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 38 annotations for this variant. Register or sign in to see them.
There are 3 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in MTHFR
The MTHFR:1298A>C was first identified in patients with [Neural Tube Defects|PA445095]with elevated Homocysteine that could not be completely explained by presence of a MTHFR:677C>T genotype, van der Put et al, 1998, [Article: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, (see Donnelly JG, 2000, [Article: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, [Article:12083967].
MTHFR:1298A has been shown in White (Caucasian) but not Black or African American (African-American) [Rheumatoid Arthritis|PA443434]patients to be associated with increased risk of methotrexate toxicity [Article:16439441]. In 98 White (French) [5-fluorouracil|PA128406956]treated [colorectal cancer|PA446108]patients, MTHFR:1298A>C polymorphism was significantly linked to specific survival, with homozygous mutated patients having the worst prognosis [Article:15608557]. However, in a different study of 94 White (Spanish) [5-fluorouracil|PA128406956]treated [colorectal cancer|PA446108]patients, MTHFR genotype could not be considered as an independent factor of outcome [Article:16187112]. Larger studies representing different populations are needed to determine the role of this polymorphism in patient responses to antifolates and antimetabolites.
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 (2)
|
| Diseases | Alzheimer Disease Arthritis, Rheumatoid Cardiovascular Diseases Cleft Lip Cleft Palate Down Syndrome Hyperhomocysteinemia Neoplasms Neural Tube Defects Pre-Eclampsia |
Appendix
| gp 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 |
| 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 [Article: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% | [Article: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% | [Article:16638790] | |||
| Taiwanese Breast Cancer Cases | Asian | Breast Neoplasms | 84% | 16% | 284 | 142 | 73.2% | 21.1% | 5.7% | [Article:16777985] | C protective | |
| Taiwanese Controls | Asian | 77% | 23% | 570 | 285 | 60.3% | 33.3% | 6.4% | [Article:16777985] | |||
| African American Rheumatoid Arthritis Cases | Black or African American | methotrexate | Arthritis, Rheumatoid | 86.6% | 13.4% | 276 | 138 | 74% | 25% | 1% | [Article: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% | [Article:16439441] | |||
| Caucasian Rheumatoid Arthritis Cases | White | methotrexate | Arthritis, Rheumatoid | 66.3% | 33.7% | 786 | 393 | 45% | 42% | 13% | [Article:16439441] | A allele was associated with MTX toxicity |
| Caucasian Rheumatoid Arthritis Controls | White | 69% | 31% | 100 | 50 | 50% | 38% | 12% | [Article:16439441] | |||
| Arab (95% Saudi Arabian) | White | 68.3% | 31.7% | 1022 | 511 | 46.8% | 43.1% | 10.2% | [Article:15111988] | |||
| West African (Coastal Togo, Savannah Togo and Coastal Benin) | Black or African American | 86.1% | 13.9% | 930 | 465 | NA | NA | 1.9% | [Article:16522920] | |||
| French | White | 64.3% | 35.7% | 732 | 366 | NA | NA | 11.5% | [Article:16522920] | |||
| Italian (Sicily) | White | 71.9% | 28.1% | 292 | 146 | NA | NA | 7.5% | [Article:16522920] | |||
| Mexican | Hispanic or Latino | 85.3% | 14.7% | 600 | 300 | NA | NA | 2.3% | [Article:16522920] |
Connected Drugs
Connected Diseases
Publications related to rs1801131 at chr1:11854476: 43
Cross-References
- UCSC Golden Path:
- chr1:11854476
- dbSNP:
- rs1801131
- ALFRED:
- SI003687Y
- HapMap:
- rs1801131
Platform Availability
- Affymetrix
- Illumina