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Open AccessArticle

Clinical and Laboratory Associations with Methotrexate Metabolism Gene Polymorphisms in Rheumatoid Arthritis

Northern Ireland Centre for Stratified Medicine (NICSM), Biomedical Sciences Research Institute, Ulster University, C-TRIC Building, Londonderry BT47 6SB, UK
Respiratory Medicine Department and Clinical Trials Unit, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK
Rheumatology Department, Western Health and Social Care Trust, Londonderry BT47 6SB, UK
Cardiac Assessment Unit, Western Health and Social Care Trust, Omagh BT79 0NR, UK
Mass Spectrometry Centre, Biomedical Sciences Research Institute (BMSRI), School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine BT52 1SA, UK
Author to whom correspondence should be addressed.
J. Pers. Med. 2020, 10(4), 149;
Received: 20 August 2020 / Revised: 21 September 2020 / Accepted: 24 September 2020 / Published: 26 September 2020
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that causes loss of joint function and significantly reduces quality of life. Plasma metabolite concentrations of disease-modifying anti-rheumatic drugs (DMARDs) can influence treatment efficacy and toxicity. This study explored the relationship between DMARD-metabolising gene variants and plasma metabolite levels in RA patients. DMARD metabolite concentrations were determined by tandem mass-spectrometry in plasma samples from 100 RA patients with actively flaring disease collected at two intervals. Taqman probes were used to discriminate single-nucleotide polymorphism (SNP) genotypes in cohort genomic DNA: rs246240 (ABCC1), rs1476413 (MTHFR), rs2231142 (ABCG2), rs3740065 (ABCC2), rs4149081 (SLCO1B1), rs4846051 (MTHFR), rs10280623 (ABCB1), rs16853826 (ATIC), rs17421511 (MTHFR) and rs717620 (ABCC2). Mean plasma concentrations of methotrexate (MTX) and MTX-7-OH metabolites were higher (p < 0.05) at baseline in rs4149081 GA genotype patients. Patients with rs1476413 SNP TT or CT alleles have significantly higher (p < 0.001) plasma poly-glutamate metabolites at both study time points and correspondingly elevated disease activity scores. Patients with the rs17421511 SNP AA allele reported significantly lower pain scores (p < 0.05) at both study intervals. Genotyping strategies could help prioritise treatments to RA patients most likely to gain clinical benefit whilst minimizing toxicity. View Full-Text
Keywords: rheumatoid arthritis; SNP; DMARD; methotrexate; pharmacogenomics rheumatoid arthritis; SNP; DMARD; methotrexate; pharmacogenomics
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D’Cruz, L.G.; McEleney, K.G.; Tan, K.B.C.; Shukla, P.; Gardiner, P.V.; Connolly, P.; Conway, C.; Cobice, D.; Gibson, D.S. Clinical and Laboratory Associations with Methotrexate Metabolism Gene Polymorphisms in Rheumatoid Arthritis. J. Pers. Med. 2020, 10, 149.

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