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, James Robert O'Dell, J. R. Curtis, Ted R Mikuls, S. L. Bridges, D. K. Arnett

Research output: Contribution to journalArticle

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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 (US)
Pages (from-to)48-53
Number of pages6
JournalPharmacogenomics Journal
Volume14
Issue number1
DOIs
StatePublished - Feb 1 2014

Fingerprint

Methotrexate
Rheumatoid Arthritis
chondroitin 4-sulfotransferase
Genes
Cytochrome P-450 Enzyme System
Carbohydrates
Demography
Therapeutics
Mitochondrial Aldehyde Dehydrogenase
Pharmacogenomic Variants

Keywords

  • methotrexate
  • pharmacogenetics
  • rheumatoid arthritis

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis : Results from the treatment of early aggressive rheumatoid arthritis trial. / Aslibekyan, S.; Brown, E. E.; Reynolds, R. J.; Redden, D. T.; Morgan, S.; Baggott, J. E.; Sha, J.; Moreland, L. W.; O'Dell, James Robert; Curtis, J. R.; Mikuls, Ted R; Bridges, S. L.; Arnett, D. K.

In: Pharmacogenomics Journal, Vol. 14, No. 1, 01.02.2014, p. 48-53.

Research output: Contribution to journalArticle

Aslibekyan, S, Brown, EE, Reynolds, RJ, Redden, DT, Morgan, S, Baggott, JE, Sha, J, Moreland, LW, O'Dell, JR, Curtis, JR, Mikuls, TR, Bridges, SL & Arnett, DK 2014, 'Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: Results from the treatment of early aggressive rheumatoid arthritis trial', Pharmacogenomics Journal, vol. 14, no. 1, pp. 48-53. https://doi.org/10.1038/tpj.2013.11
Aslibekyan, S. ; Brown, E. E. ; Reynolds, R. J. ; Redden, D. T. ; Morgan, S. ; Baggott, J. E. ; Sha, J. ; Moreland, L. W. ; O'Dell, James Robert ; Curtis, J. R. ; Mikuls, Ted R ; Bridges, S. L. ; Arnett, D. K. / Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis : Results from the treatment of early aggressive rheumatoid arthritis trial. In: Pharmacogenomics Journal. 2014 ; Vol. 14, No. 1. pp. 48-53.
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