1. ¹Dermatological Sciences, The University of Manchester, Salford Royal Hospital, Manchester, UK
2. ²arc Epidemiology Unit, The University of Manchester, Manchester, UK
3. ³Skin Therapy Research Unit, King's College, St John's Institute of Dermatology, Guy's Hospital Campus, London, UK

Correspondence: Dr Richard B. Warren, Dermatological Sciences, The University of Manchester, Salford Royal Hospital, Manchester M6 8HD, UK. E-mail: richard.warren@manchester.ac.uk

Received 9 August 2007; Revised 29 November 2007; Accepted 14 December 2007; Published online 7 February 2008.

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 (r²>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.