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25-05-2018 | Rheumatoid arthritis | Article

Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients

The Pharmacogenomics Journal

Authors: John C. Taylor, Tim Bongartz, Jonathan Massey, Borbala Mifsud, Athina Spiliopoulou, Ian C. Scott, Jianmei Wang, Michael Morgan, Darren Plant, Marco Colombo, Peter Orchard, Sarah Twigg, Iain B. McInnes, Duncan Porter, Jane E. Freeston, Jackie L. Nam, Heather J. Cordell, John D. Isaacs, Jenna L. Strathdee, Donna Arnett, Maria J. H. de Hair, Paul P. Tak, Stella Aslibekyan, Ronald F. van Vollenhoven, Leonid Padyukov, S. Louis Bridges, Costantino Pitzalis, Andrew P. Cope, Suzanne M. M. Verstappen, Paul Emery, Michael R. Barnes, Felix Agakov, Paul McKeigue, Taisei Mushiroda, Michiaki Kubo, Richard Weinshilboum, Anne Barton, Ann W. Morgan, Jennifer H. Barrett, on behalf of the MATURA,  and PAMERA,  Consortia

Publisher: Nature Publishing Group UK


Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10−7 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.

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