Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms.
BACKGROUND
The use of methotrexate is limited by interindividual variability in response. Previous studies in patients with either rheumatoid arthritis or psoriasis suggest that genetic variation across the methotrexate metabolic pathway might enable prediction of both efficacy and toxicity of the drug.


OBJECTIVE
To assess if single nucleotide polymorphisms (SNPs) across four genes that are relevant to methotrexate metabolism [folypolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC)] are related to treatment outcomes in patients with psoriasis.


METHODS
DNA was collected from 374 patients with psoriasis who had been treated with methotrexate. Data were available on individual outcomes to therapy, namely efficacy and toxicity. Haplotype-tagging SNPs (r(2) > 0.8) for the four genes with a minor allele frequency of > 5% were selected from the HAPMAP phase II data. Genotyping was undertaken using the MassARRAY spectrometric method (Sequenom).


RESULTS
There were no significant associations detected between clinical outcomes in patients with psoriasis treated with methotrexate and SNPs in the four genes investigated.


CONCLUSIONS
Genetic variation in four key genes relevant to the intracellular metabolism of methotrexate does not appear to predict response to methotrexate therapy in patients with psoriasis.
Warren
R B
RB
Dermatological Sciences, Salford Royal Hospital, The University of Manchester, Manchester M6 8HD, UK. richard.warren@manchester.ac.uk
Smith
R L
RL
Campalani
E
E
Eyre
S
S
Smith
C H
CH
Barker
J N W N
JN
Worthington
J
J
Griffiths
C E M
CE
D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D003879:Dermatologic Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D009097:Multienzyme Complexes / Q000235:genetics; D009709:Nucleotide Deaminases / Q000235:genetics; D010453:Peptide Synthases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011565:Psoriasis / Q000188:drug therapy* / Q000235:genetics; D016896:Treatment Outcome; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics
D003879:Dermatologic Agents; D009097:Multienzyme Complexes; C113120:inosine monophosphate synthase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D019877:Hydroxymethyl and Formyl Transferases; D011623:gamma-Glutamyl Hydrolase; D009709:Nucleotide Deaminases; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D008727:Methotrexate