Important Variant Information for MTHFR
Submitted by: Caroline F. Thorn (PharmGKB)
Reviewed by: Under Review
Submitted date: July 31, 2006
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There are Two Important Variants for MTHFR.
| Gene HGNC Name: | MTHFR |
|---|---|
| Variant Summary: | The MTHFR 677C>T variant was first discovered by Frosst et al, as being the causal variant for the thermolabile MTHFR protein [Frosst et al, 1995, PMID: 7647779 ].The thermolabile MTHFR protein is associated with 50% lower activity in vitro [Kang et al, 1991 PMID: 1998339]. It was the first genetic risk factor identified for Spina Bifida [reviewed in van der Linden et al, 2006, PMID: 16672082]. Although this SNP was initially reported to occur at nucleotide 677, and is commonly referred to as such in the literature, the actual location is at nucleotide 665 of the coding region if the A of the ATG start codon is considered position 1 [Donnelly JG, 2000, PMID: 10677336 and related letters]. It is occasionally referred to by the HinF1 restriction digest used for RFLP. There is a huge body of work on this variant, in association with a variety of drugs, phenotypes and diseases, and much of it is contradictory [reviewed in Schwann and Rozen, 2001, PMID: 12083967 and from a cardiovascular perspective by Lewis et al, 2005, PMID: 16216822]. It has been examined in a myriad of diseases including cardiovascular diseases, cancers and disorders of pregnancy and development and in the context of drugs such as methotrexate (both as chemotherapy and for inflammation), 5-fluorouracil and folic acid supplementation. In general, studies have found that the T allele is associated with higher total homocysteine than the C allele particularly in individuals with lower plasma folate. Together with the observations that the T allele is found at particularly high frequencies in Italian and Mexican populations, and at low frequencies in African populations this has led to the hypothesis that the T allele confers selective advantage under conditions of high dietary folic acid [Gueant-Rodriguez et al, 2006, PMID: 16522920]. For extracted information about frequencies in different populations see the table below. In studies of methotrexate-treated pediatric ALL patients, the T allele was associated with a lower probability of event free survival [PMID: 14647408; 15781665] but was not a risk factor for toxicity or seizures [PMID:12915598]. In White (Caucasian) Rheumatoid Arthritis patients treated with methotrexate, in one study the T allele was associated with adverse events [PMID: 11710708], but in another study of White (Caucasian) and Black or African American (African American) Rheumatoid Arthritis patients treated with methotrexate only the MTHFR:1298C>A variant, A allele was significant in Whites and rs4846051 C allele in Black or African American. In a study of 43 patients with metastatic colorectal adenocarcinoma treated with fluoropyrimidine-based chemotherapy, responders were more likely to carry the T allele than non-responders [PMID:12738713]. However, in a different study of 94 White (Spanish) 5-fluorouracil treated colorectal cancer patients, MTHFR genotype could not be considered as an independent factor of outcome [PMID: 16187112]. Some studies have shown that the T allele may be protective compared to the C allele in disease incidence [Colorectal Neoplasms, PMID: 16638790; Breast Neoplasms, PMID: 16777985]. Larger studies representing different populations are needed to determine the role of this polymorphism in response to antifolates and antimetabolites and to conclusively define its role in disease. |
| Key PubMed IDs: | 7647779; 1998339; 10677336; 12083967; 16216822, 16522920; 14647408; 15781665; 12915598; 16638790; 16777985; 16439441; 16538173; 11710708; 12738713; 16187112 |
| GoldenPath Position: | Chr1:11778965 (hg18) |
| mRNA Variant & GenBank ID: | C>T at 849 on NM_005957 |
| Protein Variant & GenBank ID: | Ala/Val at 222 on NP_005948.3 |
| dbSNP rs#: | rs1801133 |
| Key Drugs/Substrates: | 5-fluorouracil; folic acid; leukovorin; methotrexate |
| Key Phenotypes/Diseases: | Phenotypes: Folate, Homocysteine and Vitamin B12 in Young Healthy Individuals (PA134653669) - A particularly strong interaction was observed between the TT genotype and serum folate, which led to a high total plasma Homocysteine phenotype that was more pronounced in males. Homocysteine concentrations in leukemia patients (PA128747822) - observed no significant differences in plasma or CSF homocysteine levels or in toxicity based on the MTHFR: 677C>T genotype. Diseases: Hyperhomocysteinemia; Cardiovascular Diseases; Alzheimer Disease; Neural Tube defects; Down syndrome; Cleft Lip; Cleft Palate; Preeclampsia; Neoplasms; Rheumatoid Arthritis |
| Key Haplotypes | Linkage disequilibrium across the gene is very different in 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]. |
Frequency Table
| Population Reported | Population OMB | drug | disease | % C Allele |
% T Allele |
number of chromosomes | number of samples | % CC | % heterozygote | % TT | PMID | notes |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Swedish Colorectal Cancer Cases | White | Colorectal Neoplasms | 75.2% |
24.8% | 440 | 220 | 55.9% | 38.6% | 5.5% | 16638790 | T allele protective | |
| Swedish Colorectal Cancer Controls | White | 70.5% |
29.5% | 830 | 415 | 51.1% | 38.8% |
10.1% | 16638790 | |||
| Taiwanese Breast Cancer Cases | Asian | Breast Neoplasms | 69% |
31% | 284 | 142 | 51.4% | 35.9% | 12.7% | 16777985 | T allele protective | |
| Taiwanese Controls |
Asian | 67% |
33% | 570 | 285 | 46.3% | 42.1% | 11.6% | 16777985 |
|||
| African American Rheumatoid Arthritis Cases | Black or African American | methotrexate |
Arthritis, Rheumatoid | 88.8% |
11.2% | 276 | 138 | 79% | 20% | 1% | 16439441 | No effect of this SNP on methotrexate (MTX) efficacy or toxicity in this study, rs4846051 C allele was associated with MTX toxicity |
| African American Rheumatoid Arthritis Controls |
Black or African American |
86.5% | 13.5% | 104 |
52 | 75% | 23% | 2% | 16439441 |
|||
| Caucasian Rheumatoid Arthritis Cases |
White | methotrexate | Arthritis, Rheumatoid |
69.8% | 30.2% | 786 | 393 | 50% | 40% | 10% | 16439441 |
No effect of this SNP on methotrexate (MTX) efficacy or toxicity in this study, MTHFR:1298C>A variant, A allele was associated with MTX toxicity |
| Caucasian Rheumatoid Arthritis Controls |
White | 72% | 28% | 100 | 50 | 50% | 44% | 6% | 16439441 |
|||
| Guayami Tribe (Costa Rican Amerindian) | American Indian or Alaska Native | 17.8% | 82.2% | 314 | 157 | 5.73% |
24.2% |
70.07% |
14689519 | |||
| Huetar Tribe (Costa Rican Amerindian) | American Indian or Alaska Native | 39.5% | 60.5% | 306 | 153 | 13.73% |
51.63% |
34.69% |
14689519 |
Not in Hardy Weinberg equilibrium |
||
| South Asian Canadian |
Asian | 82.9% | 17.1% |
572 | 286 |
70.3% |
25.2% | 4.2% |
15380460 | |||
| Chinese Canadian |
Asian | 77.3% | 22.6% | 552 | 276 |
62.05 |
30.8% | 7.2% |
15380460 |
|||
| European Canadian | White | 65.6% |
34.4% | 526 | 263 |
42.6% |
46.0% | 11.4% | 15380460 |
|||
| Arab (95% Saudi Arabian) |
White | 85.1% | 14.9% | 1022 | 511 | 72.8% | 24.7% | 2.5% | 15111988 | |||
| West African (Coastal Togo, Savannah Togo and Coastal Benin) |
Black or African American | 91.0% | 9.0% | 930 | 465 | NA | NA | 0.8% | 16522920 | |||
| French | White | 63.9% | 36.1% | 732 | 366 | NA | NA | 14.2% | 16522920 |
|||
| Italian (Sicily) |
White | 52.7% | 47.3% | 292 | 146 | NA | NA | 19.9% | 16522920 |
|||
| Mexican | Hispanic or Latino |
42.0% | 58.0% | 600 | 300 | NA | NA | 35.7% | 16522920 |
| Gene HGNC Name: | MTHFR |
|---|---|
| Variant Summary | The MTHFR:1298A>C was first identified in patients with Neural Tube Defects with elevated Homocysteine that could not be completely explained by presence of a MTHFR:677C>T genotype [van der Put et al, 1998, PMID: 9545395]. They did not observe any C alleles in individuals who were MTHFR:677C>T homozygous TT, suggesting that these variants arose independently and that there is linkage disequilibrium in the White (Dutch) populations tested. In other populations the haplotype structure is different (see below). As with MTHFR:677C>T, the naming of the variant is confusing and the actual location is at nucleotide 1289 of the coding region if the A of the ATG start codon is considered position 1, although the variant is consistently described as 1298A>C in the literature [Donnelly JG, 2000, PMID: 10677336 and related letters]. MTHFR:1298A>C has been examined with respect to many diseases including Hyperhomocysteinemia, Cardiovascular Diseases, Alzheimer Disease, Neural Tube defects, and Neoplasms with some studies showing an effect of the polymorphisms and others finding no significance [reviewed in Schwan and Rozen, 2001, PMID:12083967]. MTHFR:1298A has been shown in White (Caucasian) but not Black or African American (African-American) Rheumatoid Arthritis patients to be associated with increased risk of methotrexate toxicity [PMID: 16439441]. In 98 White (French) 5-fluorouracil treated colorectal cancer patients, MTHFR:1298A>C polymorphism was significantly linked to specific survival, with homozygous mutated patients having the worst prognosis [PMID: 15608557]. However, in a different study of 94 White (Spanish) 5-fluorouracil treated colorectal cancer patients, MTHFR genotype could not be considered as an independent factor of outcome [PMID: 16187112]. Larger studies representing different populations are needed to determine the role of this polymorphism in patient responses to antifolates and antimetabolites. |
| Key PubMed IDs: | 12083967; 9545395; 10677336; 16439441; 15608557; 16187112; 16638790; 16777985; 16439441; 15111988; 16522920 |
| GoldenPath Position: | chr1:11777063 (hg18) |
| mRNA Variant & GenBank ID: | A>C at 1470 on NM_005957 |
| Protein Variant & GenBank ID: | Glu/Ala at 429 on NP_005948.3 |
| dbSNP rs#: | rs1801131 |
| Key Drugs/Substrates: | folic acid; methotrexate; |
| Key Phenotypes/Disease: | Hyperhomocysteinemia; Cardiovascular Diseases; Alzheimer Disease; Neural Tube defects; Down syndrome; Cleft Lip; Cleft Palate; Preeclampsia; Neoplasms; Rheumatoid Arthritis |
| Key Haplotypes | Linkage disequilibrium across the gene is very different in 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]. |
Frequency Table
| Population Reported | Population OMB | drug | disease | % A Allele |
% C Allele |
number of chromosomes | number of samples | % AA | % heterozygote | % CC | PMID | notes |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Colorectal Cancer Cases | White | Colorectal Neoplasms | 62.0% |
38.0% | 440 | 220 | 38.6% | 46.8% | 14.5% | 16638790 | CC genotype increased disease risk after adjustment for BMI, smoking, alcohol and physical activity |
|
| Swedish Controls | White | 66.9% |
33.1% | 824 | 412 | 45.9% | 42.0% | 12.1% | 16638790 | |||
| Taiwanese Breast Cancer Cases | Asian | Breast Neoplasms | 84% |
16% | 284 | 142 | 73.2% |
21.1% | 5.7% | 16777985 | C protective | |
| Taiwanese Controls |
Asian | 77% |
23% | 570 | 285 | 60.3% | 33.3% | 6.4% | 16777985 |
|||
| African American Rheumatoid Arthritis Cases | Black or African American | methotrexate |
Arthritis, Rheumatoid | 86.6% |
13.4% | 276 | 138 | 74% | 25% | 1% | 16439441 |
No effect of this SNP on methotrexate (MTX) efficacy or toxicity in this study, rs4846051 C allele was associated with MTX toxicity |
| African American Rheumatoid Arthritis Controls |
Black or African American |
83% | 17% | 106 |
53 | 68% | 30% | 2% | 16439441 |
|||
| Caucasian Rheumatoid Arthritis Cases |
White | methotrexate |
Arthritis, Rheumatoid |
66.3% | 33.7% | 786 | 393 | 45% | 42% | 13% | 16439441 |
A allele was associated with MTX toxicity |
| Caucasian Rheumatoid Arthritis Controls |
White | 69% | 31% | 100 | 50 | 50% | 38% | 12% | 16439441 |
|||
| Arab (95% Saudi Arabian) |
White | 68.3% | 31.7% | 1022 | 511 | 46.8% | 43.1% | 10.2% | 15111988 | |||
| West African (Coastal Togo, Savannah Togo and Coastal Benin) |
Black or African American | 86.1% | 13.9% | 930 | 465 | NA | NA | 1.9% | 16522920 | |||
| French | White | 64.3% | 35.7% |
732 | 366 | NA | NA | 11.5% | 16522920 |
|||
| Italian (Sicily) |
White | 71.9% | 28.1% |
292 | 146 | NA | NA | 7.5% | 16522920 |
|||
| Mexican | Hispanic or Latino |
85.3% | 14.7% | 600 | 300 | NA | NA | 2.3% | 16522920 |