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Folic acid processing; homocysteine levels
Geno Mag Summary
(C;C) 0 Common genotype: normal homocysteine levels
(C;T) 2.2 1 copy of C677T allele of MTHFR = 65% efficiency in processing folic acid
(T;T) 2.8 homozygous for C677T of MTHFR = 10-20% efficiency in processing folic acid = high homocysteine, low B12 and folate levels
ReferenceGRCh38 38.1/141
is asnp
is mentioned by
dbSNP (classic)rs1801133
1000 genomesrs1801133
GWAS Ctlgrs1801133
Merged fromRs59514310
Max Magnitude2.8
? (C;C) (C;T) (T;T) 28

rs1801133 is a SNP that is relatively common and has been studied for (relatively) a long time. Also known as C677T, Ala222Val, and A222V, it encodes a variant in the MTHFR gene, which encodes an enzyme involved in folate metabolism.

Homozygous rs1801133(T;T) individuals have ~30% of the expected MTHFR enzyme activity, and rs1801133(C;T) heterozygotes have ~65% activity, compared to the most common genotype, rs1801133(C;C).

"Our Take on The MTHFR Gene," is a 23andMe blog posting (January 5, 2017), a meta-analysis finding that the past two decades of scientific evidence as it relates to specific MTHFR-influenced health conditions to be inconclusive or conflicting, with two exceptions, 1. women with two copies of C677T variant, 2. a very rare variant that may cause homocystinuria. Their takeaway, "Based on the existing data, scientists at 23andMe have concluded that people should not interpret their genotypes at the common MTHFR variants as having an effect on their health."

This reduced activity (i.e. this SNP) has been linked at least once to each of the following disorders (though not necessarily reproducibly):

PubMed lists over 3,000 studies linking rs1801133 to a long list of disorders in various populations across the world, of which only some are mentioned above. Considering the central role of MTHFR in folate metabolism and in control of homocysteine levels this is not surprising. A nice summary of the pathological significance of elevated homocysteine levels could be found in this article. However, despite the evidence that folic acid and other vitamins can reduce homocysteine levels, a review of 8 clinical trials concluded that the supplements provided no benefit in terms of decreasing blood clots, heart disease, cancer or overall mortality.[PMID 21069462]

With regard to gastric cancer, a meta-analysis combining 16 studies and ~2,700 patients concluded that the increased risk (odds ratio) associated with rs1801133 (T;T) and (C;T) genotypes, was 1.52 (CI 1.31-1.77) and 1.17 (CI 0.99-1.39), respectively, compared to the (C;C) genotype. Roughly the same risks were seen for Caucasians and Asians. Smoking and having low folate levels (presumably from diets low in fruits and veggies) increased the risk for (T;T) individuals from ~1.5x to ~2x, whereas having high folate levels almost reduced the risk for (T;T) genotypes pretty much down to the (C;C) level, ie. the average risk. [PMID 18162478]

Another meta-analysis of three studies on rs1801133 stratified according to dietary folate intake showed an increased risk for individuals with low folate intake (OR=1.37, CI: 0.92-2.06 for head and neck cancer and OR=1.28, CI: 0.97-1.68 for lung) versus high folate intake (OR=0.85, CI: 0.63-1.16 for head and neck cancer, and OR=0.94, CI: 0.79-1.12 for lung).[PMID 18789576]

rs1801131 and rs1801133 have been linked to increased risk for several types of brain cancer. The highest risk of meningioma was associated with heterozygosity for both MTHFR SNPs (odds ratio 2.11, CI: 1.42-3.12, p=0.002). The corresponding odds ratio for glioma was 1.23 (CI: 0.91-1.66, p=0.02. In general, risks were increased with genotypes associated with reduced MTHFR activity.[PMID 18483342]

Based on a study of 25,000 Caucasian women followed for 11 years (on average), the rs1801133(T;T) genotype individual was less likely to have migraine with aura (odds ratio 0.79, CI: 0.65-0.9 6, p = 0.02) and did not have increased risk for cardiovascular disease. However, if a (T;T) genotype did have migraine with aura, then the risk for cardiovascular disease was increased 3.66 fold (CI: 1.69-7.90, p = 0.001). This was apparently driven by a 4x increased risk for ischemic stroke (multivariable-adjusted relative risk 4.19, CI: 1.38-12.74, p = 0.01).[PMID 18672474OA-icon.png]

A study of 677 patients with end-stage renal disease (ESRD) concluded that the adjusted hazard ratio for mortality in all patients was 2.27 (CI: 1.07 - 4.84, p = 0.03) for rs1801133(T;T) homozygotes, in other words, they died at about twice the rate of the other 2 genotypes over the time course of this study.[PMID 19272686]

In a case-control study of 152 cases (men) and 304 age-matched healthy controls conducted in one geographical area of Iran, evidence was seen that the MTHFR polymorphisms might contribute to increased clear cell renal cell carcinoma (CCRCC) risk in men. After controlling for confounding factors, a significant increase in CCRCC risk was found among carriers of the 677CT genotype compared with those with the 677CC genotype (odds ratio 2.21, 95% confidence interval 1.31-3.76), with a significant trend (P=0.014). Statistically significant odds ratios were also found in patients homozygous for MTHFR C677T, who have a 1.58-fold higher risk of developing CCRCC (95% confidence interval=1.21-2.44; P=0.024). Compared with the MTHFR 677CC genotype, the odds ratio (95% confidence interval) for the MTHFR 677TT genotype was 6.18 (95% confidence interval=4.75-8.34) for stage IV cancer and 4.68 (95% confidence interval=2.72-6.54) for grade 3 CCRCC (both P=0.0001). Clin Oncol (R Coll Radiol). 2012 May;24(4):269-81. doi: 10.1016/j.clon.2011.03.005. Epub 2011 Apr 13. [PMID 21489764]

[PMID 19648163OA-icon.png] A 2-year follow-up study of 122 newly diagnosed patients with acute lymphoblastic leukemia (ALL) found that carriers of a rs1801133(T) allele were at increased risk for hepatic toxicity from methotrexate treatment. Hepatic toxicity was increased ~2x and ~5x for heterozygous and homozygous rs1801133(T) genotypes, respectively (p=0.028). If a carrier of a rs1801133(T) allele was also a carrier of a rs70991108 deletion allele, the risk for hepatic toxicity was even higher (odds ratio 6.8, p=0.018).

Note: Another SNP in dbSNP, rs59514310, represents the same location as rs1801133.

10.1007/s00223-010-9361-4 rs1801133(T;T) post-menopausal women said to be at 2x higher risk for osteoporosis.

[PMID 27342765OA-icon.png] Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis.

[PMID 19332210OA-icon.png] Candidate genetic variants in the fibrinogen, methylenetetrahydrofolate reductase, and intercellular adhesion molecule-1 genes and plasma levels of fibrinogen, homocysteine, and intercellular adhesion molecule-1 among various race/ethnic groups: Data from the Women's Genome Health Study

[PMID 19336565] Folate Intake, Methylenetetrahydrofolate Reductase Polymorphisms, and Breast Cancer Risk in Women from the Malmo Diet and Cancer Cohort.

[PMID 19465420] MTHFR polymorphisms and 5-FU-based adjuvant chemotherapy in colorectal cancer

[PMID 19493349OA-icon.png] 118 SNPs of folate-related genes and risks of spina bifida and conotruncal heart defects

[PMID 19737740] Associations of folate and choline metabolism gene polymorphisms with orofacial clefts

[PMID 19746410] Association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age of onset in schizophrenia

[PMID 19744961OA-icon.png] Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway

[PMID 19759169] Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele

[PMID 20031128] Cardiorespiratory fitness modifies the association between the UCP3-55C>T (rs1800849) polymorphism and plasma homocysteine in Swedish youth

GWAS snp
PMID [PMID 20031578OA-icon.png]
Trait Plasma homocysteine
Title Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population: A Genome-Wide Evaluation of 13 974 Participants in the Women's Genome Health Study
Risk Allele A
P-val 8E-35
Odds Ratio 0.05 [NR] unit increase in log(homocysteine)

[PMID 20056627OA-icon.png] Genetic variability in the MTHFR gene and colorectal cancer risk using the colorectal cancer family registry

[PMID 20154341OA-icon.png] Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 n women and a stronger MTHFR effect in young adults

[PMID 20421849] Habituation in prepulse inhibition is affected by a polymorphism on the NMDA receptor 2B subunit gene (GRIN2B)

[PMID 19593234OA-icon.png] Association analyses suggest multiple interaction effects of the methylenetetrahydrofolate reductase polymorphisms on timing of menarche and natural menopause in white women

[PMID 20523222] MTHFR genotype and differential evolution of metabolic parameters after initiation of a second generation antipsychotic: an observational study

[PMID 20817226OA-icon.png] MTHFR polymorphisms in relation to ovarian cancer risk

[PMID 20863444] Associations between the genetic polymorphisms of MTHFR and outcomes of methotrexate treatment in rheumatoid arthritis

[PMID 20944139] Significant Association of Methylenetetrahydrofolate Reductase Single Nucleotide Polymorphisms with Prostate Cancer Susceptibility in Taiwan

[PMID 20946434] MTHFR 677C>T Polymorphism and Cluster Headache


[PMID 10930360OA-icon.png] MTHFR 677C→T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 1.91

Gene-wide association study between the methylenetetrahydrofolate reductase gene (MTHFR) and schizophrenia in the Japanese population, with an updated meta-analysis on currently available data. [PMID 20692813]

[PMID 21125565] Folate pathway and nonsyndromic cleft lip and palate

[PMID 21178087OA-icon.png] Polymorphisms in Serine Hydroxymethyltransferase 1 and Methylenetetrahydrofolate Reductase Interact to Increase Cardiovascular Disease Risk in Humans

[PMID 21210953] MTHFR polymorphisms and cognitive ageing in the ninth decade: the Lothian Birth Cohort 1921

[PMID 21254359OA-icon.png] Folate pathway and nonsyndromic cleft lip and palate

[PMID 21291465] The association of genetic polymorphisms with cerebral palsy: a meta-analysis

[PMID 21302350] rs1801133 shows no consistent association with schizophrenia overall in 12 studies totaling 3,000+ patients


[PMID 21567207] Tetra primer ARMS-PCR relates folate/homocysteine pathway genes and ACE gene polymorphism with coronary artery disease

[PMID 21635773OA-icon.png] Methylenetetrahydrofolate Reductase Gene Variant (MTHFR C677T) and Migraine: A Case Control Study and Meta-analysis

[PMID 21980405OA-icon.png] A Hypomethylating Variant of MTHFR, 677C>T, Blunts the Neural Response to Errors in Patients with Schizophrenia and Healthy Individuals

[PMID 22015309] MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction

[PMID 21429654] Polymorphic variants of folate and choline metabolism genes and the risk of endometriosis-associated infertility

[PMID 22044028] The C677T polymorphism in the MTHFR gene is associated with the toxicity of methotrexate in a Spanish rheumatoid arthritis population

[PMID 22103680OA-icon.png] Folate network genetic variation, plasma homocysteine, and global genomic methylation content: a genetic association study

[PMID 22144047OA-icon.png] A single-nucleotide polymorphism in the MTHFR (methylene tetrahydrofolate reductase) gene is associated with risk of radiation pneumonitis in lung cancer patients treated with thoracic radiation therapy

[PMID 22283972OA-icon.png] C677T and A1298C Polymorphisms of MTHFR Gene and Their Relation to Homocysteine Levels in Turner Syndrome

[PMID 21913742] Genetic predictors of response to photodynamictherapy

[PMID 22440940] The rs1801133 polymorphism of methylenetetrahydrofolate reductase gene- the association with 5-year survival in patients with ST-elevation myocardial infarction

[PMID 22363213OA-icon.png] Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias

[PMID 22457816OA-icon.png] Association of the MTHFR A1298C Variant with Unexplained Severe Male Infertility

[PMID 22649255OA-icon.png] Folate Network Genetic Variation Predicts Cardiovascular Disease Risk in Non-Hispanic White Males

[PMID 22648968OA-icon.png] Risk of retinoblastoma is associated with a maternal polymorphism in dihydrofolatereductase (DHFR) and prenatal folic acid intake

[PMID 22669161OA-icon.png] Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

[PMID 22707612OA-icon.png] Genetic Risk Factors for Thrombosis in Systemic Lupus Erythematosus

[PMID 11781870OA-icon.png] The frequent 5,10-methylenetetrahydrofolate reductase C677T polymorphism is associated with a common haplotype in whites, Japanese, and Africans.

[PMID 12384833OA-icon.png] A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group.

[PMID 14724163OA-icon.png] Analysis of candidate modifier loci for the severity of colonic familial adenomatous polyposis, with evidence for the importance of the N-acetyl transferases.

[PMID 17035141OA-icon.png] Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions.

[PMID 17107626OA-icon.png] Comparison of PrASE and Pyrosequencing for SNP Genotyping.

[PMID 17115239] MTHFR polymorphism and bone mineral density: meta-analysis of published studies.

[PMID 17119116OA-icon.png] Gene-nutrient interactions among determinants of folate and one-carbon metabolism on the risk of non-Hodgkin lymphoma: NCI-SEER case-control study.

[PMID 17301261] Dietary folate intake, MTHFR genetic polymorphisms, and the risk of endometrial cancer among Chinese women.

[PMID 17366837OA-icon.png] Genetic studies of a cluster of acute lymphoblastic leukemia cases in Churchill County, Nevada.

[PMID 17659576OA-icon.png] Genetic polymorphisms in the methylenetetrahydrofolate reductase and thymidylate synthase genes and risk of hepatocellular carcinoma.

[PMID 17697348OA-icon.png] Technology to accelerate pangenomic scanning for unknown point mutations in exonic sequences: cycling temperature capillary electrophoresis (CTCE).

[PMID 17712717] MTHFR C677T polymorphism and osteoporotic fractures.

[PMID 17903296OA-icon.png] Genome-wide association with bone mass and geometry in the Framingham Heart Study.

[PMID 18098291] Folate metabolism genes, vegetable intake and renal cancer risk in central Europe.

[PMID 18182569OA-icon.png] Pharmacogenetics of minimal residual disease response in children with B-precursor acute lymphoblastic leukemia: a report from the Children's Oncology Group.

[PMID 18191955OA-icon.png] Correlating observed odds ratios from lung cancer case-control studies to SNP functional scores predicted by bioinformatic tools.

[PMID 18199722] Dietary vitamin B6 intake and the risk of colorectal cancer.

[PMID 18203168OA-icon.png] Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts.

[PMID 18221821] Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population.

[PMID 18230680OA-icon.png] Choline metabolism and risk of breast cancer in a population-based study.

[PMID 18285546OA-icon.png] A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group.

[PMID 18339682OA-icon.png] Maternal and offspring genetic variants of AKR1C3 and the risk of childhood leukemia.

[PMID 18355300] The methylenetetrahydrofolate reductase 677C>T gene polymorphism is not associated with chronic plaque psoriasis.

[PMID 18454680OA-icon.png] Genetic basis for adverse events after smallpox vaccination.

[PMID 18513389OA-icon.png] New application of intelligent agents in sporadic amyotrophic lateral sclerosis identifies unexpected specific genetic background.

[PMID 18521744OA-icon.png] BRCA1 promoter methylation is associated with increased mortality among women with breast cancer.

[PMID 18538037OA-icon.png] A simple and accurate SNP scoring strategy based on typeIIS restriction endonuclease cleavage and matrix-assisted laser desorption/ionization mass spectrometry.

[PMID 18547414OA-icon.png] Genotyping panel for assessing response to cancer chemotherapy.

[PMID 18603647OA-icon.png] Functional genetic polymorphisms and female reproductive disorders: Part I: Polycystic ovary syndrome and ovarian response.

[PMID 18661527OA-icon.png] Folate-related gene polymorphisms as risk factors for cleft lip and cleft palate.

[PMID 18669903OA-icon.png] Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study.

[PMID 18708404OA-icon.png] B-vitamin intake, one-carbon metabolism, and survival in a population-based study of women with breast cancer.

[PMID 18708408OA-icon.png] Vitamins B2, B6, and B12 and risk of new colorectal adenomas in a randomized trial of aspirin use and folic acid supplementation.

[PMID 18715757OA-icon.png] Genetic associations with schizophrenia: meta-analyses of 12 candidate genes.

[PMID 18778477OA-icon.png] Genomic variation in myeloma: design, content, and initial application of the Bank On A Cure SNP Panel to detect associations with progression-free survival.

[PMID 18787887OA-icon.png] Genetic variation in candidate osteoporosis genes, bone mineral density, and fracture risk: the study of osteoporotic fractures.

[PMID 18830724OA-icon.png] Assessment of Alzheimer's disease case-control associations using family-based methods.

[PMID 18842806OA-icon.png] Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folate, homocysteine, and DNA uracil concentrations.

[PMID 18922824OA-icon.png] Genetic susceptibility to childhood leukaemia.

[PMID 18936436OA-icon.png] Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994.

[PMID 18988738OA-icon.png] MTHFR 677C --> T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val --> Met.

[PMID 18992148OA-icon.png] Low-penetrance alleles predisposing to sporadic colorectal cancers: a French case-controlled genetic association study.

[PMID 19048631OA-icon.png] Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study.

[PMID 19062539] [Genetic diversity and the structure of linkage disequilibrium in the methylenetetrahydrofolate reductase locus].

[PMID 19064578OA-icon.png] No association of single nucleotide polymorphisms in one-carbon metabolism genes with prostate cancer risk.

[PMID 19112534OA-icon.png] Lack of association of polymorphisms in homocysteine metabolism genes with pseudoexfoliation syndrome and glaucoma.

[PMID 19131662OA-icon.png] A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients.

[PMID 19190136OA-icon.png] Association of thymidylate synthase gene with endometrial cancer risk in a Chinese population.

[PMID 19193698OA-icon.png] Investigation of candidate polymorphisms and disease activity in rheumatoid arthritis patients on methotrexate.

[PMID 19263529OA-icon.png] Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach.

[PMID 19330901OA-icon.png] Association of 77 polymorphisms in 52 candidate genes with blood pressure progression and incident hypertension: the Women's Genome Health Study.

[PMID 19336559OA-icon.png] Global DNA hypomethylation (LINE-1) in the normal colon and lifestyle characteristics and dietary and genetic factors.

[PMID 19376481OA-icon.png] One-carbon metabolism and breast cancer: an epidemiological perspective.

[PMID 19421414OA-icon.png] Genetic variation in the methylenetetrahydrofolate reductase gene, MTHFR, does not alter the risk of visual failure in Leber's hereditary optic neuropathy.

[PMID 19427845] Diagnostic method validation: High resolution melting (HRM) of small amplicons genotyping for the most common variants in the MTHFR gene.

[PMID 19442614] Multiple osteoporosis susceptibility genes on chromosome 1p36 in Chinese.

[PMID 19525478OA-icon.png] Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study.

[PMID 19538716OA-icon.png] Thrombotic genetic risk factors and warfarin pharmacogenetic variants in Sao Miguel's healthy population (Azores).

[PMID 19559392OA-icon.png] A candidate gene association study of 77 polymorphisms in migraine.

[PMID 19587357OA-icon.png] A systematic meta-analysis of genetic association studies for diabetic retinopathy.

[PMID 19591822] Prevalence of genetic thrombophilic polymorphisms in the Sri Lankan population--implications for association study design and clinical genetic testing services.

[PMID 19657388OA-icon.png] Lack of association between genetic polymorphisms in enzymes associated with folate metabolism and unexplained reduced sperm counts.

[PMID 19693005OA-icon.png] Executive function, neural circuitry, and genetic mechanisms in schizophrenia.

[PMID 19700502] Synopsis and synthesis of candidate-gene association studies in chronic lymphocytic leukemia: the CUMAGAS-CLL information system.

[PMID 19706843OA-icon.png] Alcohol consumption and genetic variation in methylenetetrahydrofolate reductase and 5-methyltetrahydrofolate-homocysteine methyltransferase in relation to breast cancer risk.

[PMID 19706844] Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis.

[PMID 19776626OA-icon.png] Polymorphisms in methionine synthase, methionine synthase reductase and serine hydroxymethyltransferase, folate and alcohol intake, and colon cancer risk.

[PMID 19808787OA-icon.png] Genetics of human neural tube defects.

[PMID 19822020OA-icon.png] Genetic factors associated with intestinal metaplasia in a high risk Singapore-Chinese population: a cohort study.

[PMID 19841454OA-icon.png] Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture.

[PMID 19911060OA-icon.png] Persistence criteria for susceptibility genes for schizophrenia: a discussion from an evolutionary viewpoint.

[PMID 19930673OA-icon.png] Association between the methylenetetrahydrofolate reductase C677T polymorphism and hepatocellular carcinoma risk: a meta-analysis.

[PMID 20003265OA-icon.png] Extent of differential allelic expression of candidate breast cancer genes is similar in blood and breast.

[PMID 20065319] Interaction of methylenetetrahydrofolate reductase genotype and smoking habit in Taiwanese lung cancer patients.

[PMID 20078877OA-icon.png] Gene polymorphisms in association with emerging cardiovascular risk markers in adult women.

[PMID 20111745OA-icon.png] Gene-gene interactions in the folate metabolic pathway and the risk of conotruncal heart defects.

[PMID 20472929] Folate pathway enzyme gene polymorphisms and the efficacy and toxicity of methotrexate in psoriatic arthritis.

[PMID 20565774OA-icon.png] Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project.

[PMID 20661822] Evaluation of MTHFR677C>T polymorphism in prediction and prognosis of esophageal squamous cell carcinoma: a case-control study in a northern Indian population.

[PMID 20960050OA-icon.png] Dietary methyl donors, methyl metabolizing enzymes, and epigenetic regulators: diet-gene interactions and promoter CpG island hypermethylation in colorectal cancer.

[PMID 20962791] Methylenetetrahydrofolate reductase gene polymorphisms and cerebral palsy in Chinese infants.

[PMID 21211571] MTHFR and MTRR genotype and haplotype analysis and colorectal cancer susceptibility in a case-control study from the Czech Republic.

[PMID 21255267] MTHFR polymorphisms and cognitive ageing in the ninth decade: the Lothian Birth Cohort 1921.

[PMID 21349258] Folate and choline metabolism gene variants and development of uterine cervical carcinoma.

[PMID 21362212] [Detection of single nucleotide polymorphisms of mthfr and dpyd genes in leukemia cell lines K562 and K562/A02].

[PMID 21422408] Clotting factor gene polymorphisms and colorectal cancer risk.

[PMID 21461582] Lack of association between methylenetetrahydrofolate reductase genetic polymorphisms and postmenopausal breast cancer risk.

[PMID 21663380] Association between the MTHFR gene and Alzheimer's disease: a meta-analysis.

[PMID 21688148OA-icon.png] Polymorphic variants of genes involved in homocysteine metabolism in celiac disease.

[PMID 21819229] Methylenetetrahydrofolate reductase gene polymorphisms in Turkish children with attention-deficit/hyperactivity disorder.

[PMID 21897271] Analysis of 4 single-nucleotide polymorphisms in relation to cervical dysplasia and cancer development using a high-throughput ligation-detection reaction procedure.

[PMID 21931346] MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms.

[PMID 21960995OA-icon.png] Common variants of homocysteine metabolism pathway genes and risk of type 2 diabetes and related traits in Indians.

[PMID 22183302] Folate and choline metabolism gene variants in relation to ovarian cancer risk in the Polish population.

[PMID 22290307] Predictive index for the onset of medication overuse headache in migraine patients.

[PMID 22388795] Functional polymorphisms of folate metabolism and response to chemotherapy for colorectal cancer, a systematic review and meta-analysis.

[PMID 22424391OA-icon.png] MTHFR 677T Is a Strong Determinant of the Degree of Hearing Loss Among Polish Males with Postlingual Sensorineural Hearing Impairment.

[PMID 22495907OA-icon.png] Gene variants in the folate-mediated one-carbon metabolism (FOCM) pathway as risk factors for conotruncal heart defects.

[PMID 22540831] Candidate gene study of genetic thrombophilic polymorphisms in pre-eclampsia and recurrent pregnancy loss in Sinhalese women.

[PMID 23036708] Association of MTHFR and PPARγ2 genes polymorphism in relation to type 2 diabetes mellitus cases among north Indian population

[PMID 23076983OA-icon.png] Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age at onset of schizophrenia: No consistent evidence for an association in the nordic population

[PMID 23090267] The relationship between the C677T polymorphism of the MTHFR gene and serum levels of luteinizing hormone in males with erectile dysfunction

[PMID 23391848] OLR1 , PON1 and MTHFR Gene Polymorphisms, Conventional Risk Factors and the Severity of Coronary Atherosclerosis in a Chinese Han Population

[PMID 22957669OA-icon.png] Association of dietary and genetic factors related to one-carbon metabolism with global methylation level of leukocyte DNA

[PMID 23490201] C677T polymorphism of methylenetetrahydrofolate reductase may contribute to cervical cancer risk in complete over-dominant model

[PMID 22798153] Homocysteinylated protein levels in internal mammary artery (IMA) fragments and its genotype-dependence. S-homocysteine-induced methylation modifications in IMA and aortic fragments

[PMID 23631762OA-icon.png] Genotyping analysis and 18FDG uptake in breast cancer patients: a preliminary research

[PMID 23353103] COMT and MTHFR polymorphisms interaction on cognition in schizophrenia: an exploratory study

[PMID 23450474] [Influence of methylenetetrahydrofolate reductase gene polymorphisms on antidepressant response]

[PMID 23955684OA-icon.png] Lack of association of MTHFR rs1801133 polymorphism and CTCFL mutations with sperm methylation errors in infertile patients

Risk Rs1801133(T;T)
Alt Rs1801133(T;T)
Reference Rs1801133(C;C)
Significance Other
Disease MTHFR deficiency Gastrointestinal stromal tumor not provided cyclophosphamide response - Toxicity/ADR carboplatin response - Efficacy Neural tube defects methotrexate response - Dosage Neoplasm of stomach not specified
Variation info
CLNDBN MTHFR deficiency, thermolabile type Gastrointestinal stromal tumor not provided cyclophosphamide response - Toxicity/ADR carboplatin response - Efficacy Neural tube defects, folate-sensitive methotrexate response - Dosage, Efficacy, Toxicity/ADR Neoplasm of stomach not specified
Reversed 1
HGVS NC_000001.10:g.11856378G>A
CLNSRC HGMD OMIM Allelic Variant PharmGKB Clinical Annotation UniProtKB (protein)
CLNACC RCV000003697.6, RCV000144921.1, RCV000153516.4, RCV000211133.1, RCV000211336.1, RCV000259890.1, RCV000417131.1, RCV000427078.1, RCV000428048.1,

[PMID 24023947OA-icon.png] Methylenetetrahydrofolate reductase gene polymorphism and risk of type 2 diabetes mellitus

[PMID 23186985] Using Alzgene-like approaches to investigate susceptibility genes for vascular cognitive impairment

[PMID 24103477] Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G polymorphisms influence on leukocyte genomic DNA methylation level

[PMID 23401104] Folate-genetics and colorectal neoplasia: what we know and need to know next

[PMID 24380661] MTHFR C677T and A1298C polymorphisms and risk of nonsyndromic orofacial clefts in a south Indian population

[PMID 23484733] Association between polymorphisms in genes encoding methylenetetrahydrofolate reductase and the risk of Ménière's disease

GWAS snp
PMID [PMID 23824729OA-icon.png]
Trait Homocysteine levels
Title Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease.
Risk Allele A
P-val 4E-104
Odds Ratio .16 [0.14-0.17] unit increase

[PMID 22021659OA-icon.png] Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia.

[PMID 22052259OA-icon.png] MTHFR polymorphisms, folate intake and carcinogen DNA adducts in the lung.

[PMID 22579472] The IL6 gene polymorphism -634C>G and IL17F gene polymorphism 7488T>C influence bone mineral density in young and elderly Japanese women.

[PMID 22706675] Folic acid supplementation, MTHFR and MTRR polymorphisms, and the risk of childhood leukemia: the ESCALE study (SFCE).

[PMID 22847291] Population distribution of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C risk alleles for methotrexate toxicity in Israel.

[PMID 22890010] Association of COMT, MTHFR, and SLC19A1(RFC-1) polymorphisms with homocysteine blood levels and cognitive impairment in Parkinson's disease.

[PMID 22903727OA-icon.png] Maternal and infant gene-folate interactions and the risk of neural tube defects.

[PMID 22982411] No association between MTHFR C677T polymorphism and completed suicide.

[PMID 23054000] Genetic variants in metabolizing genes NQO1, NQO2, MTHFR and risk of prostate cancer: a study from North India.

[PMID 23107763] Host genetic risk factors for community-acquired pneumonia.

[PMID 23130019OA-icon.png] Frequencies of 23 functionally significant variant alleles related with metabolism of antineoplastic drugs in the chilean population: comparison with caucasian and asian populations.

[PMID 23175176OA-icon.png] Variation in PAH-related DNA adduct levels among non-smokers: the role of multiple genetic polymorphisms and nucleotide excision repair phenotype.

[PMID 23217001OA-icon.png] Association of MTHFR Ala222Val (rs1801133) polymorphism and breast cancer susceptibility: An update meta-analysis based on 51 research studies.

[PMID 23274712OA-icon.png] Genetic polymorphisms and the risk of myocardial infarction in patients under 45 years of age.

[PMID 23333443] Analysis of polymorphisms and haplotypes in genes associated with vascular tone, hypertension and oxidative stress in Mexican-Mestizo women with severe preeclampsia.

[PMID 23355348] Interactions of several single nucleotide polymorphisms and high body mass index on serum lipid traits.

[PMID 23591986] Influence of obesity on association between genetic variants identified by genome-wide association studies and hypertension risk in Chinese children.

[PMID 23648444] The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: a meta-analysis in patients with cancer.

[PMID 23649653] Association between MTHFR Ala222Val (rs1801133) polymorphism and bladder cancer susceptibility: a systematic review and meta-analysis.

[PMID 23661361] The potential effect of gender in CYP1A1 and GSTM1 genotype-specific associations with pediatric brain tumor.

[PMID 23773402OA-icon.png] Quantitative assessment of the association between MHTFR C677T (rs1801133, Ala222Val) polymorphism and susceptibility to bladder cancer.

[PMID 24801553OA-icon.png] Analysis of multiple genetic polymorphisms in aggressive-growing and slow-growing abdominal aortic aneurysms

[PMID 24908438] Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia

[PMID 25007187] Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia

[PMID 25010186OA-icon.png] Dissociable Genetic Contributions to Error Processing: A Multimodal Neuroimaging Study

[PMID 25007516] [Analysis of the effect of N5, N10-methylenetetrahydrofolate reductase gene C(677)-->T polymorphism on the ischemic stroke development in persons with various risk factors]

[PMID 25020710] P324Circadian genes in the regulation of lipids in coronary artery disease

[PMID 25039261] Association Study of MTHFD1 Coding Polymorphisms R134K and R653Q With Migraine Susceptibility

[PMID 25052622OA-icon.png] Maternal homocysteine in pregnancy and offspring birthweight: epidemiological associations and Mendelian randomization analysis

[PMID 25075036] Evaluation of the Contribution of Methylenetetrahydrofolate Reductase Genotypes to Taiwan Breast Cancer

[PMID 24274352] Green tea consumption and breast cancer risk in Japanese women: a case-control study

[PMID 25246760OA-icon.png] Plasma homocysteine and genetic variants of homocysteine metabolism enzymes in patients from central Greece with primary open-angle glaucoma and pseudoexfoliation glaucoma

[PMID 25599563] The MTHFR 677CC and GGH 401TT and CT genotype were associated with a reduction in the number of methotrexate-related adverse events in rheumatoid arthritic patients (Caucasian)

[PMID 25688352OA-icon.png] Genetic Association between Methylenetetrahydrofolate Reductase Gene Polymorphism and Risk of Osteonecrosis of the Femoral Head

[PMID 25808365] rs1801133C>T polymorphism in MTHFR is a risk factor for nonsyndromic cleft lip with or without cleft palate in the Brazilian population

[PMID 25102261] Maternal folate, alcohol and energy metabolism-related gene polymorphisms and the risk of recurrent pregnancy loss

[PMID 25909872] Association of the rs1801133 variant in the MTHFR gene and sporadic Parkinson's disease

[PMID 26022245] Functional Polymorphism rs13306560 of the MTHFR Gene Is Associated with Essential Hypertension in a Mexican-Mestizo Population

[PMID 24458267] MTHFR C677T genotype and cardiovascular risk in a general population without mandatory folic acid fortification

[PMID 26196053] Association between genetic polymorphisms in folate-related enzyme genes and infertile men with non-obstructive azoospermia

[PMID 25566964] Polymorphisms in the MTHFR gene are associated with breast cancer risk and prognosis in a Chinese population

[PMID 25520092] Lack of association between polymorphisms in genes MTHFR and MDR1 with risk of childhood acute lymphoblastic leukemia

[PMID 26303648] Association of vdr, cyp27b1, cyp24a1 and mthfr gene polymorphisms with oral lichen planus risk

[PMID 26314858] Influences of ERCC1, ERCC2, XRCC1, GSTP1, GSTT1, and MTHFR polymorphisms on clinical outcomes in gastric cancer patients treated with EOF chemotherapy

[PMID 26336903] Impact of MTHFR rs1801133, MTHFR rs1801131 and ABCB1 rs1045642 polymorphisms with increased susceptibility of rheumatoid arthritis in the West Algerian population: A case-control study

[PMID 26451011OA-icon.png] Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas

[PMID 26540672] Non-syndromic cleft lip with or without cleft palate in Asian populations: Association analysis on three gene polymorphisms of the folate pathway

[PMID 26579581] Genetic and environmental predictors of chronic kidney disease in patients with type 2 diabetes and diabetic foot ulcer: a pilot study

[PMID 26689687OA-icon.png] Associations of Polymorphisms in MTHFR Gene with the Risk of Age-Related Cataract in Chinese Han Population: A Genotype-Phenotype Analysis.

[PMID 26862484OA-icon.png] Polymorphisms of glutathione S-transferase and methylenetetrahydrofolate reductase genes in Moldavian patients with ulcerative colitis: Genotype-phenotype correlation.

[PMID 27097558] Polymorphisms in the MTHFR and MTR genes and the risk of varicose veins in ethnical Russians.

[PMID 28192769] Disorganization at the stage of schizophrenia clinical outcome: Clinical-biological study.

[PMID 28405167OA-icon.png] Genetic variants and increased risk of meningioma: an updated meta-analysis.

[PMID 29392422] Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China.

[PMID 29544444OA-icon.png] Significant association between ERCC2 and MTHR polymorphisms and breast cancer susceptibility in Moroccan population: genotype and haplotype analysis in a case-control study.

[PMID 29600437] CBS mutations and MTFHR SNPs causative of hyperhomocysteinemia in Pakistani children.

[PMID 29627528] The association between donor genetic variations in one-carbon metabolism pathway genes and hepatitis B recurrence after liver transplantation.

[PMID 30084051] Interaction of MTHFR gene with smoking and alcohol use and haplotype combination susceptibility to psoriasis in Chinese population.

[PMID 30213564] Clinical utility of ABCB1 genotyping for preventing toxicity in treatment with irinotecan.

[PMID 30542483OA-icon.png] NOX4 rs11018628 polymorphism associates with a decreased risk and better short-term recovery of ischemic stroke.

[PMID 30843750] Genetic variants linked to folliculogenesis and successful pregnancy are not associated with twin births in a twins' town.

[PMID 31115963] The implication of single-nucleotide polymorphisms in ovarian hyperstimulation syndrome.

[PMID 31418317] Association study of high-frequency variants of MTHFR gene with retinal vein occlusion in a Spanish population.

[PMID 31507426OA-icon.png] Discovery of Novel Biomarkers of Therapeutic Responses in Han Chinese Pemetrexed-Based Treated Advanced NSCLC Patients.

[PMID 32117640OA-icon.png] Single nucleotide polymorphism of MTHFR rs1801133 associated with elevated Hcy levels affects susceptibility to cerebral small vessel disease.

[PMID 32124929OA-icon.png] SNPs  in folate pathway are associated with the risk of nonsyndromic cleft lip with or without cleft palate, a meta-analysis.

[PMID 32295184OA-icon.png] MTHFR and VDR Polymorphisms Improve the Prognostic Value of MYCN Status on Overall Survival in Neuroblastoma Patients.

[PMID 32682401OA-icon.png] Association of ESR1 (rs2234693 and rs9340799), CETP (rs708272), MTHFR (rs1801133 and rs2274976) and MS (rs185087) polymorphisms with Coronary Artery Disease (CAD).

[PMID 33019481OA-icon.png] MTHFR polymorphisms (rs1801133) and systemic lupus erythematosus risk: A meta-analysis.

[PMID 33269075OA-icon.png] Associations of the MTHFR rs1801133 polymorphism with gastric cancer risk in the Chinese Han population.

[PMID 33574311OA-icon.png] Differences in MTHFR and LRRK2 variant's association with sporadic Parkinson's disease in Mexican Mestizos correlated to Native American ancestry.