Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis.
Genome-wide association analysis of anti-TNF drug response in patients with rheumatoid arthritis.
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DOI：
10.1136/annrheumdis-2012-202405
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发表时间：
2013-08
影响因子：
27.4
通讯作者：
Coenen MJ
中科院分区：
文献类型：
--
作者：
Umiċeviċ Mirkov M;Cui J;Vermeulen SH;Stahl EA;Toonen EJ;Makkinje RR;Lee AT;Huizinga TW;Allaart R;Barton A;Mariette X;Miceli CR;Criswell LA;Tak PP;de Vries N;Saevarsdottir S;Padyukov L;Bridges SL;van Schaardenburg DJ;Jansen TL;Dutmer EA;van de Laar MA;Barrera P;Radstake TR;van Riel PL;Scheffer H;Franke B;Brunner HG;Plenge RM;Gregersen PK;Guchelaar HJ;Coenen MJ
事实证明，阻断肿瘤坏死因子（抗 TNF）的治疗策略对类风湿性关节炎（RA）患者非常成功。然而，很大一部分患者由于未知原因没有反应。目前没有办法在治疗前识别这些患者。本研究旨在利用全基因组关联方法确定预测 RA 患者抗 TNF 治疗结果的遗传因素。我们进行了一项多阶段、全基因组关联研究，通过荷兰类风湿性关节炎监测 (DREAM) 登记处和 Apotheekzorg 数据库，对 882 名接受抗 TNF 治疗的 RA 患者的 2,557,253 个单核苷酸多态性 (SNP) 进行了初步分析。使用加法模型对治疗 14 周后 28 个关节的疾病活动评分变化进行线性回归分析。选择 p<10−3 的标记在来自三个独立队列的 1,821 名 RA 患者中进行复制。使用 Ingenuity 进行路径分析，包括 p 值 < 10−3 的所有 SNP。 772 个标记物证明了与初始阶段治疗结果相关的证据。与第一阶段相比，在总体荟萃分析中，8 个基因位点显示出更高的 p 值，其中 3 个（rs1568885、rs1813443 和 rs4411591）在所有四个研究队列中显示出方向一致性。我们无法复制先前报道的与抗 TNF 结果相关的标记物。网络分析表明炎症反应和细胞形态的生物过程密切相关。我们采用多阶段策略，确定了 8 个与抗 TNF 治疗反应相关的基因位点。需要进一步的研究来在更多的患者集合中验证这些发现。
Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA). However, a significant subset of patients does not respond for unknown reasons. Currently there are no means of identifying these patients prior to treatment. This study was aimed at identifying genetic factors predicting anti-TNF treatment outcome in patient with RA using a genome-wide association approach. We conducted a multi-stage, genome-wide association study with a primary analysis of 2,557,253 single nucleotide polymorphisms (SNPs) in 882 RA patients receiving anti-TNF therapy included through the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry and the database of Apotheekzorg. Linear regression analysis of changes in the Disease Activity Score in 28 joints after 14 weeks of treatment was performed using an additive model. Markers with a p<10−3 were selected for replication in 1,821 RA patients from three independent cohorts. Pathway analysis including all SNPs with a p-value < 10−3 was performed using Ingenuity. Seven hundred seventy two markers demonstrated evidence of association with treatment outcome in the initial stage. Eight genetic loci showed improved p-value in the overall meta-analysis compared to the first stage, three of which (rs1568885, rs1813443 and rs4411591) showed directional consistency over all four studied cohorts. We were unable to replicate markers previously reported to be associated with anti-TNF outcome. Network analysis indicated strong involvement of biological processes underlying inflammatory response and cell morphology. Using a multi-stage strategy, we have identified 8 genetic loci associated with response to anti-TNF treatment. Further studies are required to validate these findings in additional patient collections.
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影响因子：
--
作者：
Keystone, EC;Kavanaugh, AF;Chartash, EK
通讯作者：
Chartash, EK
影响因子：
--
作者：
Cui, Jing;Saevarsdottir, Saedis;Thomson, Brian;Padyukov, Leonid;van der Helm-van Mil, Annette H. M.;Nititham, Joanne;Hughes, Laura B.;de Vries, Niek;Raychaudhuri, Soumya;Alfredsson, Lars;Askling, Johan;Wedren, Sara;Ding, Bo;Guiducci, Candace;Wolbink, Gert Jan;Crusius, J. Bart A.;van der Horst-Bruinsma, Irene E.;Herenius, Marieke;Weinblatt, Michael E.;Shadick, Nancy A.;Worthington, Jane;Batliwalla, Franak;Kern, Marlena;Morgan, Ann W.;Wilson, Anthony G.;Isaacs, John D.;Hyrich, Kimme;Seldin, Michael F.;Moreland, Larry W.;Behrens, Timothy W.;Allaart, Cornelia F.;Criswell, Lindsey A.;Huizinga, Tom W. J.;Tak, Paul P.;Bridges, S. Louis, Jr.;Toes, Rene E. M.;Barton, Anne;Klareskog, Lars;Gregersen, Peter K.;Karlson, Elizabeth W.;Plenge, Robert M.
通讯作者：
Plenge, Robert M.
影响因子：
4.4
作者：
Nagar, Meital;Jacob-Hirsch, Jasmine;Goldstein, Itamar
通讯作者：
Goldstein, Itamar
影响因子：
9.8
作者：
Chen, Wei-Min;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.
影响因子：
5.5
作者：
Hyrich, K. L.;Watson, K. D.;Symmons, D. P. M.
通讯作者：
Symmons, D. P. M.