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

Leon D'Cruz, Kevin G McEleney, Kyle B.C. Tan, Priyank Shukla, Philip Gardiner, Patricia Connolly, C Conway, Diego Cobice, David Gibson

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12 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Article number149
Pages (from-to)1-14
Number of pages14
JournalJournal of Personalized Medicine
Volume10
Issue number4
Early online date26 Sept 2020
DOIs
Publication statusPublished (in print/issue) - 31 Dec 2020

Bibliographical note

Funding Information:
Funding: This research was funded by the Research and Development Office, Health and Social Care NI (RADAR study), The Northern Ireland Rheumatism Trust, and Invest Northern Ireland (PoC 631/731) in support of this work.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • Arthritis
  • Pharmacogenomics
  • polymorphism
  • Methotrexate
  • SNP
  • Rheumatoid arthritis
  • DMARD

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