INNATE IMMUNE PATHWAYS AND THE MICROBIOME IN HISPANICS WITH INFLAMMATORY BOWEL DISEASE

 描述(申请人提供)：炎症性肠病(IBD)是一种常见的、毁灭性的免疫介导性疾病，其粘膜免疫系统异常识别导致慢性炎症的肠道细菌群。IBD的原因可能在于宿主反应基因和具有致病特性的微生物群之间的相互作用。大多数IBD研究都集中在北美和欧洲的高加索人群。在美国，拉美裔人口正在迅速增长，这一群体中IBD的发病率也在迅速上升--然而，人们对可能导致易感性的基因或可能促进疾病表现的微生物群等因素知之甚少。最近对IBD易感性的荟萃分析，利用全基因组数据，在欧洲血统人群的研究中确定了140个CD特异性基因座。我们有一个独特的机会来研究南佛罗里达州西语裔CD患者的遗传学、免疫学和微生物组之间的相互作用。初步分析表明，尽管拉美裔和NHW之间的遗传负担相似，但特定IBD变异的频率不同。我们发现，在外国出生的拉美裔患者的微生物区系与在美国出生的拉美裔IBD患者不同。基于这些观察，我们假设，在西班牙裔IBD患者中，不同的先天性免疫途径发生了变化，这是由他们潜在的混合遗传祖先决定的。我们进一步假设，与美国出生的拉美裔美国人或NHW相比，拉美裔移民的黏膜微生物组将显示出向日益有害的微生物区系的转变，这将反映在黏膜基因表达的变化上。为了验证这一假设，我们将追求三个相关但独立相关的具体目标。在目标1中，我们将探索西班牙裔CD患者的IBD风险等位基因和遗传结构及其与表型预后的关系。我们计划将收集的IBD拉美裔患者增加到1000人，这是以前从未做过的。我们将研究已知的和新的西班牙裔特有基因和表型之间的关系。AIM 2将研究患有CD的西班牙裔移民与第一代西班牙裔美国人或非西班牙裔白人相比的微生物群变化。我们开发了一种创新的策略，包括对固有层吞噬细胞中的微生物区系进行深度测序。目的3，将分析西班牙裔移民与第一代西班牙裔美国人和患有CD的非西班牙裔白人黏膜的先天免疫反应。我们将与Eric Schadt博士合作，整合在三个目标中收集的数据，以确定以前从未以如此全面、分层的方式探索的途径。通过关注患有CD的移民和第一代拉美裔美国人之间的靶向基因组、转录和微生物组差异，我们希望启迪基因和微生物如何相互作用导致CD的不同表型表现。我们将以此为平台，利用NIDDK IBD遗传学联盟(IBDGC)在高加索美国人中正在进行的努力。

 DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a common and devastating immune-mediated disease in which the mucosal immune system abnormally recognizes the intestinal bacterial flora leading to chronic inflammation. The causes of IBD may lie in the interplay between host response genes and a microbiome with pathogenic properties. Most IBD studies have focused on Caucasian populations in North America and Europe. In the US, the population of Hispanics is rising rapidly as is the incidence of IBD in this group-yet litte is known about the genes that may confer susceptibility or factors such as the microbiome that may be promoting disease expression. The most recent meta-analysis of IBD susceptibility, using genome-wide data, identified 140 CD specific loci in studies of European descent populations. We have a unique opportunity to study the interface of genetics, immunology, and the microbiome in South Florida Hispanic patients with CD. A preliminary analysis shows that although the genetic burden is similar between Hispanics and NHWs, the frequency of specific IBD variants is not. We have found that the microbiota of foreign-born Hispanic patients differs from US-born Hispanic IBD patients. Based on these observations, we hypothesize that distinct innate immune pathways are altered in Hispanics with IBD shaped by their underlying admixed genetic ancestry. We further hypothesize that the mucosal microbiome of Hispanic immigrants compared with US-born Hispanics or NHWs will demonstrate a shift towards increasingly dysbiotic microbiota that will be reflected in gene expression changes in the mucosa. To test this hypothesis, we will pursue three related but independently-relevant Specifc Aims. In Aim 1, we will Explore IBD risk alleles and genetic structure in Hispanic patients with CD and its relationship to phenotypic outcomes. We plan to increase our collection to 1000 Hispanic patients with IBD which has never been done before. We will look at the relationship of known and novel Hispanic-specific genes and phenotype. Aim 2 will examine microbiome changes in Hispanic immigrants compared with first-generation Hispanic-Americans or non-Hispanic whites with CD. We have developed an innovative strategy involving deep sequencing of the microbiota in lamina propria phagocytes. Aim 3, will analyze innate immune responses in the mucosa of Hispanic immigrants compared with first-generation Hispanic-Americans and non-Hispanic whites with CD. We will collaborate with Dr. Eric Schadt to integrate the data gathered in the three aims to identify pathways that have not been previously explored in such a comprehensive, layered fashion. By focusing on targeted genomic, transcriptomic, and microbiome differences between immigrant and first-generation Hispanic-Americans with CD, we hope to edify how genes and microbes interact to result in diverse phenotypic manifestations of CD. We will use this as a platform to leverage the ongoing efforts of the NIDDK IBD Genetics Consortium (IBDGC) in Caucasian-Americans.