Clinical Annotations
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Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
There are 55 annotations for this variant. Register or sign in to see them.
There are 15 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in MTHFR
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, [Article:7647779]. The thermolabile MTHFR protein is associated with 50% lower activity in vitro, Kang et al, 1991 [Article:1998339]. It was the first genetic risk factor identified for Spina Bifida, reviewed in van der Linden et al, 2006, [Article: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, [Article: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, [Article:12083967] and from a cardiovascular perspective by Lewis et al, 2005, [Article: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|PA128406956]and [folic acid|PA449692]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, [Article: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 [Articles:14647408, 15781665] but was not a risk factor for toxicity or seizuresPMID:12915598. In White (Caucasian) Rheumatoid Arthritis patients treated with methotrexate, in one study the T allele was associated with adverse events [Article:11710708], but in another study of White (Caucasian) and Black or African American (African American) [Rheumatoid Arthritis|PA443434]patients treated with methotrexate only the MTHFR:1298C>A variant, A allele was significant in Whites and [rs4846051|http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=4846051] C allele in Black or African American. In a study of 43 patients with metastatic [colorectal adenocarcinoma|PA446108]treated with fluoropyrimidine-based chemotherapy, responders were more likely to carry the T allele than non-responders [Article:12738713]. However, in a different study of 94 White (Spanish) [5-fluorouracil|PA128406956]treated colorectal cancer patients, MTHFR genotype could not be considered as an independent factor of outcome [Article:16187112]. Some studies have shown that the T allele may be protective compared to the C allele in disease incidence [Colorectal Neoplasms, [Article:16638790]; Breast Neoplasms, [Article: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.
Note: The MTHFR gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
| Key Publications: | |
|---|---|
| Drugs / Other Molecules |
Drug (3)
|
| Diseases | Alzheimer Disease Arthritis, Rheumatoid Cardiovascular Diseases Cleft Lip Cleft Palate Down Syndrome Hyperhomocysteinemia Neoplasms Neural Tube Defects Pre-Eclampsia |
Appendix
MTHFR:677C>T
| gp 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 |
| 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, [Article: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% | [Article:16638790] | T allele protective |
| Swedish Colorectal Cancer Controls | White | | 70.5% | 29.5% | 830 | 415 | 51.1% | 38.8% | 10.1% | [Article:16638790] | ||
| Taiwanese Breast Cancer Cases | Asian | Breast Neoplasms | 69% | 31% | 284 | 142 | 51.4% | 35.9% | 12.7% | [Article:16777985] | T allele protective | |
| Taiwanese Controls | Asian | 67% | 33% | 570 | 285 | 46.3% | 42.1% | 11.6% | [Article:16777985] | |||
| African American Rheumatoid Arthritis Cases | Black or African American | methotrexate | Arthritis, Rheumatoid | 88.8% | 11.2% | 276 | 138 | 79% | 20% | 1% | [Article:16439441] | No effect of this SNP on methotrexate (MTX) efficacy or toxicity in this study, rs4846051C allele was associated with MTX toxicity |
| African American Rheumatoid Arthritis Controls | Black or African American | 86.5% | 13.5% | 104 | 52 | 75% | 23% | 2% | [Article:16439441] | |||
| Caucasian Rheumatoid Arthritis Cases | White | methotrexate | Arthritis, Rheumatoid | 69.8% | 30.2% | 786 | 393 | 50% | 40% | 10% | [Article: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% | [Article:16439441] | |||
| Guayami Tribe (Costa Rican Amerindian) | American Indian or Alaska Native | 17.8% | 82.2% | 314 | 157 | 5.73% | 24.2% | 70.07% | [Article:14689519] | |||
| Huetar Tribe (Costa Rican Amerindian) | American Indian or Alaska Native | 39.5% | 60.5% | 306 | 153 | 13.73% | 51.63% | 34.69% | [Article:14689519] | Not in Hardy Weinberg equilibrium | ||
| South Asian Canadian | Asian | 82.9% | 17.1% | 572 | 286 | 70.3% | 25.2% | 4.2% | [Article:15380460] | |||
| Chinese Canadian | Asian | 77.3% | 22.6% | 552 | 276 | 62.05% | 30.8% | 7.2% | [Article:15380460] | |||
| European Canadian | White | 65.6% | 34.4% | 526 | 263 | 42.6% | 46.0% | 11.4% | [Article:15380460] | |||
| Arab (95% Saudi Arabian) | White | 85.1% | 14.9% | 1022 | 511 | 72.8% | 24.7% | 2.5% | [Article:15111988] | |||
| West African (Coastal Togo, Savannah Togo and Coastal Benin) | Black or African American | 91.0% | 9.0% | 930 | 465 | NA | NA | 0.8% | [Article:16522920] | |||
| French | White | 63.9% | 36.1% | 732 | 366 | NA | NA | 14.2% | [Article:16522920] | |||
| Italian (Sicily) | White | 52.7% | 47.3% | 292 | 146 | NA | NA | 19.9% | [Article:16522920] | |||
| Mexican | Hispanic or Latino | 42.0% | 58.0% | 600 | 300 | NA | NA | 35.7% | [Article:16522920] |
Connected Drugs
Connected Drug Classes
| Evidence | Drug Class |
|---|---|
| Clinical Annotation, Variant Annotation | antipsychotics |
Connected Diseases
Publications related to rs1801133 at chr1:11856378: 57
Cross-References
- UCSC Golden Path:
- chr1:11856378
- dbSNP:
- rs1801133
- ALFRED:
- SI001032G
- HapMap:
- rs1801133
- JSNP:
- IMS-JST071013
Platform Availability
- Affymetrix
- Illumina