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Overview
| Generic Names: | Amethopterin; Amethopterine; HDMTX; L-Amethopterin; MTX; Methopterin; Methotextrate; Methotrexat; Methotrexate Sodium; Methylaminopterin; Methylaminopterinum; N-Bismethylpteroylglutamic Acid |
|---|---|
| Trade Names: | Abitrexate; Antifolan; Arbitrexate; Emtexate; Folex; Ledertrexate; Metatrexan; Methotrate; Mexate; Rheumatrex; Trexall |
| PharmGKB Accession Id: | PA450428 |
Description
An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. PubChem (source: Drug Bank)
Indication
For the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Also for the treatment of severe psoriasis and severe, active, classical or definite rheumatoid arthritis. (source: Drug Bank)
ATC Therapeutic Categories
- L01BA:Folic acid analogues
- L04AX:Other immunosuppressants
Pharmacology, Interactions, and Contraindications
Mechanism Of Action
Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known. (source: Drug Bank)
Pharmacology
Methotrexate is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines and at one stage in the synthesis of pyrimidines, one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Methotrexate selectively affects the most rapidly dividing cells (neoplastic and psoriatic cells). Methotrexate is also indicated in the management of severe, active, classical, or definite rheumatoid arthritis. (source: Drug Bank)
Food Interactions
Milk appears to reduce its absorption.
Take without regard to meals. Limit caffeine intake.
(source:
Drug Bank)
Absorption, Distribution, Metabolism, Elimination & Toxicity
Biotransformation
Hepatic. (source: Drug Bank)
Protein Binding
50%, primarily to albumin (source: Drug Bank)
Absorption
Generally well absorbed with a mean bioavailability of about 60%. (source: Drug Bank)
Toxicity
Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity. LD<sub>50</sub>=43mg/kg(orally in rat). (source: Drug Bank)
Isomeric SMILES Code:
CN(Cc1cnc2c(n1)c(nc(n2)N)N)c3ccc(cc3)C(=O)NC(CCC(=O)O)C(=O)O (source: Drug Bank)
In-Depth Annotations (
)
-
rs1801131
at chr1:11777063
in
MTHFR
Well studied, associated with multiple phenotypes.- Variant Name:
- MTHFR:1298A>C
- Related Drugs:
- folic acid, methotrexate
- Evidence:
-
http://www.pharmgkb.org/.../variant.jsp
-
rs1801133
at chr1:11778965
in
CLCN6,
MTHFR
Well studied, associated with multiple phenotypes.- Variant Name:
- MTHFR:677C>T
- Related Drugs:
- fluorouracil, folic acid, methotrexate
- Evidence:
-
http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforMTHFR-677CT
-
rs34743033
at chr18:647646
in
C18orf56,
TYMS
A polymorphic tandem repeat in the 5'UTR of the TYMS enhancer region (TSER) resulting in from 2 (TSER*2) up to 9 (TSER*9) copies of a 28bp repeated sequence has been identified. Data suggests that increased number of repeats increase TYMS RNA and protein expression. Several studies have identified links between TSER genotype (predominantly TSER*2 and *3) and response to chemotherapy.- Variant Name:
- TYMS: 28 bp tandem repeat
- Related Drugs:
- fluorouracil, methotrexate
- Evidence:
-
http://www.pharmgkb.org/.../variant.jsp
-
rs34489327
at chr18:663451
in
ENOSF1,
TYMS
This SNP is a 6bp deletion 447bp downstream of the TYMS transcription stop codon. Data suggests that this deletion alters TYMS mRNA stability.- Variant Name:
- TYMS:1494del TTAAAG
- Related Drugs:
- fluorouracil, methotrexate
- Evidence:
-
http://www.pharmgkb.org/.../variant.jsp
-
rs1051266
at chr21:45782222
in
SLC19A1
Functional effects have been observed in vitro.- Variant Name:
- SLC19A1:Arg27His
- Related Drugs:
- methotrexate, raltitrexed
- Evidence:
-
http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforSLC19A1-Arg27His
Curated Annotations (
)
-
rs4846051
at chr1:11777044
in
MTHFR
The C allele of this variant was associated with increased risk of toxicity in African American Rheumatoid Arthritis patients receiving methotrexate.- Variant Name:
- MTHFR:Phe435PHE; MTHFR:1317T>C
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:16439441
-
rs1801131
at chr1:11777063
in
MTHFR
At 6 months methotrexate and folic acid therapy, of early rheumatoid arthritis patients with the MTHFR 1298AA genotype showed good improvement relative to combined CA and AA genotypes (OR 2.3), while 1298C allele carriers developed more adverse drug events (OR 2.5) (e.g. pneumonitis, gastrointestinal ADEs, skin and mucosal ADEs, and elevated liver enzyme levels). Patients with MTHFR 1298AA / 677CC diplotype showed greater clinical improvement.- Variant Name:
- MTHFR:1298A>C
- Related Drugs:
- folic acid, methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:16572443
-
rs1801131
at chr1:11777063
in
MTHFR
In 330 patients who completed 3 months methotrexate treatment for psoriasis, no significant genotypic associations were found between clinical outcome (e.g. efficacy, toxicity) and 50 SNPs in pathway genes for methotrexate metabolism (ATIC, FPGS, GGH, MTHFR), including 47 common ( >5% minor allele frequency) haplotype-tagging SNPs (r(2) > 0.8) plus 3 additional SNPs.- Variant Name:
- MTHFR:298A>C
- Related Drugs:
- folic acid, methotrexate
- Related Diseases:
- Psoriasis
- Evidence:
-
PMID:19016697
-
rs1801133
at chr1:11778965
in
CLCN6,
MTHFR
This variant is associated with methotrexated-induced alopecia in African Americans with rheumatoid arthritis.- Variant Name:
- MTHFR: 677 C > T
- Related Drugs:
- methotrexate
- Related Diseases:
- Alopecia, Arthritis, Rheumatoid, Drug Toxicity
- Evidence:
-
PMID:18381794
-
rs1801133
at chr1:11778965
in
CLCN6,
MTHFR
This variant is associated with methotrexated-induced mucositis, thrombocytopenia and hepatic toxicity- Variant Name:
- MTHFR: 677 C > T
- Related Drugs:
- methotrexate
- Related Diseases:
- Drug Toxicity, Thrombocytopenia
- Evidence:
-
PMID:17488658
-
rs1801133
at chr1:11778965
in
CLCN6,
MTHFR
Given methotrexate and folic acid therapy, patients with the MTHFR 1298AA / 677CC diplotype showed greater clinical improvement for early rheumatoid arthritis.- Variant Name:
- MTHFR:677C>T
- Related Drugs:
- folic acid, methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:16572443
-
rs1801133
at chr1:11778965
in
CLCN6,
MTHFR
In 330 patients who completed 3 months methotrexate treatment for psoriasis, no significant genotypic associations were found between clinical outcome (e.g. efficacy, toxicity) and 50 SNPs in pathway genes for methotrexate metabolism (ATIC, FPGS, GGH, MTHFR), including 47 common ( >5% minor allele frequency) haplotype-tagging SNPs (r(2) > 0.8) plus 3 additional SNPs.- Variant Name:
- MTHFR:667C>T
- Related Drugs:
- folic acid, methotrexate
- Related Diseases:
- Psoriasis
- Evidence:
-
PMID:19016697
-
rs1801133
at chr1:11778965
in
CLCN6,
MTHFR
MTHFR rs1801133, 667CT or 667TT genotypes were associated with an increased risk of methotrexate treatment discontinuation due to adverse events (relative risk 2.01), mostly as a result of increased risk of elevated levels of liver enzyme alanine aminotransferase (relative risk 2.38) in rheumatoid arthritis patients.- Variant Name:
- MTHFR:677C>T, MTHFR:665C>T (dbSNP Build 130), (Ala222Val)
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:11710708
-
rs1801133
at chr1:11778965
in
CLCN6,
MTHFR
In patients with chronic myelogenous leukemia undergoing bone marrow transplantation and taking methotrexate, carriers of the MTHFR 677TT genotype versus CT and CC genotypes showed significantly greater post-allograft drug-induced toxicity in the form of oral mucositis (p=0.046), and a non-significant trend toward slower platelet recovery.- Variant Name:
- MTHFR:677C>T, MTHFR:665C>T (dbSNP Build 130), (Ala222Val)
- Related Drugs:
- methotrexate
- Related Diseases:
- Leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Transplantation
- Evidence:
-
PMID:11418485
-
rs1801133
at chr1:11778965
in
CLCN6,
MTHFR
In a retrospective analysis of 61 Italian patients experiencing methotrexate toxicity during treatment for acute lymphoblastic leukemia or acute promyelocytic leukemia, carriers of the MTHFR 677TT genotype (60%) showed significantly greater drug-induced toxicity (p=0.03) compared to CC and CT genotypes.- Variant Name:
- MTHFR:677C>T, MTHFR:665C>T (dbSNP Build 130), (Ala222Val)
- Related Drugs:
- methotrexate
- Related Diseases:
- Leukemia, Leukemia, Promyelocytic, Acute, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:12453860
-
rs1801133
at chr1:11778965
in
CLCN6,
MTHFR
In 53 newly diagnosed patients with childhood acute lymphoblastic leukemia who were treated with two courses of high-dose methotrexate (MTX), no association was found between MTX-induced increases in plasma or cerebrospinal fluid homocysteine levels or MTX-induced toxicity (seizures or thrombosis) based upon the MTHFR 677C>T or RFC (SLC19A1) 80G>A genotypes.- Variant Name:
- MTHFR:677C>T, MTHFR:665C>T (dbSNP Build 130), (Ala222Val)
- Related Drugs:
- methotrexate
- Related Diseases:
- Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:12915598
-
rs1801133
at chr1:11778965
in
CLCN6,
MTHFR
Risk or phenotype-associated allele: CT and TT genotypes. Phenotype: The 677 CT or TT genotypes were associated with greater incidence of discontinuation of methorexate treatment because of adverse events, mainly due to elevation of liver enzymes. Study size: 236. Study population/ethnicity: Patients who started methorexate treatment with (n = 157) or without (n = 79) folic or folinic acid supplementation for rheumatoid arthritis. Significance metric(s): RR = 2.01 Type of association: CO, GN.- Variant Name:
- MTHFR:677C>T, 665C>T (dbSNP Build 130), (Ala222Val)
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:11710708
-
rs3862227
at chr1:43493581
This variant is associated with end-of-induction minimal risidual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) from 2 independent cohorts (GWAS result). Risk Allele: G, MAF= 0.32, combined P value= 5.53E-05. It is also associated with greater methotrexate clearance.- Related Drugs:
- methotrexate
- Related Diseases:
- Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19176441
-
rs2372536
at chr2:215898265
in
ATIC
In 330 patients who completed 3 months methotrexate treatment for psoriasis, no significant genotypic associations were found between clinical outcome (e.g. efficacy, toxicity) and 50 SNPs in pathway genes for methotrexate metabolism (ATIC, FPGS, GGH, MTHFR), including 47 common ( >5% minor allele frequency) haplotype-tagging SNPs (r(2) > 0.8) plus 3 additional SNPs.- Variant Name:
- ATIC:347C>G
- Related Drugs:
- folic acid, methotrexate
- Related Diseases:
- Psoriasis
- Evidence:
-
PMID:19016697
-
rs2372536
at chr2:215898265
in
ATIC
Rheumatoid arthritis patients taking methotrexate (MTX) >3 months who carry the ATIC 347GG (116Ser/Ser) genotype showed lower disease activity as assessed by the physician (p = 0.02) and fewer swollen joints (p = 0.06) compared with carriers of combined ATIC CG and CC genotypes; and a pharmacogenetic index of the combined variant alleles for MTX pathway gene variants, TYMS *2, ATIC 347C>G (116Ser), and SLC19A1 (RFC-1) 80A>G (27Arg), was associated with less tender joints (p = 0.012), less swollen joints (p = 0.004), less physician-assessed disease activity (p = 0.0004), and less patient-assessed difficulty with physical tasks (p = 0.001).- Variant Name:
- ATIC:347C>G (Thr116Ser)
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:15457444
-
rs2372536
at chr2:215898265
in
ATIC
Risk or phenotype-associated allele: ATIC 347CC (116Thr/Thr) > GC (116Thr/Ser) > GG (116Ser/Ser) Phenotype: A composite pharmacogenetic index (additive from zero to five) was calculated using the following values: ATIC 347CC or TSER*3/*3 or SLC19A1 80GG or SLC19A1 80GA genotypes were valued as 0, ATIC 347CG or TSER*2/*3 or SLC19A1 80AA genotypes were valued as 1, and ATIC 347GG or TSER*2/*2 genotypes were valued as 2. The sum originating from each component (ATIC + TSER + SLC19A1) was calculated and constitutes the pharmacogenetic index for the patient. There was a significant association between smaller pharmacolgical index and greater number of tender joints (p = 0.002), swollen joints (p = 0.003), greater physician's global assessment of disease activity (p = 0.032), and higher modified Health Assessment Questionnaire (mHAQ) (p = 0.047). Study size: Study population/ethnicity: Significance metric(s): p < 0.05. Type of association: PD; PK; GN; FA- Variant Name:
- ATIC: 347C>G, mRNA 521C>G, Thr116Ser
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:15677700
-
rs13120400
at chr4:89252551
in
ABCG2
SNP is associated with clinical reponse to methotrexate in patients with psoriasis.- Related Drugs:
- methotrexate
- Related Diseases:
- Psoriasis
- Evidence:
-
PMID:18256692
-
rs17731538
at chr4:89274403
in
ABCG2
SNP is associated with clinical reponse to methotrexate in patients with psoriasis.- Related Drugs:
- methotrexate
- Related Diseases:
- Psoriasis
- Evidence:
-
PMID:18256692
-
rs70991108
at chr5:79985919
in
DHFR,
MSH3
Risk or phenotype-associated allele: del Phenotype: Carriage of the deletion allele was associated with a 2.42-fold increased risk of hepatic toxicity to methotrexate. Study size: 122 Study population/ethnicity: Caucasian; Italy; Adults aged 18-80 years; 83% had B-ALL and 17% had TALL Significance metric(s): p = 0.052 Type of association: TOX- Variant Name:
- DHFR 19 bp deletion
- Related Drugs:
- methotrexate
- Related Diseases:
- Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19648163
-
rs351855
at chr5:176452849
in
FGFR4
This variant is associated with cancer progression and tumor cell motility. Patients carrying arg388 allele was associated with metastasis and poor prognosis in breast cancer and in colon cancer as well as poor clinical outcome for head and neck squamous cell carcinoma. possible association with sensitivity to cisplatin. It is associated with resistence to adjuvent systemic therapy in primary breast cancer.- Variant Name:
- FGFR4:GLY388ARG; FGFR4:Arg388
- Related Drugs:
- cisplatin, cyclophosphamide, fluorouracil, methotrexate, tamoxifen
- Related Diseases:
- Breast Neoplasms
- Evidence:
-
PMID:11830541
PMID:15197773
PMID:16822847
PMID:17084840
PMID:18487077
-
rs9345389
at chr6:94497325
This variant is associated with end-of-induction minimal risidual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) from 2 independent cohorts (GWAS result). Risk Allele: G, MAF= 0.05, combined P value= 1.12E-04. It is also associated with greater methotrexate clearance.- Related Drugs:
- methotrexate
- Related Diseases:
- Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19176441
-
rs4723619
at chr7:37232877
in
ELMO1
This variant is associated with end-of-induction minimal risidual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) from 2 independent cohorts (GWAS result). Risk Allele: C, MAF= 0.07, combined P value= 3.05E-06. It is also associated with greater methotrexate and etoposide clearance.- Related Drugs:
- etoposide, methotrexate
- Related Diseases:
- Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19176441
-
rs1045642
at chr7:86976581
in
ABCB1
Indian rheumatoid arthritis patients heterozygous for this SNP (CT genotype) had about double the risk of non-response to methotrexate.- Variant Name:
- ABCB1:C3435T, MDR1:C3435T
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:19093297
-
rs2070744
at chr7:150321012
in
NOS3
Risk or phenotype-associated allele: C. Phenotype: Women assigned to chemotherapy who had NOS3 −786 CC and 894 TT genotypes had an increased risk of recurrence compared with those with common alleles. Study size: 1153. Study population/ethnicity: Women with Breast Neoplasms receiving CMF (cyclophosphamide, methotrexate and fluorouracil) or CAF (cyclophosphamide, doxorubicin and fluorouracil) adjuvant therapy. Significance metric(s): HR = 2.32 (95% CI, 1.26-4.25); p = 0.008. Type of association: CO.- Variant Name:
- NOS3:(-786)T>C
- Related Drugs:
- cyclophosphamide, doxorubicin, fluorouracil, methotrexate
- Evidence:
-
PMID:19671875
-
rs1799983
at chr7:150327044
in
NOS3
Risk or phenotype-associated allele: T. Phenotype: Women assigned to chemotherapy who had NOS3 −786 CC and 894 TT genotypes had an increased risk of recurrence compared with those with common alleles. Study size: 1153. Study population/ethnicity: Women with Breast Neoplasms receiving CMF (cyclophosphamide, methotrexate and fluorouracil) or CAF (cyclophosphamide, doxorubicin and fluorouracil) adjuvant therapy. Significance metric(s): HR = 2.32 (95% CI, 1.26-4.25); p = 0.008. Type of association: CO.- Variant Name:
- NOS3:894G>T
- Related Drugs:
- cyclophosphamide, doxorubicin, fluorouracil, methotrexate
- Evidence:
-
PMID:19671875
-
rs11545078
at chr8:64101318
in
GGH
GGH 452C>T has been associated with decreased catalytic activity and higher accumulation of long-chain methotrexate-polyglutamate.- Variant Name:
- GGH: 452C>T
- Related Drugs:
- methotrexate
- Evidence:
-
PMID:17286537
-
rs11545078
at chr8:64101318
in
GGH
Patients (n= 66) with acute lymphoblastic leukemia showed large individual differences in cellular accumulation of long-chain MTXPG after high-dose methotrexate treatment. The frequency of the rs11545078 (452C>T, Thr127Ile) in GGH was significantly different among patients with low (17.6%), intermediate (9.4%) and high (0%) GGH activity (P = 0.025). Caucasians had a significantly higher frequency of the Ile127 allele (10.0%) than African-Americans (4.4%) (P = 0.033). Rs11545078 was detected in 2 of 4 patients with low GGH activity and none of the five patients with high GGH activity. This missense variant significantly increased Km for long chain polyglutamated methotrexate (MTXPG5) (2.7-fold, P = 0.021), and significantly reduced catalytic efficiency (Vmax/Km) for MTXPG5 (by 67.5%, P = 0.003). The structural impact of this missense variant, based on modelling and enzyme kinetic analysis, indicated a significant reduction GGH binding affinity for long chain MTXPG (MTXPG5).- Variant Name:
- GGH: c.452C>T, p.Thr151Ile; p.Thr127Ile
- Related Drugs:
- methotrexate
- Related Diseases:
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:15284538
-
rs11786893
at chr8:64110819
in
GGH
Patients (n= 66) with acute lymphoblastic leukemia showed large individual differences in cellular accumulation of long-chain MTXPG after high-dose methotrexate. The synonymous SNP in exon 2 of GGH (174G>A, A34A) was detected in only one of four patients with low GGH activity who were sequenced for the gene.- Variant Name:
- GGH: 174G>A, p.Ala34Ala, p.Ala58Ala
- Related Drugs:
- methotrexate
- Related Diseases:
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:15284538
-
rs1800909
at chr8:64113866
in
GGH
This study found that only patients with the GGH 16C-allele and one or no copies of the GGH 452C-16T haplotype were associated with good clinical improvement at 3 months upon treatment with methotrexate.- Variant Name:
- GGH: 16T>C
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:17286537
-
rs1800909
at chr8:64113866
in
GGH
Patients (n= 66) with acute lymphoblastic leukemia showed large individual differences in cellular accumulation of long-chain MTXPG after high-dose methotrexate treatment. A SNP in the endoplasmic reticulum targeting sequence of human GGH, rs1800909 (16T>C), was detected in three acute lymphoblastic leukaemia patients with low GGH activity and four patients with high GGH activity.- Variant Name:
- GGH: c.16T>C, p.Cys6Arg
- Related Drugs:
- methotrexate
- Related Diseases:
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:15284538
-
rs3758149
at chr8:64114282
in
GGH
Risk or phenotype-associated allele: TT genotype. Phenotype: Patients with the GGH 401TT genotype were 4.8-fold (p = 0.002) more likely to have methotrexate polyglutamate (MTXPG3-5) levels below the group median compared to patient carriers of the 401CC or CT genotype. Study size: 226. Study population/ethnicity: Adult rheumatoid arthritis patients from Tennessee and Florida who received low-dose MTX therapy for at least 3 months. Significance metric(s): OR = 4.8; p = 0.002. Type of association: PD, GN- Variant Name:
- GGH: promoter -401C>T
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:15564880
-
rs1544105
at chr9:129602546
in
FPGS
Risk or phenotype-associated allele (s): A/A and A/G. Phenotype: Carriers of the FPGS rs1544105 AA and AG genotypes [OR (95% CI) = 3.47 (1.19-10.12)] were predictors of poor response to methotrexate among rheumatoid arthritis patients Study size: 281. Study population/ethnicity: Indian metric(s): OR (95% CI) = 3.47 (1.19-10.12). Type of association: GN.- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:19902562
-
rs10994982
at chr10:63380110
in
ARID5B
This SNP located in intron 3 of the ARID5B gene differed between pediatric acute lymphoblastic leukemia (ALL) and non-ALL groups (rs10994982, P = 5.7 x 10(-9), OR = 1.62) and also distinguished B-hyperdiploid ALL from other subtypes (rs10994982, P = 0.003, OR 1.72). This SNP was in linkage disequilibrium with rs10821936 (r2 = 0.42, P < 1 10-10). The study found found that the same alleles of this ARID5B SNP rs10994982 that were associated with B-hyperdiploid ALL were also associated with greater methotrexate polyglutamate accumulation (P = 0.021).- Related Drugs:
- methotrexate
- Related Diseases:
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19684603
-
rs10821936
at chr10:63393583
in
ARID5B
This SNP located in intron 3 of the ARID5B gene differed between pediatric acute lymphoblastic leukemia (ALL) and non-ALL groups (rs10821936, P = 1.4 x 10(-15), odds ratio (OR) = 1.91) and also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P = 1.62 x 10(-5), OR = 2.17). This SNP was in linkage disequilibrium with rs10994982 (r2 = 0.42, P < 1 10-10). The study found found that the same alleles of this ARID5B SNP rs10821936 that were associated with B-hyperdiploid ALL were also associated with greater methotrexate polyglutamate accumulation (P = 0.005).- Related Drugs:
- methotrexate
- Related Diseases:
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19684603
-
rs1359645
at chr10:108035647
This variant is associated with end-of-induction minimal risidual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) from 2 independent cohorts (GWAS result). Risk Allele: G, MAF= 0.08, combined P value= 1.62E-04. It is also associated with greater methotrexate clearance- Related Drugs:
- methotrexate
- Related Diseases:
- Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19176441
-
rs4149056
at chr12:21222816
in
SLCO1B1
Risk or phenotype-associated allele: C allele (174Ala). Phenotype: Genome-wide analysis of 398,699 germline SNPs showed association of the rs4149056 C allele (174Ala) with methotrexate (MTX) plasma clearance. Study size: 434 (discovery cohort), 206 (independent validation cohort). Study population/ethnicity: Multiethnic children (5.92 median age , 1.02-18.85 range) with ALL given 3,014 courses of methotrexate at 2-5 g/m(2) enrolled in Tennessee. Significance metric(s): p = 1.9 x 10(-7) (n = 434); p = 1.2 x 10(-7) (n = 206). Type of association: CO; GN; PK- Variant Name:
- OATP1B1: c.521T>C; mRNA 616T>C, p.Val174Ala
- Related Drugs:
- methotrexate
- Related Diseases:
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19901119
-
rs4149081
at chr12:21269288
in
SLCO1B1
Risk or phenotype-associated allele: G allele, with additive genotypic effect. Phenotype: Genome-wide analysis of 398,699 germline SNPs showed association of the rs4149081 G allele with increased methotrexate (MTX) plasma clearance, with an additive effect per G allele (increase of 12.7 mL/min/m(2) per allele in 434 subjects), after adjusting for age, race, sex, and MTX regimen. Variants rs11045879 and rs4149081 were in linkage disequilibrium (r(2) = 1). The G allele was associated with increased risk of gastrointestinal toxicity (mucositis) (OR = 15.3, p = 0.03). Pharmacokinetics differed by ethnicity (MTX clearance: African>Caucasian). Study size: 434 (discovery cohort), 206 (independent validation cohort), 640 (combined cohort). Study population/ethnicity: Multiethnic children (5.92 median age , 1.02-18.85 range) with ALL given 3,014 courses of methotrexate at 2-5 g/m(2) enrolled in Tennessee. Significance metric(s): increased MTX clearance: p = 1.7 x 10(-9) (n = 434), p = 0.017 (n = 206), p = 6.7 x 10(-10) (n = 640); increased GI toxicity: OR = 15.3, p = 0.03. Type of association: CO; GN; PK; ADR; TOX- Variant Name:
- OATP1B1: intronic A/G
- Related Drugs:
- methotrexate
- Related Diseases:
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19901119
-
rs11045879
at chr12:21273886
in
SLCO1B1
Risk or phenotype-associated allele: T allele, with additive genotypic effect. Phenotype: Genome-wide analysis of 398,699 germline SNPs showed association of the rs11045879 T allele increased methotrexate (MTX) plasma clearance, with additive effect per T allele (increase of 13.1 mL/min/m(2) per allele in 434 subjects), after adjusting for age, race, sex, and MTX regimen. Variants rs11045879 and rs4149081 were in linkage disequilibrium (r(2) = 1). The T allele was associated with increased risk of gastrointestinal toxicity (mucositis) (OR = 16.4, p = 0.004). Pharmacokinetics differed by ethnicity (MTX clearance: African>Caucasian). Study size: 434 (discovery cohort), 206 (independent validation cohort), 640 (combined cohort). Study population/ethnicity: Multiethnic children with ALL (5.92 median age , 1.02-18.85 range) given 3,014 courses of methotrexate at 2-5 g/m(2) enrolled in Tennessee. Significance metric(s): increased MTX clearance: p = 1.7 x 10(-10) (n = 434), p = 0.018 (n = 206), p = 8.2 x 10(-11) (n = 640); increased GI toxicity: OR = 16.4, p = 0.004. Type of association: CO; GN; PK; ADR; TOX- Variant Name:
- OATP1B1: intronic C/T
- Related Drugs:
- methotrexate
- Related Diseases:
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19901119
-
rs7992226
at chr13:100595841
in
NALCN
This variant is associated with end-of-induction minimal risidual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) from 2 independent cohorts (GWAS result). Risk Allele: A, MAF= 0.25, combined P value= 1.28E-04. It is also associated with greater methotrexate clearance.- Related Drugs:
- methotrexate
- Related Diseases:
- Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19176441
-
rs11160533
at chr14:99145526
in
CCDC85C
This variant is associated with end-of-induction minimal risidual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) from 2 independent cohorts (GWAS result). Risk Allele: C, MAF= 0.29, combined P value= 1.65E-04. It is also associated with greater methotrexate clearance.- Related Drugs:
- methotrexate
- Related Diseases:
- Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19176441
-
rs4905865
at chr14:99145812
in
CCDC85C
This variant is associated with end-of-induction minimal risidual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) from 2 independent cohorts (GWAS result). Risk Allele: T, MAF= 0.29, combined P value= 2.57E-04. It is also associated with greater methotrexate clearance.- Related Drugs:
- methotrexate
- Related Diseases:
- Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19176441
-
rs3784862
at chr16:16018392
in
ABCC1
SNP is associated with the onset of toxicity to methotrexate in patients with psoriasis.- Related Drugs:
- methotrexate
- Related Diseases:
- Psoriasis
- Evidence:
-
PMID:18256692
-
rs246240
at chr16:16026525
in
ABCC1
SNP is associated with the onset of toxicity to methotrexate in patients with psoriasis.- Related Drugs:
- methotrexate
- Related Diseases:
- Psoriasis
- Evidence:
-
PMID:18256692
-
rs246240
at chr16:16026525
in
ABCC1
SNP is associated with development of hepatic or gastrointestinal toxicity to methotrexate in patients with psoriasis.- Related Drugs:
- methotrexate
- Evidence:
-
PMID:18256692
-
rs35592
at chr16:16049324
in
ABCC1
SNP influences the efficacy of methotrexate in patients with psoriasis.- Related Drugs:
- methotrexate
- Evidence:
-
PMID:18256692
-
rs4148356
at chr16:16084776
in
ABCC1
system: membrane vessicles from HEK cells transfected with WT or variant; FA: variant had approx 50% decrease in transport of tritium labelled 17[beta]-estradiol-17[beta]-D-glucuronide and tritium labelled methotrexate- Variant Name:
- Arg723Gln
- Related Drugs:
- methotrexate
- Evidence:
-
PMID:16041243
-
rs2238476
at chr16:16121373
in
ABCC1
SNP influences the efficacy of methotrexate in patients with psoriasis.- Related Drugs:
- methotrexate
- Evidence:
-
PMID:18256692
-
rs28364006
at chr16:16135750
in
ABCC1
SNP influences the efficacy of methotrexate in patients with psoriasis.- Related Drugs:
- methotrexate
- Related Diseases:
- Psoriasis
- Evidence:
-
PMID:18256692
-
rs4888024
at chr16:77996875
This variant is associated with end-of-induction minimal risidual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) from 2 independent cohorts (GWAS result). Risk Allele: G, MAF= 0.44, combined P value= 2.08E-04. It is also associated with greater methotrexate clearance.- Related Drugs:
- methotrexate
- Related Diseases:
- Neoplasm, Residual, Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:19176441
-
rs34743033
at chr18:647646
in
C18orf56,
TYMS
Risk or phenotype-associated allele: TYMS TSER*3/*3 > *2/*3 > *2/*2 genotypes. Phenotype: A composite pharmacogenetic index (additive from zero to five) was calculated using the following values: ATIC 347CC or TSER*3/*3 or SLC19A1 80GG or SLC19A1 80GA genotypes were valued as 0, ATIC 347CG or TSER*2/*3 or SLC19A1 80AA genotypes were valued as 1, and ATIC 347GG or TSER*2/*2 genotypes were valued as 2. The sum originating from each component (ATIC + TSER + SLC19A1) was calculated and constitutes the pharmacogenetic index for the patient. There was a significant association between smaller pharmacolgical index and greater number of tender joints (p = 0.002), swollen joints (p = 0.003), greater physician's global assessment of disease activity (p = 0.032), and higher modified Health Assessment Questionnaire (mHAQ) (p = 0.047). Study size: 226 (165 female). Study population/ethnicity: Rheumatoid arthritis patients of at least 18 years of age, recruited at 3 sites (Knoxville, TN, Albany, NY, Daytona Beach, FL) from December 2002 to November 2003, who received low dose methotrexate (MTX) treatment for at least 3 months. Significance metric(s): p < 0.05. Type of association: PD; PK; GN; FA- Variant Name:
- TYMS: TSER *2/*3, double (*2) and triple (*3) 28-bp tandem repeats
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:15677700
-
rs45445694
at chr18:647646
in
C18orf56,
TYMS
Rheumatoid arthritis patients taking methotrexate (MTX) >3 months who carry the TYMS or TSER (TYMS enhancer region) *2/*2 (2, 28-bp repeat) genotype showed lower disease activity assessment as assessed by the physician (p = 0.049), lower patient's assessment of disease activity (p = 0.06), and less difficulty with physical tasks (p = 0.05) compared with carriers of a third 28-bp repeat (TSER*3/*3 and TSER*2/*3 combined); and a pharmacogenetic index of the combined variant alleles for MTX pathway gene variants, TYMS *2, ATIC 347C>G (116Ser), and SLC19A1 (RFC-1) 80A>G (27Arg), was associated with less tender joints (p = 0.012), less swollen joints (p = 0.004), less physician-assessed disease activity (p = 0.0004), and less patient-assessed difficulty with physical tasks (p = 0.001). The TYMS*3 allele is designated rs34743033.- Variant Name:
- TYMS:*2 (2, 28-bp tandem repeats located in the TS enhancer region of 5'UTR)
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:15457444
-
rs2853539
at chr18:649829
in
C18orf56,
TYMS
Risk or phenotype-associated allele (s): A/A. Phenotype: Carriers of TYMS rs2853539 AA genotype [OR (95% CI) = 2.76 (1.50-5.07)] were predictors of poor response to methotrexate among rheumatoid arthritis patients Study size: 281. Study population/ethnicity: Indian metric(s): OR (95% CI) = 2.76 (1.50-5.07). Type of association: GN.- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:19902562
-
rs1051266
at chr21:45782222
in
SLC19A1
Rheumatoid arthritis patients taking methotrexate (MTX) >3 months who carry the SLC19A1 (RFC-1) 80AA (27Arg/Arg) genotype showed lower disease activity as assessed by the physician (p < 0.01), less patient-assessed difficulty with physical tasks (p = 0.02), and fewer swollen joints (p = 0.02) compared with carriers 27His-carrying RFC-1 GG and GA genotypes combined; and a pharmacogenetic index of the combined variant alleles for MTX pathway gene variants, TYMS *2, ATIC 347C>G (116Ser), and SLC19A1 (RFC-1) 80G>A (27Arg), was associated with less tender joints (p = 0.012), less swollen joints (p = 0.004), less physician-assessed disease activity (p = 0.0004), and less patient-assessed difficulty with physical tasks (p = 0.001).- Variant Name:
- SCL19A1:80G>A (His27Arg)
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:15457444
-
rs1051266
at chr21:45782222
in
SLC19A1
In 53 newly diagnosed patients with childhood acute lymphoblastic leukemia who were treated with two courses of high-dose methotrexate (MTX), no association was found between MTX-induced increases in plasma or cerebrospinal fluid homocysteine levels or MTX-induced toxicity (seizures or thrombosis) based upon the MTHFR 677C>T or RFC (SLC19A1) 80G>A genotypes.- Variant Name:
- SCL19A1:80G>A (His27Arg)
- Related Drugs:
- methotrexate
- Related Diseases:
- Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:12915598
-
rs1051266
at chr21:45782222
in
SLC19A1
Risk or phenotype-associated allele: TT genotype. Phenotype: Patients with the SLC19A1 80AA genotype were 3.4-fold (p = 0.007) more likely to have methotrexate polyglutamate (MTXPG3-5) levels above the group median compared to those with the SLC19A1 80GG or 80GA genotype. Study size: 226. Study population/ethnicity: Adult rheumatoid arthritis patients from Tennessee and Florida who received low-dose MTX therapy for at least 3 months. Significance metric(s): OR = 3.4; p = 0.007. Type of association: PD, GN- Variant Name:
- SLC19A1: c.80G>A, p.His27Arg
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:15564880
-
rs1051266
at chr21:45782222
in
SLC19A1
Risk or phenotype-associated allele: SLC19A1: c.80A, p.His27. Phenotype: Children with acute lymphoblastic leukemia that carry the A allele of rs1051266 (c.80A, p.His27) had significantly worse prognoses than patients with the GG genotype (p = 0.04; OR = 3.0) in event-free survival. Homozygous 80A/A patients had higher plasma levels of methotrexate (p = 0.004) than the other genotype groups. Study size: Subsets of 204 cases. Study population/ethnicity: French Canadian patients of childhood ALL who received high-dose MTX therapy with leucovorin rescue therapy. Significance metric(s): OR = 3.0; p less than 0.05. Type of association: CO; GN- Variant Name:
- SLC19A1: c.80G>A, p.His27Arg
- Related Drugs:
- methotrexate
- Related Diseases:
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Evidence:
-
PMID:12411325
-
rs1051266
at chr21:45782222
in
SLC19A1
SNP is associated with the onset of toxicity to methotrexate in patients with psoriasis. SNP was also found in association with clinical response to methotrexate in patients with rheumatoid arthritis.- Variant Name:
- SLC19A1:G80A
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid, Psoriasis
- Evidence:
-
PMID:15457444
PMID:17410198
PMID:18256692
-
rs1051266
at chr21:45782222
in
SLC19A1
Risk or phenotype-associated allele: SLC19A1 80GG (27Arg/Arg) and GA (27His/Arg)>AA (27His/His) genotypes. Phenotype: A composite pharmacogenetic index (additive from zero to five) was calculated using the following values: ATIC 347CC or TSER*3/*3 or SLC19A1 80GG or SLC19A1 80GA genotypes were valued as 0, ATIC 347CG or TSER*2/*3 or SLC19A1 80AA genotypes were valued as 1, and ATIC 347GG or TSER*2/*2 genotypes were valued as 2. The sum originating from each component (ATIC + TSER + SLC19A1) was calculated and constitutes the pharmacogenetic index for the patient. There was a significant association between smaller pharmacological index and greater number of tender joints (p = 0.002), swollen joints (p = 0.003), greater physician's global assessment of disease activity (p = 0.032), and higher modified Health Assessment Questionnaire (mHAQ) (p = 0.047). Study size: Study population/ethnicity: Significance metric(s): p < 0.05. Type of association: PD; PK; GN; FA- Variant Name:
- SLC19A1 (RFC-1): 80A>G, mRNA 199A>G, His27Arg
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid
- Evidence:
-
PMID:15677700
-
rs5760410
at chr22:23145406
in
CYTSA
SNP is associated with the onset of toxicity to methotrexate in patients with psoriasis.- Related Drugs:
- methotrexate
- Related Diseases:
- Psoriasis
- Evidence:
-
PMID:18256692
-
rs5760410
at chr22:23145406
in
CYTSA
Risk or phenotype-associated allele: rs5760410 G allele. Phenotype: Carriers of 1 or 2 copies of the G allele for rs5760410 showed increased risk of any (OR = 3.07, CI 1.22-8.76, p = 0.01) or gastrointestinal-specific (OR = 4.58, CI = 1.01-42.05, p = 0.03) adverse events. Study size: 309 RA patients, including 147 good MTX responders, 101 MTX inefficacy failures, and 61 adverse event (AE) MTX failures (e.g. gastrointestinal (n = 24), abnormal liver function tests (n = 20), haematological (n = 7), skin rashes (n = 6), and other (n = 17). Study population/ethnicity: Rheumatoid arthritis (RA) patients aged over 18 yrs, of White Caucasian ethnic origin, classified as having RA according to ARA criteria that were retrospectively recruited from University Hospital of North Staffordshire (UHNS) and Central Manchester and Manchester Children's University Hospitals Trust (CMMC) in England. Significance metric(s): OR = 3.07-4.58, p = 0.01-0.03. Type of association: GN; PD; TOX; ADR.- Variant Name:
- ADORA2A: g.4205975G>A
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid, Drug Toxicity
- Evidence:
-
PMID:18539621
-
rs2298383
at chr22:23155511
in
ADORA2A
Risk or phenotype-associated allele: rs2298383 T allele. Phenotype: Carriers of 1 or 2 copies of the T allele for rs2298383 showed increased risk of any (OR = 2.23, CI 1.03-5.07, p = 0.03) or gastrointestinal-specific (OR = 2.65, CI = 0.8-11.35, p = 0.09) adverse events. Study size: 309 RA patients, including 147 good MTX responders, 101 MTX inefficacy failures, and 61 adverse event (AE) MTX failures (e.g. gastrointestinal (n = 24), abnormal liver function tests (n = 20), haematological (n = 7), skin rashes (n = 6), and other (n = 17). Study population/ethnicity: Rheumatoid arthritis (RA) patients aged over 18 yrs, of White Caucasian ethnic origin, classified as having RA according to ARA criteria that were retrospectively recruited from University Hospital of North Staffordshire (UHNS) and Central Manchester and Manchester Children's University Hospitals Trust (CMMC) in England. Significance metric(s): OR = 2.23-2.65, p = 0.03-0.09. Type of association: GN; PD; TOX; ADR.- Variant Name:
- ADORA2A: g.4216080C>T
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid, Drug Toxicity
- Evidence:
-
PMID:18539621
-
rs3761422
at chr22:23156672
in
ADORA2A
Risk or phenotype-associated allele: rs3761422 T allele. Phenotype: Carriers of 1 or 2 copies of the T allele for rs3761422 showed increased risk of any (OR = 2.11, CI = 1.04-4.39, p = 0.02) or gastrointestinal-specific (OR = 1.91, CI = 0.69-5.77, p = 0.17) adverse events. Study size: 309 RA patients, including 147 good MTX responders, 101 MTX inefficacy failures, and 61 adverse event (AE) MTX failures (e.g. gastrointestinal (n = 24), abnormal liver function tests (n = 20), haematological (n = 7), skin rashes (n = 6), and other (n = 17). Study population/ethnicity: Rheumatoid arthritis (RA) patients aged over 18 yrs, of White Caucasian ethnic origin, classified as having RA according to ARA criteria that were retrospectively recruited from University Hospital of North Staffordshire (UHNS) and Central Manchester and Manchester Children's University Hospitals Trust (CMMC) in England. Significance metric(s): OR = 2.11 and 1.91, p = 0.02-0.17. Type of association: GN; PD; TOX; ADR.- Variant Name:
- ADORA2A: g.4217241T>C
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid, Drug Toxicity
- Evidence:
-
PMID:18539621
-
rs2267076
at chr22:23160595
in
ADORA2A
Risk or phenotype-associated allele: rs2267076 T allele Phenotype: Carriers of 1 or 2 copies of the T allele for rs2267076 showed increased risk of any (OR = 2.1, CI 1.05-4.27, p = 0.02) or gastrointestinal-specific (OR = 1.77, CI = 0.65-5.77, p = 0.22) adverse events. Study size: 309 RA patients, including 147 good MTX responders, 101 MTX inefficacy failures, and 61 adverse event (AE) MTX failures (e.g. gastrointestinal (n = 24), abnormal liver function tests (n = 20), haematological (n = 7), skin rashes (n = 6), and other (n = 17). Study population/ethnicity: Rheumatoid arthritis (RA) patients aged over 18 yrs, of White Caucasian ethnic origin, classified as having RA according to ARA criteria that were retrospectively recruited from University Hospital of North Staffordshire (UHNS) and Central Manchester and Manchester Children's University Hospitals Trust (CMMC) in England. Significance metric(s): OR = 2.1 and 1.77, p = 0.02-0.22. Type of association: GN; PD; TOX; ADR.- Variant Name:
- ADORA2A: g.4221164T>C
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid, Drug Toxicity
- Evidence:
-
PMID:18539621
-
rs2236624
at chr22:23166024
in
ADORA2A
Risk or phenotype-associated allele: rs2236624 T allele. Phenotype: Carriers of 1 or 2 copies of the T allele for rs2236624 showed increased risk of any (OR = 2.73, CI 1.4-5.39, p = 0.002) or gastrointestinal-specific (OR = 2.7, CI = 1.02-7.49, p = 0.04) adverse events. Study size: 309 RA patients, including 147 good MTX responders, 101 MTX inefficacy failures, and 61 adverse event (AE) MTX failures (e.g. gastrointestinal (n = 24), abnormal liver function tests (n = 20), haematological (n = 7), skin rashes (n = 6), and other (n = 17). Study population/ethnicity: Rheumatoid arthritis (RA) patients aged over 18 yrs, of White Caucasian ethnic origin, classified as having RA according to ARA criteria that were retrospectively recruited from University Hospital of North Staffordshire (UHNS) and Central Manchester and Manchester Children's University Hospitals Trust (CMMC) in England. Significance metric(s): OR = 2.7, p = 0.002-0.04. Type of association: GN; PD; TOX; ADR.- Variant Name:
- ADORA2A: g.4226593T>C
- Related Drugs:
- methotrexate
- Related Diseases:
- Arthritis, Rheumatoid, Drug Toxicity
- Evidence:
-
PMID:18539621
Non-Curated Annotations (
)
-
rs72559749
at chr12:21344626
in
SLCO1A2
Reduced uptake of estrone sulfate and methotrexate in oocytes- Variant Name:
- SLCO1A2: N278DEL
- Related Drugs:
- conjugated estrogens, methotrexate
- Evidence:
-
PMID:19940846
-
rs11568563
at chr12:21348701
in
SLCO1A2
Reduced uptake of estrone sulfate and methotrexate in oocytes- Variant Name:
- SLCO1A2: E172D
- Related Drugs:
- conjugated estrogens, methotrexate
- Evidence:
-
PMID:19940846
-
rs11568564
at chr12:21348715
in
SLCO1A2
Reduced uptake of estrone sulfate and methotrexate in oocytes- Variant Name:
- SLCO1A2: R168C
- Related Drugs:
- conjugated estrogens, methotrexate
- Evidence:
-
PMID:19940846
Variant names are different names that have been used in the literature and other resources to
refer to the same variant.
Non-curated variant information is accumulated solely by computational methods and has not
been verified by the scientific staff at PharmGKB.
The following genes are in curated knowledge about this drug.
A list of non-curated publications that mention this drug along with other genes is available.
Drug Targets
| Gene | Description | |
|---|---|---|
| ATIC |
|
(source: PharmGKB) |
| DHFR |
|
(source: Drug Bank) |
| PPAT |
|
(source: PharmGKB) |
| GART |
|
(source: PharmGKB) |
| TYMS |
|
(source: PharmGKB) |
PharmGKB Curated Pathways
The following drugs are in curated knowledge about this drug.
| Drug | Relationship | Evidence | |
|---|---|---|---|
|
allopurinol |
|
Publications |
|
|
rasburicase |
|
Publications |
A list of non-curated publications that mention this drug along with other drugs is available.
Drug Interactions
| Drug | Description | |
|---|---|---|
| acitretin |
|
Acitretin/etretinate increases the effect and toxicity of methotrexate (source: Drug Bank) |
| amoxicillin |
|
The penicillin increases the effect and toxicity of methotrexate (source: Drug Bank) |
| ampicillin |
|
The penicillin increases the effect and toxicity of methotrexate (source: Drug Bank) |
| aspirin |
|
The salicylate increases the effect and toxicity of methotrexate (source: Drug Bank) |
| carbenicillin |
|
The penicillin increases the effect and toxicity of methotrexate (source: Drug Bank) |
| cholestyramine |
|
Decreased levels of methotrexate (source: Drug Bank) |
| ciprofloxacin |
|
Ciprofloxacin increases methotrexate toxicity (source: Drug Bank) |
| cisplatin |
|
Cisplatin increases methotrexate toxicity (source: Drug Bank) |
| cloxacillin |
|
The penicillin increases the effect and toxicity of methotrexate (source: Drug Bank) |
| cyclosporine |
|
Cyclosporine increases the effect and toxicity of methotrexate (source: Drug Bank) |
| diclofenac |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| digoxin |
|
The antineoplasic agent decreases the effect of digoxin (source: Drug Bank) |
| doxycycline |
|
The tetracycline increases methotrexate toxicity (source: Drug Bank) |
| etodolac |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| etretinate |
|
Acitretin/etretinate increases the effect and toxicity of methotrexate (source: Drug Bank) |
| fenoprofen |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| flurbiprofen |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| ibuprofen |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| indomethacin |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| ketoprofen |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| ketorolac |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| meclofenamic acid |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| mefenamic acid |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| mephenytoin |
|
The antineoplasic agent decreases the effect of hydantoin (source: Drug Bank) |
| nabumetone |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| nafcillin |
|
The penicillin increases the effect and toxicity of methotrexate (source: Drug Bank) |
| naproxen |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| omeprazole |
|
Omeprazole increases the levels of methotrexate (source: Drug Bank) |
| oxaprozin |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| penicillin g |
|
The penicillin increases the effect and toxicity of methotrexate (source: Drug Bank) |
| phenylbutazone |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| phenytoin |
|
The antineoplasic agent decreases the effect of hydantoin (source: Drug Bank) |
| piperacillin |
|
The penicillin increases the effect and toxicity of methotrexate (source: Drug Bank) |
| piroxicam |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| probenecid |
|
Probenecid increases the effect and toxicity of methotrexate (source: Drug Bank) |
| procarbazine |
|
Increased nephrotoxicity with this combination (source: Drug Bank) |
| rofecoxib |
|
Rofecoxib increases the levels of methotrexate (source: Drug Bank) |
| salicylate-magnesium |
|
The salicylate increases the effect and toxicity of methotrexate (source: Drug Bank) |
| salicylate-sodium |
|
The salicylate increases the effect and toxicity of methotrexate (source: Drug Bank) |
| sulfadiazine |
|
The sulfamide increases the toxicity of methotrexate (source: Drug Bank) |
| sulfadoxine |
|
The sulfamide increases the toxicity of methotrexate (source: Drug Bank) |
| sulfamethazine |
|
The sulfamide increases the toxicity of methotrexate (source: Drug Bank) |
| sulfamethoxazole |
|
The sulfamide increases the toxicity of methotrexate (source: Drug Bank) |
| sulindac |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| tetracycline |
|
The tetracycline increases methotrexate toxicity (source: Drug Bank) |
| ticarcillin |
|
The penicillin increases the effect and toxicity of methotrexate (source: Drug Bank) |
| tolmetin |
|
The NSAID increases the effect and toxicity of methotrexate (source: Drug Bank) |
| trimethoprim |
|
Timethoprim increases methotrexate toxicity (source: Drug Bank) |
Curated Information
The following diseases are in curated knowledge about this drug.
Non-Curated Information
A list of non-curated publications that mention this drug along with other diseases is available.
Curated Phenotype Datasets
These datasets are sorted alphabetically by title.
- Homocysteine concentrations in leukemia patients
- PD
Submitted by Mary Relling, PharmD involving MTHFR, SLC19A1, methotrexate, , Leukemia and Precursor Cell Lymphoblastic Leukemia-Lymphoma - Pharmacogenetic Risk Factors for Osteonecrosis of the Hip Among Children With Leukemia
- CO
Submitted by Mary Relling, PharmD involving ABCB1, CYP3A4, CYP3A5, GSTM1, GSTP1, GSTT1, MTHFR, NR3C1, SLC19A1, TPMT, TYMS, UGT1A1, VDR, dexamethasone, methotrexate, prednisone, , Osteonecrosis and Precursor Cell Lymphoblastic Leukemia-Lymphoma - Pharmacokinetics of methotrexate in children with ALL
- PK
Submitted by Mary Relling, PharmD involving methotrexate, and Precursor Cell Lymphoblastic Leukemia-Lymphoma - SLC22A6 Functional Protein Variants
- FA
Submitted by Kathleen M. Giacomini, PhD involving SLC22A6, , aminohippurate, methotrexate, ochratoxin A and probenecid - Treatment-specific changes in gene expression (top 150 discriminating genes)
- FA
Submitted by William Evans, PharmD involving ABCA2, ACAT2, ACTL6A, ALMS1, ANXA2, AP1S2, ARL4C, ATM, AZU1, BAX, BEST1, BMI1, BNIP3L, BPI, BTF3L1, BTF3L3, BYSL, C1R, C8G, CAMP, CBFA2T2, CDKN1B, CENTB2, CEP170, CHD1L, COG2, COMP, CTSG, CUL4B, CYFIP2, CYR61, DEFA1, DEFA3, DYRK1A, E2F5, EIF1AY, ELA2, FAAH, FAM175B, FOS, FZD6, G6PD, GADD45A, GNAS, GP5, GPLD1, GRM5, GSS, HAT1, HHLA1, HOXC6, IGFBP5, IGHG3, IL32, KLF11, LAPTM4B, LCN2, LILRB1, MET, MICA, MICB, MLH1, MPO, MRE11A, MUC3A, MYC, NALCN, NMT2, NR2C1, NR2C2, NRXN2, NTRK3, OLFM4, ORC2L, PBX2, PCM1, PDE6B, PIK3R3, PLS1, PMVK, POLR3C, PRF1, PRKY, PTPRG, RABL3, RALBP1, RBBP8, RBM19, RCC1, RFX4, S100A12, S100A2, S100A4, S100A8, S100A9, SEC22B, SERPING1, SERPINI2, SIM1, SLA, SLC14A2, SLC15A1, SLC1A4, SLC1A7, SMCHD1, SPOCK2, SREBF2, STAG1, STAT1, STK24, STK38, STRAP, TCEAL4, TGIF, THOC2, TOB2, TRA@, TRB@, TXK, TYROBP, UBE2G1, UCHL3, UROS, VARS, YY1, ZBTB1, ZFPL1, ZNF217, ZNF263, mercaptopurine, methotrexate, and Precursor Cell Lymphoblastic Leukemia-Lymphoma - Treatment-specific changes in gene expression (top treatment-specific genes)
- FA
Submitted by William Evans, PharmD involving AATF, BYSL, CEP170, CHD1L, CKS2, CTSL1, DEFA1, ELA2, GALNT1, GDF10, GSS, HHLA1, HTATSF1, LILRB1, MDN1, MRPL33, PIK3R3, PLS1, POLG2, POLR3C, PTPRG, RALBP1, RBBP8, RBM19, S100A8, S100A9, SERPING1, SFPQ, SREBF2, STRAP, TERF1, TGDS, TGIF, TOB2, TRA@, UBE2G1, mercaptopurine, methotrexate, and Precursor Cell Lymphoblastic Leukemia-Lymphoma
Additional Datasets
These datasets are minimally curated and are sorted alphabetically by title.
- 10K data in therapy-related AML
- Acquired variation outweighs germline variation in multimodality whole genome analysis of methotrexate accumulation in leukemia
- Bone Density in Acute Lymphoblastic Leukemia Survivors
- Development of a Large-Scale Chemogenomics Database to Improve Drug Candidate Selection
- Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects.
- Germline genomic variants associated with childhood acute lymphoblastic leukemia subtypes
- In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile.
- Pharmacogenetics of Minimal Residual Disease Response in Children with B-Precursor Acute Lymphoblastic Leukemia (ALL): A Report from the Children's Oncology Group
- Physicochemical determinants of human renal clearance
- The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease
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Non-Curated Publications
A list of non-curated publications that mention this drug is available.