Defining the genetic architecture of IBD in Ashkenazi Jewish populations

定义德系犹太人群体中 IBD 的遗传结构

基本信息

批准号：
8371995
负责人：
JUDY H. CHO
金额：
$ 52.61万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8371995
关键词：
19p13 19q13 Accounting Address Affect Alleles American Antigen-Antibody Complex Architecture Ashkenazim Biological Assay Case-Control Studies Cells Chromosomes Crohn&apos s disease Custom Data Data Set Development Disease Disease Association Disease model Epidemiology Etiology European Frequencies Functional disorder Gene Frequency Genes Genetic Genetic Drift Genome Genotype Haplotypes Heritability Immune Inflammatory Bowel Diseases Knowledge Logistic Regressions Major Histocompatibility Complex Maps Measures Mediating Medical Modeling Molecular Morbidity - disease rate Nature Odds Ratio Pathogenesis Pattern Play Population Predisposition Prevalence Recording of previous events Recruitment Activity Regression Analysis Resolution Risk Role Signal Transduction TNF gene Testing Ulcerative Colitis Variant base case control cohort exome follower of religion Jewish genome sequencing genome wide association study improved mortality population based response success

项目摘要

DESCRIPTION (provided by applicant): The inflammatory bowel diseases (IBD) are comprised of Crohn's disease and ulcerative colitis and affect approximately 1.4 million Americans. A central feature of IBD epidemiology is the 4.3-7.7 fold increased prevalence of disease in Ashkenazi Jewish populations. It is unknown at present what factors account for this higher disease prevalence. This proposal will address this gap through testing two hypotheses. First, we hypothesize that uncommon variation of higher effects not well assayed by present genome-wide association study (GWAS) platforms contributes to IBD in Ashkenazi Jewish populations. An alternative hypothesis is that positive selection in the Ashkenazim, possibly involving a functional network of multiple loci involving common alleles, significantly contributes to the higher disease prevalence. Preliminary data are provided detailing a) the genetic architecture of IBD, with the unique absence of a dominant major histocompatibility complex in Crohn's disease, b) the precise nature of the population substructure between Jewish and non-Jewish European ancestry cohort, c) results of a genome-wide association study in Ashkenazi Jewish Crohn's disease which demonstrate a largely similar genetic architecture for common alleles, d) exome sequencing results in Jewish Crohn's disease cases, demonstrating the presence of uncommon alleles unique to the Ashkenazim, e) the present inadequacy of present reference sequences in critical immunoregulatory regions such as the KIR region on chromosome 19p13, f) enrichment of immune-mediated association signals in Th17-enriched cell subsets, and g) the improved molecular resolution achieved through RNASeq. A complete exploration of the underlying etiology for the markedly increased IBD prevalence in the Ashkenazim will be achieved through the interrogation of uncommon SNPs in the exome and throughout the genome through case control studies (Specific Aim 1). Important in this regard will be the ascertainment of large case-control cohorts, for which additional recruitment is proposed. The presence of uncommon risk alleles in the Ashkenazim might result from genetic drift, given their unique population history. An alternate possibility is that positive selection wthin the Ashkenazim at multiple loci, acting as a functional module, increases risk for IBD, and contributes to the higher disease prevalence compared to non-Jewish European ancestry cohorts. Refined definitions of associated alleles through regression analysis and functional annotation, together with interrogation of weaker effect alleles, will result in an aggregate estimate of the extent to which identified susceptibility alleles account for the higher disease prevalence in the Ashkenazim (Specific Aim 2). As with heritability, these estimates will provide a key measure of assessing the completeness of identified genetic factors in defining disease pathophysiology. PUBLIC HEALTH RELEVANCE: Defining the genetic factors that are associated to inflammatory bowel disease will help define the earliest steps in disease development. A major pathophysiologic clue to disease pathogenesis is the several-fold higher disease prevalence in the Ashkenazi Jewish population. This proposal outlines several complementary approaches to fully leverage unique features of this population to define mechanisms of disease pathogenesis. Identifying these early factors thoroughly will assist ultimately with the development of improved therapies.

描述（由申请人提供）：炎症性肠病（IBD）由克罗恩病和溃疡性结肠炎组成，影响大约 140 万美国人。 IBD 流行病学的一个核心特征是德系犹太人群体中疾病患病率增加了 4.3-7.7 倍。目前尚不清楚是什么因素导致了这种较高的疾病患病率。该提案将通过测试两个假设来解决这一差距。首先，我们假设当前全基因组关联研究 (GWAS) 平台未充分分析的不常见的较高效应变异导致德系犹太人群体中的 IBD。另一种假设是德系犹太人中的正选择，可能涉及涉及共同等位基因的多个基因座的功能网络，显着有助于导致疾病患病率较高。提供了初步数据，详细说明了 a) IBD 的遗传结构，克罗恩病中独特地缺乏显性的主要组织相容性复合物，b) 犹太人和非犹太人欧洲血统群体之间人口亚结构的精确性质，c) 结果德系犹太人克罗恩病的一项全基因组关联研究证明了常见等位基因的遗传结构在很大程度上相似，d) 犹太克罗恩病病例的外显子组测序结果表明存在德系犹太人独有的罕见等位基因，e) 关键免疫调节区域（例如染色体 19p13 上的 KIR 区域）中现有参考序列的不足，f) 富含 Th17 的细胞亚群中免疫介导的关联信号的富集，以及 g) 改进的通过 RNASeq 实现分子分辨率。通过病例对照研究（具体目标 1），对外显子组和整个基因组中不常见的 SNP 进行询问，从而全面探索德系犹太人 IBD 患病率显着增加的根本病因。在这方面，重要的是确定大型病例对照队列，为此建议进行额外招募。鉴于德系犹太人独特的种群历史，其罕见风险等位基因的存在可能是由遗传漂变造成的。另一种可能性是，与非犹太欧洲血统群体相比，德系犹太人中多个基因座的正选择作为功能模块，增加了 IBD 的风险，并导致更高的疾病患病率。通过回归分析和功能注释对相关等位基因进行精确定义，再加上对较弱效应等位基因的询问，将得出对已确定的易感性等位基因在德系犹太人中较高疾病患病率的解释程度的总体估计（具体目标 2）。与遗传力一样，这些估计值将提供评估已确定的遗传因素在定义疾病病理生理学方面的完整性的关键措施。公共卫生相关性：定义与炎症性肠病相关的遗传因素将有助于确定疾病发展的最早步骤。疾病发病机制的一个主要病理生理学线索是德系犹太人群体中疾病患病率高出数倍。该提案概述了几种补充方法，以充分利用该人群的独特特征来定义疾病发病机制。彻底识别这些早期因素将最终有助于开发改进的疗法。