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

描述（由申请人提供）：最近使用全基因组关联研究（GWAS）在克罗恩病（CD）和溃疡性结肠炎（UC）中的基因组发现增加了我们对IBD遗传易感性的理解。这一新的遗传信息为炎症参与疾病发病的各种机制提供了重要信息。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，这类治疗的疗效和安全性结果存在明显的个体差异，这尚未得到解释。这些差异可能完全由遗传变异来解释，因为它与疾病发病机制或直接与这些治疗的作用机制有关。在这项应用中，我们假设抗肿瘤坏死因子（tnf）在患有IBD的儿童和年轻人中的治疗结果与个体间遗传变异有关。总体目标是确定全基因组关联研究（GWAS）和其他IBD单独或联合临床和/或免疫标记物的遗传研究中鉴定的遗传位点是否与儿科IBD患者对抗tnf治疗的治疗反应性相关。具体目的包括：目的1：研究全基因组关联研究（GWAS）鉴定的基因位点与抗肿瘤坏死因子治疗反应性之间的关系。将从年龄< 21岁的患有CD和UC的儿童中采集血液进行DNA采样。我们将在患者队列中检测最重要的GWAS IBD变体和已建立的基因位点，并使用高通量基因分型技术进行基因分型。将分析基因型与抗肿瘤坏死因子治疗无应答之间的关系，并确定基因型与应答丧失之间的关系。目的2：确定是否存在与抗肿瘤坏死因子（tnf）反应性相关的临床和免疫标记，并评估它们与已确定的遗传标记的相互作用。采集CD和UC患儿血液标本，进行血清学免疫反应检测、细胞因子mRNA表达和药代动力学检测。将使用标准化数据收集表格收集和存储基线和每个方案的表型和实验室数据。分析将包括使用多变量统计分析测试关联和评估遗传、免疫和临床因素的相互作用。目的3：建立IBD患儿对抗tnf治疗反应性的预测模型。从这项初步研究中获得的新的药理学信息不仅有可能改善临床中使用现有抗tnf（药物）的患者的管理，而且最终改变我们进行大规模临床试验的方式，这样，只有对特定治疗有较高反应可能性的患者才会被招募，以消除无效治疗的暴露，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。

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.