Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Leon D'Cruz
ORCID logo ,
Kevin McEleney
,
Kyle Tan
,
Priyank Shukla
ORCID logo ,
Philip Gardiner
ORCID logo ,
Patricia Connolly
,
Caroline Conway
,
Diego Cobice
,
David S. Gibson
* ORCID logo
Version 1 : Received: 20 August 2020 / Approved: 24 August 2020 / Online: 24 August 2020 (07:33:05 CEST)

A peer-reviewed article of this Preprint also exists.

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. 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.

Abstract

Rheumatoid arthritis (RA); is a chronic systemic autoimmune disease which 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, C.I. 95%) at baseline in rs4149081 GA genotype patients. Patients with rs1476413 SNP TT or CT alleles in the have significantly higher (p<0.001, 95% C.I) 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, 95% C.I.) at both study intervals. Genotyping strategies could help prioritise treatments to RA patients most likely to gain clinical benefit, whilst minimizing toxicity.

Keywords

rheumatoid arthritis; SNP; DMARD; methotrexate; pharmacogenomics

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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