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初始驱动因素。在与IBD相关的163个基因座中，一系列可能的基因在许多水平上调节宿主对PRR的反应，并赋予自身免疫中观察到的一些最大的遗传效应大小。尽管在过去的几年里在IBD相关的多态性方面有了重大的发现，但这些基因座中的绝大多数的功能后果还没有确定。细菌和病毒产物激活PRR的一个主要结果是诱导细胞因子的分泌。在很大程度上，IBD的特点是细胞因子的调节失调，而细胞因子的调节在IBD的治疗中起着主要作用。PRR诱导的细胞因子分泌的个体差异影响感染易感性和炎症性疾病之间的平衡。我们假设，多个IBD相关基因的多态有助于PRR诱导的细胞因子分泌的个体间差异。全面定义疾病相关人类变异驱动的功能变化的系统、强大的研究将为IBD的核心机制提供巨大的洞察力；利用自然发生的人类遗传变异来系统地“扰乱”一个实验系统代表了一种高度创新的方法，用于精确定义已建立的和新的PRR介导的细胞因子分泌机制。因此，我们将利用一个庞大的、功能强大的队列来筛选导致PRR启动的细胞因子分泌在个体之间变化的IBD相关多态，然后定义涉及的IBD相关基因以及已识别的多态调节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.