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

• 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
• 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' 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

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，影响约140万美国人。IBD流行病学的一个中心特征是德系犹太人的患病率增加了4.3-7.7倍。目前尚不清楚是什么因素导致了这种较高的发病率。本提案将通过测试两个假设来解决这一差距。首先，我们假设，目前的全基因组关联研究（GWAS）平台没有很好地分析高影响的罕见变异导致了德系犹太人的IBD。另一种假设是，德系犹太人的正选择，可能涉及涉及共同等位基因的多个位点的功能网络，显著贡献