Whole-exome sequencing for inflammatory bowel disease patients treated with biologic agents

炎症性肠病（IBD）是一组复发缓解型且迄今无法治愈的免疫介导的疾病，其特征在于整个胃肠道的炎症和溃疡。中度至重度IBD通常使用生物制剂治疗，主要是肿瘤坏死因子（TNF）抑制剂（例如英夫利昔单抗或阿达木单抗）。近期，一项国际多中心临床研究显示，Vedolizumab在达到临床缓解方面优于阿达木单抗上级;尽管过去10年的全基因组关联研究（GWAS）通过鉴定疾病相关的遗传变异加深了我们对IBD发病机制的理解，这些鉴定的变体作为个体化药物（PM）的标记物的用途在IBD中受到限制。我们假设，与生物制剂治疗反应相关的蛋白质编码变体的鉴定具有巨大的潜力，有助于开发治疗IBD的新型PM方法。作为一项原理验证研究，我和我的同事最近对总共139名接受英夫利西单抗治疗的韩国和77名德国抗TNF初治IBD患者进行了全外显子组测序（WES）研究。我们发现了5种与英夫利西单抗原发性无应答（PNR）相关的蛋白质编码变异体，在韩国和德国队列中，ZNF 133中的rs 2228273均相关（P=6.49×10-7; OR [95%CI] = 11.94 [3.8-37.4]）。此外，包括遗传和临床变量的组合PNR预测模型的性能上级仅包括遗传变量或仅包括临床变量的模型。我们申请资助773名IBD患者的全外显子组测序（WES）实验，这些患者来自研究RUNcd（乌司奴单抗/TNF抑制剂的头对头比较）和VEDOibd（头对头比较Vedolizumab/TNF抑制剂），以研究IL 12/IL 23应答/无应答的功能遗传基础（乌司奴单抗）、α4β7-整联蛋白（Vedolizumab）和TNF（英夫利西单抗或阿达木单抗）抑制。这773例IBD患者的WES数据将与来自BioCrohn（英夫利西单抗/阿达木单抗头对头比较）和BioColitis（英夫利西单抗/阿达木单抗头对头比较）登记研究的另外1，219例IBD患者的现有WES数据合并。我们的目标是确定支持个体预测预期治疗反应的遗传标记，并详细描述生物制剂乌司奴单抗、维多珠单抗和英夫利西单抗/阿达木单抗反应的（可能具有性别特异性）功能遗传基础，以及反应之间可能的因果关系和治疗后出现的合并症事件。

Inflammatory bowel diseases (IBD) represent a group of relapsing-remitting and so far uncurable immune-mediated disorders, characterized by inflammation and ulceration of the entire gastrointestinal tract. Moderate to severe forms of IBD are often treated with biologic agents, mainly tumor necrosis factor (TNF) inhibitors (e.g. infliximab or adalimumab). Recently, an international multi-center clinical study showed that vedolizumab is superior to adalimumab in achieving clinical remission; however, only in a maximum of 32% of IBD patients clinical remission was achieved by biologic therapy.Although genome-wide association studies (GWAS) of the past 10 years have deepened our understanding of IBD pathogenesis through identification of disease-associated genetic variants, the use of these identified variants as markers for personalized medicine (PM) is limited in IBD. We hypothesize that the identification of protein-coding variants associated with response to therapy with biologic agents has enormous potential to contribute to the development of novel PM approaches in the management of IBD. As a proof-of-principle study, my colleagues and I recently performed a whole-exome-sequencing (WES) study for a total of 139 Korean and 77 German anti-TNF naïve IBD patients who received infliximab as a therapy. We identified five protein-coding variants that were associated with primary nonresponse (PNR) to infliximab, with rs2228273 in ZNF133 associated in both Korean and German cohorts (P=6.49×10-7; OR [95% CI] = 11.94 [3.8-37.4]). Further, the performance of a combined PNR prediction model including genetic and clinical variables was superior to the model including only genetic variables or only clinical variables.With this application, we apply for funding for whole-exome-sequencing (WES) experiments for 773 IBD patients from studies RUNcd (head-to-head comparison ustekinumab/TNF inhibitors) and VEDOibd (head-to-head comparison vedolizumab/TNF inhibitors) in order to investigate the functional genetic basis of the response/non-response to IL12/IL23 (ustekinumab), α4β7-Integrin (vedolizumab) and TNF (infliximab or adalimumab) inhibition. WES data of these 773 IBD patients will be combined with existing WES data from additional 1,219 IBD patients from the BioCrohn (head-to-head comparison infliximab/adalimumab) and the BioColitis (head-to-head comparison infliximab/adalimumab) register. We aim to identify genetic markers that support the individual prediction of the expected response to treatment and to characterize in detail the (possibly sex-specific) functional genetic basis of response with biologic agents ustekinumab, vedolizumab and infliximab/adalimumab as well as possible causal relationships between response and treatment-emergent comorbid events.