Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: Results from the treatment of early aggressive rheumatoid arthritis trial

S. Aslibekyan, E. E. Brown, R. J. Reynolds, D. T. Redden, S. Morgan, J. E. Baggott, J. Sha, L. W. Moreland, J. R. O'Dell, J. R. Curtis, T. R. Mikuls, S. L. Bridges, D. K. Arnett

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P<0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.

Original languageEnglish
Pages (from-to)48-53
Number of pages6
JournalPharmacogenomics Journal
Volume14
Issue number1
DOIs
StatePublished - Feb 2014

Bibliographical note

Funding Information:
We are grateful to the Heflin Genomics Core Laboratory at the University of Alabama at Birmingham for conducting the genotyping of the TEAR Trial participants using the DMET array. This work was funded by the following grants: NIH P60 AR048095 (RP Kimberly, PI: DK Arnett, Project PI) and ARRA supplement 3P60AR048095-07S1; NIH R01 AR052658 (S Louis Bridges, Jr, PI); University of Alabama at Birmingham Center for Clinical and Translational Science through the NIH National Center for Research Resources as part of its Clinical and Translational Science Award Program (5UL1RR025777-03, 5KL2RR025776-03, 5TL1RR025775-03); University of Alabama at Birmingham Comprehensive Cancer Center Core Grant 5P30-CA13148-38 (Genotyp-ing), K01 AR060848 (Richard J Reynolds, PI), and Amgen (the parent TEAR Trial).

Keywords

  • methotrexate
  • pharmacogenetics
  • rheumatoid arthritis

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

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