNPs in six one-carbon metabolism-related genes (CBS, MTHFR, MTR, MTRR, SHMT1, and TYMS) were genotyped in 859 clear cell renal cell carcinoma (ccRCC) patients and 1005 cancer-free controls by the Snapshot.
RESULTS: Strong associations with ccRCC risk were observed for rs706209 (P = 0.006) in CBS and rs9332 (P = 0.027) in MTRR. Compared with those carrying none variant allele, individuals carrying one or more variant alleles in these two genes had a statistically significantly decreased risk of ccRCC [P = 0.001, adjusted odds ratio (OR) = 0.73, 95% confidence interval (CI) = 0.06-0.90]. In addition, patients carrying one or more variant alleles were more likely to develop localized stage disease (P = 0.002, adjusted OR = 1.37, 95%CI = 1.11-1.69) and well-differentiated ccRCC (P<0.001, adjusted OR = 1.42, 95%CI = 0.87-1.68). In the subgroup analysis, individuals carrying none variant allele in older group (P = 0.007, adjusted OR = 0.67, 95%CI = 0.49-0.91), male group (P = 0.007, adjusted OR = 0.71, 95%CI = 0.55-0.92), never smoking group (P = 0.002, adjusted OR = 0.68, 95%CI = 0.53-0.88) and never drinking group (P<0.001, adjusted OR = 0.68, 95%CI = 0.53-0.88) had an increased ccRCC risk.
CONCLUSIONS: Our results suggest that the polymorphisms of the one-carbon metabolism-related genes are associated with ccRCC risk in Chinese population. Future population-based prospective studies are required to confirm the results.

Fang DH, Ji Q, Fan CH, et al.
Methionine synthase reductase A66G polymorphism and leukemia risk: evidence from published studies.
Leuk Lymphoma. 2014; 55(8):1910-4 [PubMed] Related Publications
Methionine synthase reductase (MTRR) is required for the reductive methylation of cobalamin, which is the functional cofactorial form of methionine synthase (MS) in the remethylation of homocysteine to methionine. The MTRR A66G (rs1801394) polymorphism is found to be associated with decreased enzyme affinity for MTR, the gene that encodes MS, and has been widely investigated for cancer risk, including leukemia. However, the conclusions of epidemiological studies have always been contradictory. To further clarify the association of MTRR A66G polymorphism with the risk of leukemia, this meta-analysis was performed for 2913 cases and 4764 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Pooled ORs were determined for the co-dominant model (GG vs. AA, AG vs. AA), dominant model (GG + AG vs. AA) and recessive model (GG vs. AA+ AG), respectively. No significant associations were found for all comparisons in the overall pooled analysis. However, the results of stratified analyses revealed that MTRR A66G GG genotype was associated with decreased leukemia risk in the Caucasian population, in children and for acute lymphoblastic leukemia (ALL). In contrast, increased risk was observed in the Asian population and for acute myeloid leukemia (AML). This meta-analysis suggests that MTRR A66G GG is associated with decreased risk of leukemia in a Caucasian population and in children, especially for ALL.

Deroo LA, Bolick SC, Xu Z, et al.
Global DNA methylation and one-carbon metabolism gene polymorphisms and the risk of breast cancer in the Sister Study.
Carcinogenesis. 2014; 35(2):333-8 [PubMed] Free Access to Full Article Related Publications
Global decrease in DNA methylation is a common feature of cancer and is associated with genomic and chromosomal instability. Retrospective case-control studies have reported that cancer patients have lower global methylation levels in blood DNA than do controls. We used prospectively collected samples and a case-cohort study design to examine global DNA methylation and incident breast cancer in 294 cases and a sample of 646 non-cases in the Sister Study, a study of 50 884 women aged 35-74 years who had not been diagnosed with breast cancer at the time of blood draw. Global methylation in DNA from peripheral blood was assessed by pyrosequencing of the LINE-1 repetitive element. Quartiles of LINE-1 methylation levels were associated with the risk of breast cancer in a dose-dependent fashion (P, trend = 0.002), with an increased risk observed among women in the lowest quartile compared with those in the highest quartile (hazard ratio = 1.75; 95% confidence interval 1.19, 2.59). We also examined 22 polymorphisms in 10 one-carbon metabolism genes in relation to both LINE-1 methylation levels and breast cancer. We found three single-nucleotide polymorphisms in those genes associated with LINE-1 methylation: SLC19A1 (rs1051266); MTRR (rs10380) and MTHFR (rs1537514), one of which was also associated with breast cancer risk: MTHFR (rs1537514). PON1 (rs757158) was associated with breast cancer but not methylation.

Nazki FH, Sameer AS, Ganaie BA
Folate: metabolism, genes, polymorphisms and the associated diseases.
Gene. 2014; 533(1):11-20 [PubMed] Related Publications
Folate being an important vitamin of B Complex group in our diet plays an important role not only in the synthesis of DNA but also in the maintenance of methylation reactions in the cells. Folate metabolism is influenced by several processes especially its dietary intake and the polymorphisms of the associated genes involved. Aberrant folate metabolism, therefore, affects both methylation as well as the DNA synthesis processes, both of which have been implicated in the development of various diseases. This paper reviews the current knowledge of the processes involved in folate metabolism and consequences of deviant folate metabolism, particular emphasis is given to the polymorphic genes which have been implicated in the development of various diseases in humans, like vascular diseases, Down's syndrome, neural tube defects, psychiatric disorders and cancers.

Tomita LY, D'Almeida V, Villa LL, et al.
Polymorphisms in genes involved in folate metabolism modify the association of dietary and circulating folate and vitamin B-6 with cervical neoplasia.
J Nutr. 2013; 143(12):2007-14 [PubMed] Related Publications
High folate intake has been suggested as an important factor in cancer prevention; however, previous studies on the relation among folate intake, serum folate, and plasma homocysteine (hcy) are controversial. We conducted a hospital-based, case-control study in Brazil investigating associations between dietary and circulating vitamins B-6 and B-12 and folate, hcy, genotypes of folate-metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR C677T, A1298C), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR A2756G), methionine synthase reductase (MTRR A66G), and reduced folate carrier (RFC1 G80A) and risk of cervical intraepithelial neoplasia (CIN) grades 1 (CIN1), 2 (CIN2), and 3 (CIN3). The study was composed by 453 controls, 140 CIN1, 126 CIN2, and 231 CIN3. We investigated the joint effects of genetic variants of folate-related genes using genetic risk scores (GRSs) by summing the number of risk alleles for CIN1 and CIN2+ (CIN2 and CIN3 cases). The OR (95% CI) for CIN1 and CIN2+ per each risk allele were 1.29 (1.01, 1.65) and 1.22 (1.01, 1.46), respectively. An association between folate intake and CIN2+ was observed only after stratification according to GRS: crude OR (95% CI) for lower folate intake and GRS ≥ 4 was 1.67 (0.92, 3.04) (P-trend < 0.001) compared with higher folate intake (above the median) and GRS ≤ 3. The CIN2+ risk of lower serum vitamin B-6 and GRS ≥ 4 was 2.14 (0.92, 5.02) (P-trend = 0.05) and lower serum folate (below the median) and GRS ≥ 4 was 0.49 (0.20, 1.17) (P-trend = 0.05) after adjustment for confounding variables and human papillomavirus infection. Our data suggest that polymorphisms in genes related to folate metabolism modify the association of dietary and circulating folate and vitamin B-6 with cervical neoplasia.

Zhang J, Zhou YW, Shi HP, et al.
5,10-Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) gene polymorphisms and adult meningioma risk.
J Neurooncol. 2013; 115(2):233-9 [PubMed] Related Publications
The causes of meningiomas are not well understood. Folate metabolism gene polymorphisms have been shown to be associated with various human cancers. It is still controversial and ambiguous between the functional polymorphisms of folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) and risk of adult meningioma. A population-based case–control study involving 600 meningioma patients (World Health Organization [WHO] Grade I, 391 cases; WHO Grade II, 167 cases; WHO Grade III, 42 cases) and 600 controls was done for the MTHFR C677T and A1298C, MTRR A66G, and MTR A2756G variants in Chinese Han population. The folate metabolism gene polymorphisms were determined by using a polymerase chain reaction–restriction fragment length polymorphism assay. Meningioma cases had a significantly lower frequency of MTHFR 677 TT genotype [odds ratio (OR) = 0.49, 95 % confidence interval (CI) 0.33–0.74; P = 0.001] and T allele (OR = 0.80, 95 % CI 0.67–0.95; P = 0.01) than controls. A significant association between risk of meningioma and MTRR 66 GG (OR = 1.41, 95 % CI 1.02–1.96; P = 0.04) was also observed. When stratifying by the WHO grade of meningioma, no association was found. Our study suggested that MTHFR C677T and MTRR A66G variants may affect the risk of adult meningioma in Chinese Han population.

Lautner-Csorba O, Gézsi A, Erdélyi DJ, et al.
Roles of genetic polymorphisms in the folate pathway in childhood acute lymphoblastic leukemia evaluated by Bayesian relevance and effect size analysis.
PLoS One. 2013; 8(8):e69843 [PubMed] Free Access to Full Article Related Publications
In this study we investigated whether polymorphisms in the folate pathway influenced the risk of childhood acute lymphoblastic leukemia (ALL) or the survival rate of the patients. For this we selected and genotyped 67 SNPs in 15 genes in the folate pathway in 543 children with ALL and 529 controls. The results were evaluated by gender adjusted logistic regression and by the Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) methods. Bayesian structure based odds ratios for the relevant variables and interactions were also calculated. Altogether 9 SNPs in 8 genes were associated with altered susceptibility to ALL. After correction for multiple testing, two associations remained significant. The genotype distribution of the MTHFD1 rs1076991 differed significantly between the ALL and control population. Analyzing the subtypes of the disease the GG genotype increased only the risk of B-cell ALL (p = 3.52×10(-4); OR = 2.00). The GG genotype of the rs3776455 SNP in the MTRR gene was associated with a significantly reduced risk to ALL (p = 1.21×10(-3); OR = 0.55), which resulted mainly from the reduced risk to B-cell and hyperdiploid-ALL. The TC genotype of the rs9909104 SNP in the SHMT1 gene was associated with a lower survival rate comparing it to the TT genotype (80.2% vs. 88.8%; p = 0.01). The BN-BMLA confirmed the main findings of the frequentist-based analysis and showed structural interactional maps and the probabilities of the different structural association types of the relevant SNPs especially in the hyperdiploid-ALL, involving additional SNPs in genes like TYMS, DHFR and GGH. We also investigated the statistical interactions and redundancies using structural model properties. These results gave further evidence that polymorphisms in the folate pathway could influence the ALL risk and the effectiveness of the therapy. It was also shown that in gene association studies the BN-BMLA could be a useful supplementary to the traditional frequentist-based statistical method.

Li Q, Lan Q, Zhang Y, et al.
Role of one-carbon metabolizing pathway genes and gene-nutrient interaction in the risk of non-Hodgkin lymphoma.
Cancer Causes Control. 2013; 24(10):1875-84 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Genetic polymorphisms in one-carbon metabolizing pathway genes have been associated with risk of malignant lymphoma. However, the results have been inconsistent. The objectives of this study were to examine the potential relationship between gene-nutrient interactions and the risk of non-Hodgkin lymphoma (NHL).
METHODS: We examined 25 polymorphisms in 16 one-carbon metabolism genes for their main effect and gene-nutrient interactions in relation to NHL risk among 518 incident cases and 597 population-based controls of Connecticut women enrolled between 1996 and 2000.
RESULTS: A significantly reduced risk of NHL was associated with the homozygous TT genotype in CBS (rs234706, Ex9+33C>T) (OR = 0.51, 95 % CI 0.31-0.84), the homozygous CC genotype in MBD2 (rs603097, -2176C>T) (OR = 0.37, 95 % CI 0.17-0.79), the heterozygote AG genotype in FTHFD (rs1127717, Ex21+31A>G) (OR = 0.73, 95 % CI 0.55-0.98), and a borderline significantly reduced risk of NHL was observed for the homozygous CC genotype in MTRR (rs161870, Ex5+136T>C) (OR = 0.23, 95 % CI 0.05-1.04). The reduced risk of NHL associated with these genotypes was predominately in those with higher dietary vitamin B6 and methionine intakes, as well as with higher dietary folate intake although results were less stable. A borderline significantly increased risk of NHL was also observed for CBS (rs1801181, Ex13+41C>T), FTHFD (rs2305230, Ex10-40G>T), SHMT1 (rs1979277, Ex12+138C>T), and SHMT1 (rs1979276, Ex12+236T>C), and these associations appeared to be contingent on dietary nutrient intakes.
CONCLUSION: Our results suggest that variation in several one-carbon metabolizing pathway genes may influence the risk of NHL through gene-nutrient interactions involving dietary nutrient intakes.

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