Aslibekyan S, Brown E E, Reynolds R J, Redden D T, Morgan S, Baggott J E, Sha J, Moreland L W, O'Dell J R, Curtis J R, Mikuls T R, Bridges S L, Arnett D K
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Pharmacogenomics J. 2014 Feb;14(1):48-53. doi: 10.1038/tpj.2013.11. Epub 2013 Apr 2.
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.
甲氨蝶呤（MTX）已成为早期中重度类风湿关节炎（RA）的一线治疗药物，但治疗反应的个体差异仍无法解释。我们在471名早期类风湿关节炎试验参与者中测试了863个已知药物遗传变异与MTX反应之间的关联。使用多元回归对疗效和毒性进行建模，并对人口统计学和临床协变量进行调整。使用惩罚回归模型来测试标记物和/或协变量与结果的联合关联。与疗效最强的基因关联存在于CHST11（五个标记物，P<0.003）中，该基因编码碳水化合物（硫酸软骨素4）磺基转移酶11。与MTX毒性相关的顶级标记物存在于细胞色素p450基因CYP20A1和CYP39A1、溶质载体基因SLC22A2和SLC7A7以及线粒体醛脱氢酶基因ALDH2中。所选标记物在毒性变异中解释的比例始终高于疗效。这些发现可为未来个性化治疗方法的发展提供参考。
