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Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients

The Pharmacogenomics Journal volume 13, pages 227–234 (2013)Cite this article

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Abstract

We investigated the effect of single-nucleotide polymorphisms (SNPs) spanning 10 methotrexate (MTX) pathway genes, namely AMPD1, ATIC, DHFR, FPGS, GGH, ITPA, MTHFD1, SHMT1, SLC19A1 (RFC) and TYMS on the outcome of MTX treatment in a UK rheumatoid arthritis (RA) patient cohort. Tagging SNPs were selected and genotyping was performed in 309 patients with predefined outcomes to MTX treatment. Of the 129 SNPs tested, 11 associations were detected with efficacy (P-trend ⩽0.05) including four SNPs in the ATIC gene (rs12995526, rs3821353, rs7563206 and rs16853834), six SNPs in the SLC19A1 gene region (rs11702425, rs2838956, rs7499, rs2274808, rs9977268 and rs7279445) and a single SNP within the GGH gene (rs12681874). Five SNPs were significantly associated with adverse events; three in the DHFR gene (rs12517451, rs10072026, and rs1643657) and two of borderline significance in the FPGS gene. The results suggest that genetic variations in several key MTX pathway genes may influence response to MTX in the RA patients. Further studies will be required to validate these findings and if confirmed these results could contribute towards a better understanding of and ability to predict MTX response in RA.

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Acknowledgements

We thank the Arthritis Research UK for their support (grant reference no 17552). SH, PM, INB, AB, WT are funded by the Arthritis Research UK and SAO's salary is funded by Pfizer. We acknowledge the NIHR Manchester Biomedical Research Centre for their support.

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  1. Arthritis Research UK Epidemiology Unit, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK

    S A Owen, P Martin, I N Bruce, A Barton & W Thomson

  2. Arthritis Research UK, National Primary Care Centre, Keele University, Staffordshire, UK

    S L Hider

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Owen, S., Hider, S., Martin, P. et al. Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients. Pharmacogenomics J 13, 227–234 (2013). https://doi.org/10.1038/tpj.2012.7

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