THE ROLE OF GWAS IDENTIFIED VARIANTS AS PREDICTORS OF OUTCOME TO ANTI-TNFa THERAP

描述(由申请人提供)：最近在克罗恩病(CD)和溃疡性结肠炎(UC)中使用基因组广泛关联研究(GWAS)的基因组学发现增加了我们对IBD遗传易感性的理解。这种新的遗传信息提供了有关炎症在疾病发病机制中的各种机制的重要信息。针对这些不同的途径进行有效的治疗是成功治疗IBD患者的关键。然而，这种疗法的有效性和安全性结果在个体之间存在明显的差异，这一点尚未得到解释。这些差异可以完全由遗传变异来解释，因为它与疾病的发病机制有关，或者与这些疗法的作用机制有关。在这项应用中，我们假设抗肿瘤坏死因子(在患有IBD的儿童和年轻人中)的治疗结果与个体间的遗传变异有关。总体目标是确定在IBD中单独或结合临床和/或免疫标记物进行的基因组广谱关联研究和其他遗传学研究确定的遗传位点是否与儿童IBD患者对抗肿瘤坏死因子(治疗)的治疗反应有关。具体目的包括：目的1：研究基因组广谱关联研究(Genome Wide Association Studies，GWAS)确定的基因座与抗肿瘤坏死因子治疗反应之间的关系。血液将从21岁的儿童身上采集，用CD和UC进行DNA采样。我们将检测患者队列中最重要的GWASIBD变异和已建立的基因位点，并将使用高通量基因分型技术进行基因分型。将分析基因与抗肿瘤坏死因子(抗肿瘤坏死因子)治疗无反应之间的关系，并将确定基因与反应丧失之间的关系。目的2：确定是否存在与抗肿瘤坏死因子应答相关的临床和免疫标记物，并评价它们与已识别的遗传标记物的相互作用。采集CD、UC患儿血标本，进行血清学免疫反应、细胞因子基因表达及药代动力学检测。将使用标准化数据收集表格收集和存储基线和方案的表型和实验室数据。这些分析将包括测试相关性，并使用多变量统计分析评估遗传、免疫学和临床因素的相互作用。目的3：建立炎症性肠病患儿抗肿瘤坏死因子治疗反应的预测模型。从这项先导性研究中获得的新的药物遗传学信息不仅有可能改善临床上使用现有抗肿瘤坏死因子(TNF)制剂的患者的管理，还可能最终改变我们进行大规模临床试验的方式，即只有对特定治疗有较高反应概率的患者才会被纳入研究，以避免接触无效治疗，并保护患者免受与治疗相关的严重和潜在致命的不良事件的影响。 相关性：从这项先导性研究中获得的新的药物遗传学信息有可能最终改变我们进行大规模临床试验的方式，这样只有对特定疗法有较高反应概率的患者才会被纳入进来，以避免暴露在无效疗法中，并保护患者免受与治疗相关的严重和潜在致命的不良事件。这项研究的数据将有助于将重要的遗传学发现转化为IBD患者的临床环境，并有可能用于所有接受抗肿瘤坏死因子(针对其他免疫介导性疾病)的患者。

DESCRIPTION (provided by applicant): Recent genomic discoveries using Genome Wide Association Studies (GWAS) in both Crohn's disease (CD) and ulcerative colitis (UC) have increased our understanding of the genetic susceptibility of IBD. This novel genetic information provides important information about the various mechanisms of inflammation involved in disease pathogenesis. Targeting these various pathways with effective therapies is the key to the successful management of the IBD patient. There is, however, clear inter-individual variability in both efficacy and safety outcomes to this class of therapy which has yet to be explained. These differences may be solely explained by genetic variability as it relates to disease pathogenesis or directed to the mechanism of action of these therapies. In this application we hypothesize that therapeutic outcomes to anti-TNF( in children and young adults with IBD are associated with inter-individual genetic variability. The overall objective is to determine whether genetic loci identified by Genome Wide Association Studies (GWAS) and other genetic studies in IBD alone or in combination with clinical and/or immune markers are associated with therapeutic responsiveness to anti-TNF( therapy in pediatric IBD patients. The specific aims include: Aim 1: To examine the association between genetic loci identified by Genome Wide Association Studies (GWAS) and therapeutic responsiveness to anti-TNF(?therapy. Blood will be obtained from children aged < 21 years of age with CD and UC for DNA sampling. We will test for the most significant GWAS IBD variants and established gene loci in the patient cohort and genotyping will be performed using high throughput genotyping techniques. Associations between genotype and primary non response to anti-TNF( therapy will be analyzed and associations between genotype and loss of response will also be determined. Aim 2: To determine if there are clinical and immune markers that are associated with anti-TNF( responsiveness and evaluate their interaction with identified genetic markers. Obtain blood specimens from children with CD and UC for serological immune response testing, mRNA expression of cytokines and pharmacokinetic testing. Phenotype and laboratory data at baseline and per protocol using standardized data collection forms will be collected and stored. The analyses will include testing associations and evaluate interactions of genetic, immunologic and clinical factors using multivariable statistical analyses. Aim 3: To develop a predictive model for responsiveness to anti-TNF( therapy in children with IBD. The novel pharmacogenetic information gained from this pilot study has the potential to not only improve the management of patients in the clinic with an existing anti-TNF( agent but also ultimately change the way we conduct large scale clinical trials, such that only patients with a higher probability of response to specific therapies will be enrolled to negate exposure to ineffective therapies and protect patients from treatment related serious and potentially fatal adverse events. RELEVANCE: The novel pharmacogenetic information gained from this pilot study has the potential to ultimately change the way we conduct large scale clinical trials such that only patients with a higher probability of response to specific therapies will be enrolled to negate exposure to ineffective therapies and protect patients from treatment related serious and potentially fatal adverse events. The data from this study will aid in the translation of significant genetic findings into the clinical setting for IBD patients and potentially for all patients receiving anti-TNF( for other immune mediated disorders.