1] Arthritis Research UK Centre for Genetics and Genomics, Institute of Inflammation and Repair, Faculty of Medical and Human Sciences, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK [2] NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester National Health Service Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
Pharmacogenomics J. 2014 Aug;14(4):356-64. doi: 10.1038/tpj.2014.3. Epub 2014 Apr 8.
Clinical response to methotrexate (MTX) treatment for children with juvenile idiopathic arthritis (JIA) displays considerable heterogeneity. Currently, there are no reliable predictors to identify non-responders: earlier identification could lead to a targeted treatment. We genotyped 759 JIA cases from the UK, the Netherlands and Czech Republic. Clinical variables were measured at baseline and 6 months after start of the treatment. In Phase I analysis, samples were analysed for the association with MTX response using ordinal regression of ACR-pedi categories and linear regression of change in clinical variables, and identified 31 genetic regions (P<0.001). Phase II analysis increased SNP density in the most strongly associated regions, identifying 14 regions (P<1 × 10(-5)): three contain genes of particular biological interest (ZMIZ1, TGIF1 and CFTR). These data suggest a role for novel pathways in MTX response and further investigations within associated regions will help to reach our goal of predicting response to MTX in JIA.
儿童幼年特发性关节炎（JIA）对甲氨蝶呤（MTX）治疗的临床反应表现出很大的异质性。目前，还没有可靠的预测指标来识别无应答者：早期识别可能会导致针对性治疗。我们对来自英国、荷兰和捷克共和国的 759 例 JIA 病例进行了基因分型。在治疗开始时和 6 个月后测量了临床变量。在第一阶段分析中，使用 ACR-pedi 类别有序回归和临床变量变化的线性回归分析样本与 MTX 反应的关联，确定了 31 个遗传区域（P<0.001）。第二阶段分析增加了最相关区域的 SNP 密度，确定了 14 个区域（P<1×10(-5))：其中三个区域包含特别具有生物学意义的基因（ZMIZ1、TGIF1 和 CFTR）。这些数据表明，在 MTX 反应中存在新的途径，进一步对相关区域的研究将有助于实现我们预测 JIA 对 MTX 反应的目标。
