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Methotrexate

Raw research findings for this medication. Mostly single studies, not curated or confirmed robust.

About Methotrexate

What it is

Methotrexate is an antifolate: it blocks the enzyme dihydrofolate reductase, which cells need to use folate for making DNA. At high doses it is a chemotherapy medicine for leukaemia, lymphoma and other cancers; at low weekly doses it calms the immune system and is a mainstay treatment for rheumatoid arthritis, psoriasis and other inflammatory conditions. It is sold as Trexall, Otrexup and other names; MTX is its short name.

How genes come into it

Methotrexate touches many genes of the folate pathway, and over 400 studies have looked at them. The most studied are MTHFR, whose common variant rs1801133 (C677T) lowers the enzyme's activity, linked in some studies to more side effects; SLC19A1, the carrier that takes methotrexate into cells; ATIC; and SLCO1B1 and ABCG2, which affect how fast high-dose methotrexate is cleared. The findings are often inconsistent between studies, and there is no CPIC or DPWG guideline.

What research found

Every published finding on gene variants and Methotrexate. Upload your DNA file to see which of these rows apply to you.

Rated evidence (175 rated variants)

PharmGKB weighs all studies of a variant and rates how strong the evidence is, from 1A (strongest) to 4.

MTHFR rs1801133: Level 2A · replicated. Toxicity: Acute lymphoblastic leukemia, Drug Toxicity, Leukopenia, Lymphoma, Mucositis, Myelosuppression, Neoplasms, Neutropenia, Osteosarcoma, Primary central nervous system lymphoma, Thrombocytopenia, Toxic liver disease. 32.

MTHFR rs1801133: Level 2A · replicated. Toxicity: Arthritis, Psoriatic, Drug Toxicity, Juvenile Rheumatoid Arthritis, Rheumatoid arthritis. 12.

SLC19A1 rs1051266: Level 2A · replicated. Efficacy: Rheumatoid arthritis. 9.

ATIC rs4673993: Level 2B · replicated. Efficacy: Rheumatoid arthritis. 5.

Metabolism (182 findings)

Studies of how quickly the body processes this medication.

ABCB1 rs1045642: Genotype AA is associated with increased concentrations of methotrexate in people with Burkitt Lymphoma, Lymphoma, T-Cell and Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype GG.

ABCB1 rs1045642: Genotype AG is associated with increased concentrations of methotrexate in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype GG.

ABCB1 rs9282564: Allele C is associated with increased concentrations of methotrexate in children with as compared to allele T.

ABCC2 rs3740066: Genotype TT is associated with decreased concentrations of methotrexate in children with Osteosarcoma as compared to genotypes CC + CT.

Response (222 findings)

Studies of how well it worked in people carrying a variant.

rs1232027: Allele A is associated with increased response to methotrexate in people with Arthritis, Psoriatic as compared to allele G.

ABCB1 rs1045642: Genotype AA is associated with decreased response to methotrexate in people with Arthritis, Rheumatoid as compared to genotypes AG + GG.

ABCB1 rs1045642: Genotype AA is associated with increased response to methotrexate in children with Arthritis, Juvenile Rheumatoid as compared to genotypes AG + GG.

ABCB1 rs1045642: Genotype GG is associated with increased response to methotrexate in people with Arthritis, Rheumatoid as compared to genotypes AA + AG.

Dosing (14 findings)

Studies of how much of the drug people needed or tolerated.

SLCO1B1 rs4149056: Genotypes CC + CT is associated with decreased dose of mercaptopurine or methotrexate in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype TT.

ABCC4 rs146708960: Genotype CT is not associated with dose of mercaptopurine or methotrexate in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype CC.

ABCC4 rs3765534: Genotype CC is not associated with dose of mercaptopurine or methotrexate in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotype CT.

IMPDH2 rs11706052: Genotype AA is not associated with dose of mercaptopurine or methotrexate in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes AG + GG.

Side effects (37 findings)

Studies of side effects in people carrying a variant.

ABCC2 rs717620: Genotypes CT + TT is associated with decreased discontinuation of methotrexate in people with Arthritis, Rheumatoid as compared to genotype CC.

ATIC rs16853826: Genotype GG is associated with increased discontinuation of methotrexate in people with Arthritis, Rheumatoid as compared to genotypes AA + AG.

GGH rs11545078: Genotypes AA + AG is associated with increased discontinuation of methotrexate in people with Arthritis, Rheumatoid as compared to genotype GG.

MTHFR rs1801133: Genotype AA is associated with decreased response to methotrexate in people with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to genotypes AG + GG.

Other findings (8 findings)

Studies that do not fall into the groups above.

FOXP3 rs3761548: Allele G is associated with decreased response to methotrexate in people with Psoriasis as compared to allele T.

SLC19A1 rs1131596: Allele G is not associated with response to methotrexate in people with Arthritis, Rheumatoid.

HLA-G rs371194629: Genotype del/del is not associated with increased response to methotrexate in people with Arthritis, Rheumatoid.

IL12B rs3212227: Allele G is not associated with response to methotrexate in people with Psoriasis as compared to allele T.

Study findings and evidence levels: PharmGKB (CC BY-SA 4.0). Guidelines: CPIC and DPWG, as bundled in PharmCAT. Most studies were done mainly in people of European ancestry.

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Not a prescribing recommendation. This page is educational information about pharmacogenomic research and clinical guidelines - it is not medical or dosing advice, and not a prediction of how any medication will work for you. Never start, stop, or change a medication or dose based on it; talk to your doctor or pharmacist, who can order clinical-grade testing if appropriate.

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Content updated September 2026.

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