title: Polymorphisms in folate, pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis.
abstract: Methotrexate is the gold standard therapy for moderate to severe psoriasis, but there is marked interpersonal variation in its efficacy and toxicity. We hypothesized that in psoriasis patients, specific common polymorphisms in folate, pyrimidine, and purine metabolic enzymes are associated with methotrexate efficacy and/or toxicity. DNA from 203 retrospectively recruited psoriasis patients treated with methotrexate was collected and genotyped by restriction endonuclease digestion or length polymorphism assays. The reduced folate carrier (RFC) 80A allele and the thymidylate synthase (TS) 3'-untranslated region (3'-UTR) 6 bp deletion were associated with methotrexate-induced toxicity (P=0.025 and P=0.025, respectively). RFC 80A and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) 347G were associated with methotrexate discontinuation (P=0.048 and P=0.038). The TS 5'-UTR 28 bp 3R polymorphism correlated with poor clinical outcome (P=0.029), however, this was not the case when patients with palmoplantar pustular psoriasis were not included in the analysis. Stronger associations between specific polymorphisms and methotrexate-induced toxicity and discontinuation were found in a subanalysis of patients on methotrexate not receiving folic acid supplementation. We have demonstrated preliminary evidence that specific polymorphisms of enzymes involved in folate, pyrimidine, and purine metabolism could be useful in predicting clinical response to methotrexate in patients with psoriasis.
authors.affiliation: King's College, Skin Therapy Research Unit, St John's Institute of Dermatology, London, UK.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Campalani
authors.forename: Monica
authors.initials: M
authors.lastname: Arenas
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Marinaki
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: Jonathan N W N
authors.initials: JN
authors.lastname: Barker
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Smith
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000243:Adenosine Deaminase / Q000235:genetics; D000328:Adult; D005492:Folic Acid / Q000378:metabolism*; D006239:Haplotypes; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics; D026901:Membrane Transport Proteins / Q000235:genetics; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D009097:Multienzyme Complexes / Q000235:genetics; D009709:Nucleotide Deaminases / Q000235:genetics; D011110:Polymorphism, Genetic; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics; D011687:Purines / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*; D058978:Reduced Folate Carrier Protein; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; D026901:Membrane Transport Proteins; D009097:Multienzyme Complexes; D011687:Purines; D011743:Pyrimidines; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C113120:inosine monophosphate synthase; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases; D000243:Adenosine Deaminase; C030986:pyrimidine; C030985:purine; D008727:Methotrexate