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To evaluate whether the efficacy and toxicity of methotrexate are associated with genetic variations, investigators examined DNA from 374 patients with chronic plaque psoriasis who had been treated with the drug.
The researchers found associations with the cellular adenosine receptors and with genes that regulate the metabolism of methotrexate: SLC19A, which transports methotrexate into cells, and ABCC1 and ABCG2, which are responsible for efflux from cells. Efficacy was associated with single nucleotide polymorphisms (SNPs) located in two introns (noncoding intragenic regions of DNA) and in exon 28, which codes for the ATP binding site in the ABCC1 transporter gene. Adverse hepatic and gastrointestinal events were associated with the intronic SNPs.
Warren RB et al. Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J Invest Dermatol 2008 Aug; 128:1925.
Comment
This large retrospective study was conducted in the U.K., where the annual cost for methotrexate is equivalent to US$110. Because, as the authors note, large numbers of SNPs were studied, appropriate statistical corrections must be made for multiple comparisons. The small number of patients with any one genotype also argues for cautious interpretation. The physiologic effect of intronic SNPs is, for the most part, unknown. Even with these reservations, the findings are exciting and suggest the possibility of genetic testing for predicting both efficacy and toxicity in methotrexate treatment. The proof of this pudding will lie in independent prospective analyses of these genes in other patients.