Functional outcomes of inflammatory bowel disease associated variants

描述（由申请人提供）：微生物和遗传易感因素之间的相互作用是炎症性肠病（IBD）发展的核心。先天机制，特别是通过模式识别受体（PRR）途径，是宿主对微生物反应的起始驱动因素。在与IBD相关的163个基因座中，广泛的可能基因在许多水平上调节宿主对PRR的反应，并赋予在自身免疫中观察到的一些最大遗传效应大小。尽管在过去的几年中IBD相关的多态性的重大发现，这些基因座的绝大多数功能的后果还有待确定。由细菌和病毒产物引起的PRR活化的中心结果是诱导细胞因子分泌。在很大程度上，IBD的特征在于失调的细胞因子，并且细胞因子的调节在IBD治疗中起主要作用。PRR诱导的细胞因子分泌的个体间差异影响对感染和炎性疾病的易感性之间的平衡。我们假设，在多个IBD相关基因的多态性有助于在PRR诱导的细胞因子分泌的个体间的变化。全面定义由疾病相关的人类变异驱动的功能改变的系统的、有力的研究将提供对IBD的中心机制的巨大洞察;利用天然存在的人类遗传变异来系统性地“扰乱”实验系统代表了用于精确定义细胞因子分泌的已建立的和新的PRR介导的机制的高度创新的方法。因此，我们将利用一个大的、效能良好的队列来筛选IBD相关的多态性，这些多态性有助于个体间PRR引发的细胞因子分泌的变化，然后定义其中所涉及的IBD相关基因以及所鉴定的多态性调节PRR诱导的细胞因子分泌的分子机制。

DESCRIPTION (provided by applicant): The interplay between microbial and genetic susceptibility factors is central to the development of inflammatory bowel disease (IBD). Innate mechanisms, in particular through pattern recognition receptor (PRR) pathways, are the initiating drivers of host responses to microbes. Of the 163 loci associated to IBD, a broad range of likely genes modulate host responses to PRR at many levels, and confer some of the largest genetic effect sizes observed in autoimmunity. Despite the significant discoveries in IBD-associated polymorphisms over the past few years, the functional consequences of the vast majority of these loci have yet to be identified. A central outcome of PRR activation by bacterial and viral products is induction of cytokine secretion. To a large extent, IBD is characterized by dysregulated cytokines, and modulation of cytokines plays a primary role in IBD treatment. Inter-individual variation in PRR- induced cytokine secretion influences the balance between susceptibility to infection and inflammatory diseases. We hypothesize that polymorphisms in multiple IBD-associated genes contribute to inter-individual variation in PRR-induced cytokine secretion. Systematic, well- powered studies comprehensively defining the functional alterations driven by disease- associated human variation will provide enormous insight into central mechanisms of IBD; leveraging naturally occurring human genetic variation to systematic "perturb" an experimental system represents a highly innovative approach for precisely defining established and novel PRR-mediated mechanisms of cytokine secretion. Therefore, we will utilize a large, well- powered cohort to screen for IBD-associated polymorphisms contributing to the variation in PRR-initiated cytokine secretion across individuals, and then define the molecular mechanisms wherein the implicated IBD-associated genes, as well as the identified polymorphisms, regulate PRR-induced cytokine secretion.