Annotated PGx Gene Information for MTHFR
Submitted by: Caroline F. Thorn (PharmGKB)
Reviewed by: Under Review
Submitted date: July 31, 2006
- Jump To:
- Important Variants
- All Annotated Genes
| Gene HGNC Name: | MTHFR |
|---|---|
| Introductory Information: | MTHFR lies at the intersection of the pathways for methylation and DNA synthesis. It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the substrate for conversion of homeocysteine to methionine. Methionine is then converted to the universal methyl donor, S-adenosylmethionine (AdoMet, SAM) which is used for methylation of DNA and proteins. 5,10-methylenetetrahydrofolate is the substrate for de novo purine synthesis (DNPS). The MTHFR gene is comprised of 11 exons with at least two splice variants [Gaughan et al, 2000 PMID: 11080594; Tran et al, 2002, PMID: 12370778]. There are several documented variants in MTHFR (data are available on 65 variants at PharmGKB), with the majority of pharmacogenomic studies looking at MTHFR: 677C>T and MTHFR: 1298C>A. Allele frequencies vary greatly between different racial and ethnic groups and there are over 20 haplotypes that are differentially represented in White (Caucasian), Black or African American (African American), Asian (Han Chinese-American) and Hispanic or Latino (Mexican American) populations [Martin et al, 2006, PMID: 16538173]. Given the role of MTHFR in DNA synthesis, it is part of pathways that are acted on by several chemotherapeutic antineoplastic and antirheumatic drugs, such as methotrexate and 5-fluorouracil, although none act directly on the MTHFR protein [reviewed in Innocenti and Ratain, 2002 PMID: 11916544 and Maring et al, 2005 PMID: 16041392]. MTHFR is also of interest to the nutrigenomics community and there are many studies on the interactions between dietary folate, MTHFR variation and disease development. MTHFR: 677C>T was the first reported risk factor for Neural Tube Defects [reviewed in van der Linden et al, 2006, PMID: 16672082]. There are many studies on cancer incidence and MTHFR, often with conflicting results [reviewed in Schwann and Rozen, 2001, PMID: 12083967]. Due to its relationship with homocysteine, there is also relevance for cardiovascular diseases. While severe deficiencies in MTHFR result in hyperhomocysteinurea, cardiovascular disease and mental retardation (OMIM: 607093), there is still some debate as to whether the common genetic variants are important risk factors for cardiovascular disease [reviewed in Lewis et al, 2005, PMID: 16216822]. Data regarding the MTHFR gene, its variants and its interaction with folic acid are important from the ethical, legal and social aspects of folate supplementation; the decision in the USA to supplement and in Europe not to supplement. Folic acid is also one of the proposed components of the Polypill, a combination of cardio-beneficial medications, which may prove controversial given the recent conflicts of evidence. |
| Key PubMed IDs: | 11080594; 12370778; 16538173 |
| Reviews: | 11916544; 16041392; 16216822; 12083967; 16672082 |
| Key Pathways: | Methotrexate Pathway; Thiopurine Pathway; 5-flurouracil (in development) |
| Drugs/Substrates: | folic acid; methotrexate; 5-fluorouracil; azathioprine; 6-mercaptopurine |
| Phenotypes/Diseases: | Phenotypes: Folate, Homocysteine and Vitamin B12 in Young Healthy Individuals (PA134653669); Homocysteine concentrations in leukemia patients (PA128747822) Diseases: Hyperhomocysteinemia; Cardiovascular Diseases; Alzheimer Disease; Neural Tube defects; Down syndrome; Cleft Lip; Cleft Palate; Preeclampsia; Neoplasms; Rheumatoid Arthritis |
| Important Variants | MTHFR:677C>T, MTHFR:1298A>C |