title: Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis.
abstract: Methotrexate, an inexpensive first-line systemic therapy for moderate-to-severe psoriasis, is limited in its use by unpredictable efficacy and toxicity. This study was designed to test the hypothesis that single-nucleotide polymorphisms (SNPs) in methotrexate transmembrane transporters and adenosine receptors are associated with efficacy and/or toxicity of the drug. DNA was collected from 374 patients with chronic plaque psoriasis who had been treated with methotrexate. Phenotypic data on efficacy and toxicity were available. Haplotype tagging SNPs (r(2)>0.8) across the relevant genes, with a minor allele frequency of >5%, were selected from the HAPMAP phase II data. SNPs within the efflux transporter genes ABCC1 (ATP-binding cassette, subfamily C, member 1) and ABCG2 (ATP-binding cassette, subfamily G, member 2) are associated with good response to methotrexate therapy in patients with psoriasis; the former gene was also associated with the onset of toxicity. With one SNP in ABCC1, rs246240, the carriage of two copies of allele 1 gives an odds ratio of 2.2 (95% confidence interval: 1.3-3.6; P=0.001) for developing toxicity to methotrexate. These data indicate that knowledge of SNPs in genes relevant to methotrexate efflux may be important in selecting patients suitable for this therapy.
authors.affiliation: Dermatological Sciences, The University of Manchester, Salford Royal Hospital, Manchester, UK. richard.warren@manchester.ac.uk
authors.forename: Richard B
authors.initials: RB
authors.lastname: Warren
authors.forename: Rhodri L L
authors.initials: RL
authors.lastname: Smith
authors.forename: Emanuela
authors.initials: E
authors.lastname: Campalani
authors.forename: Steve
authors.initials: S
authors.lastname: Eyre
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Smith
authors.forename: Jonathan N W N
authors.initials: JN
authors.lastname: Barker
authors.forename: Jane
authors.initials: J
authors.lastname: Worthington
authors.forename: Christopher E M
authors.initials: CE
authors.lastname: Griffiths
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D003879:Dermatologic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011565:Psoriasis / Q000188:drug therapy*; D043682:Receptor, Adenosine A1 / Q000235:genetics; D043705:Receptor, Adenosine A2A / Q000235:genetics; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D003879:Dermatologic Agents; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1