Pharmacogenomics of Methotrexate Membrane Transport Pathway: Can Clinical Response to Methotrexate in Rheumatoid Arthritis Be Predicted?

Abstract

Background: Methotrexate (MTX) is widely used for rheumatoid arthritis (RA) treatment. Single nucleotide polymorphisms (SNPs) could be used as predictors of patients’ therapeutic outcome variability. Therefore, this study aims to evaluate the influence of SNPs in genes encoding for MTX membrane transport proteins in order to predict clinical response to MTX. Methods: Clinicopathological data from 233 RA patients treated with MTX were collected, clinical response defined, and patients genotyped for 23 SNPs. Genotype and haplotype analyses were performed using multivariate methods and a genetic risk index (GRI) for non-response was created. Results: Increased risk for non-response was associated to SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864. GRI demonstrated that patients with Index 3 were 16-fold more likely to be non-responders than those with Index 1. Conclusions: This study revealed that SLC22A11 and ABCC1 may be important to identify those patients who will not benefit from MTX treatment, highlighting the relevance in translating these results to clinical practice. However, further validation by independent studies is needed to develop the field of personalized medicine to predict clinical response to MTX treatment.

Polymorphisms and Pharmacogenomics for the Clinical Efficacy of Methotrexate in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis

“…In addition, combined MTX and biologic disease-modifying anti-rheumatic drug (bDMARD) treatment303132 studies and reviews133 were excluded from the meta-analysis of the RFC1 80G > A (rs1051266) polymorphism. Remarkably, the same SNP (rs1051266) was identified by a different name (SLC19A1 G > A) in the research from Lima A. et al 34,. but was excluded in the present meta-analysis because it did not conforming to Hardy-Weinberg equilibrium.…”

Prediction of clinically relevant drug‐induced liver injury from structure using machine learning

“…The basolaterally expressed MRP1 (ABCC1) and the apically expressed MRP2 (ABCC2) are members of the ATP‐binding cassette family, found throughout the body (also hepatically), and involved in the transport of a wide range of compounds, both charged and uncharged. Their clinical importance can be seen in the response to and toxicity of methotrexate depending on MRP1 activity (Lima, Bernardes, Azevedo, Medeiros, & Seabra, ), or statin disposition in relation to MRP1 and MRP2 activity (Rodrigues, ).…”

“…Their clinical importance can be seen in the response to and toxicity of methotrexate depending on MRP1 activity (Lima, Bernardes, Azevedo, Medeiros, & Seabra, 2015), or statin disposition in relation to MRP1 and MRP2 activity (Rodrigues, 2010).…”

Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis

“…[65] In addition, combined MTX and biologic disease-modifying anti-rheumatic drug (bDMARD) treatment [66] were excluded from the meta-analysis of the RFC1 80G > A (rs1051266) polymorphism. Remarkably, the research from Lima et al [67] was included in the present research but not in a previous meta-analysis because the same SNP (rs1051266) was identified by a different name (SLC19A1 G > A).…”