早期类风湿关节炎患者对甲氨蝶呤反应的全基因组关联研究。
Genome-wide association study of response to methotrexate in early rheumatoid arthritis patients.
作者信息
Taylor John C, Bongartz Tim, Massey Jonathan, Mifsud Borbala, Spiliopoulou Athina, Scott Ian C, Wang Jianmei, Morgan Michael, Plant Darren, Colombo Marco, Orchard Peter, Twigg Sarah, McInnes Iain B, Porter Duncan, Freeston Jane E, Nam Jackie L, Cordell Heather J, Isaacs John D, Strathdee Jenna L, Arnett Donna, de Hair Maria J H, Tak Paul P, Aslibekyan Stella, van Vollenhoven Ronald F, Padyukov Leonid, Bridges S Louis, Pitzalis Costantino, Cope Andrew P, Verstappen Suzanne M M, Emery Paul, Barnes Michael R, Agakov Felix, McKeigue Paul, Mushiroda Taisei, Kubo Michiaki, Weinshilboum Richard, Barton Anne, Morgan Ann W, Barrett Jennifer H
机构信息
Leeds Institute of Cancer and Pathology, University of Leeds, and NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Vanderbilt University, Nashville, TN, USA.
出版信息
Pharmacogenomics J. 2018 Jul;18(4):528-538. doi: 10.1038/s41397-018-0025-5. Epub 2018 May 25.
Methotrexate (MTX) monotherapy is a common first treatment for rheumatoid arthritis (RA), but many patients do not respond adequately. In order to identify genetic predictors of response, we have combined data from two consortia to carry out a genome-wide study of response to MTX in 1424 early RA patients of European ancestry. Clinical endpoints were change from baseline to 6 months after starting treatment in swollen 28-joint count, tender 28-joint count, C-reactive protein and the overall 3-component disease activity score (DAS28). No single nucleotide polymorphism (SNP) reached genome-wide statistical significance for any outcome measure. The strongest evidence for association was with rs168201 in NRG3 (p = 10 for change in DAS28). Some support was also seen for association with ZMIZ1, previously highlighted in a study of response to MTX in juvenile idiopathic arthritis. Follow-up in two smaller cohorts of 429 and 177 RA patients did not support these findings, although these cohorts were more heterogeneous.
甲氨蝶呤（MTX）单药治疗是类风湿关节炎（RA）常见的初始治疗方法，但许多患者反应不佳。为了确定反应的基因预测指标，我们整合了两个联盟的数据，对1424名欧洲血统的早期RA患者进行了全基因组MTX反应研究。临床终点为从基线到开始治疗6个月后28个关节肿胀计数、28个关节压痛计数、C反应蛋白以及整体三分疾病活动评分（DAS28）的变化。对于任何结局指标，均无单核苷酸多态性（SNP）达到全基因组统计学显著性。最有力的关联证据是与NRG3中的rs168201相关（DAS28变化的p值为10）。在青少年特发性关节炎MTX反应研究中曾被重点提及的ZMIZ1，也获得了一些关联支持。对429名和177名RA患者组成的两个较小队列进行随访，并未支持这些发现，尽管这些队列的异质性更高。
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