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

炎症性肠病（IBD）是一组复发缓解且迄今无法治愈的免疫介导疾病，其特征是整个胃肠道的炎症和溃疡。中度至重度IBD通常用生物制剂治疗，主要是肿瘤坏死因子（TNF）抑制剂（如英夫利昔单抗或阿达木单抗）。最近，一项国际多中心临床研究表明，维多单抗在实现临床缓解方面优于阿达木单抗；然而，最多只有32%的IBD患者通过生物治疗达到临床缓解。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，但在IBD中，将这些鉴定的变异作为个性化医疗（PM）的标记物的使用受到限制。我们假设鉴定与生物制剂治疗反应相关的蛋白质编码变异具有巨大的潜力，有助于在IBD管理中开发新的PM方法。作为一项原理验证研究，我和我的同事最近对接受英夫利昔单抗治疗的139名韩国和77名德国抗tnf naïve IBD患者进行了一项全外显子组测序（WES）研究。我们确定了5种与英夫利昔单抗原发性无应答（PNR）相关的蛋白质编码变异，韩国和德国队列中ZNF133中的rs2228273与之相关（P=6.49×10-7; OR [95% CI] = 11.94[3.8-37.4]）。此外，包含遗传和临床变量的PNR联合预测模型的性能优于仅包含遗传变量或仅包含临床变量的模型。通过此申请，我们申请资助来自RUNcd（头对头比较ustekinumab/TNF抑制剂）和VEDOibd（头对头比较vedolizumab/TNF抑制剂）研究的773名IBD患者的全外显子组测序（WES）实验，以研究对IL12/IL23 (ustekinumab)， α4β7-整合素（vedolizumab）和TNF（英夫利昔单抗或阿达木单抗）抑制的反应/无反应的功能遗传学基础。这773名IBD患者的WES数据将与BioCrohn（英夫利昔单抗/阿达木单抗的头对头比较）和BioColitis（英夫利昔单抗/阿达木单抗的头对头比较）登记的另外1219名IBD患者的现有WES数据相结合。我们的目标是确定遗传标记，支持对治疗预期反应的个体预测，并详细描述生物制剂ustekinumab， vedolizumab和英夫利昔单抗/阿达木单抗反应的（可能是性别特异性的）功能遗传基础，以及反应与治疗出现的合并症事件之间可能的因果关系。

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.