title: Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: results from the treatment of early aggressive rheumatoid arthritis trial.
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.
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Aslibekyan
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Brown
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Reynolds
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Redden
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Morgan
authors.affiliation: Department of Nutritional Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Baggott
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sha
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: L W
authors.initials: LW
authors.lastname: Moreland
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center at Omaha, Omaha, NE, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: O'Dell
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Curtis
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center at Omaha, Omaha, NE, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Mikuls
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Bridges
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000235:genetics; D015415:Biomarkers / Q000032:analysis; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity*; D008875:Middle Aged; D015999:Multivariate Analysis; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D015415:Biomarkers; D008727:Methotrexate
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