University of Miami IBD Genetic Research Center: Understanding the Genetic Architecture of IBD in the LatinX Community

项目总结 炎症性肠病(IBD)是一种常见的、毁灭性的免疫介导性疾病，在这种疾病中 粘膜免疫系统异常识别导致慢性炎症的肠道细菌群。 大约有1%的美国人口受到影响。克罗恩病(CD)和溃疡性结肠炎的病因 (UC)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。IBD 发达国家的发病率已经持平，而新兴工业化国家的发病率正在上升。在美国，我们是 见证了来自世界低风险地区，特别是拉美裔美国人的移民发生率的上升。这提供了 一个发现疾病发病机制的机会，朝着预防和改进治疗的目标迈进。 不幸的是，包括IBDGC在内的大多数IBD的遗传学研究都集中在欧洲人身上。 来自北美和欧洲的祖先。此外，大多数IBD药物的临床试验包含的药物太少 西班牙裔或黑人，因此不代表受影响人口的总数。 我们小组对拉丁美洲移民和美国出生的IBD有专门的研究兴趣 西班牙裔病人。我们已经发表了被高度引用的西班牙裔IBD的基因和表型研究 佛罗里达州南部的人口。我们还描述了药物使用和手术率的差异。重要 对于IBD是由基因-环境相互作用引起的观点，我们发现IBD发生得更快 在过去的20年里，来自拉丁美洲的移民。我们的收集工作非常成功 因为我们的地理位置以及我们对拉美裔社区的承诺和参与。我们有独一无二的 在拉美裔人口中研究这种疾病的机会和义务。迈阿密-戴德县超过50% 西班牙裔。佛罗里达州是拉美裔人口第三多的州，在国家方面也是最多样化的 原产地。我们准备在IBDGC赠款的支持下，将我们的收集工作扩大到更广泛的州 来自佛罗里达州。全基因组关联研究(GWAS)促进了以前未被认识的 IBD中的基因和途径，并为公正地探索患者的基因组提供了机会 患有IBD。我们将通过以下方式探索在美国出生和在外国出生的大量拉美裔IBD病例的基因变异 关注移民和第一代移民之间的目标基因组、转录和表观遗传学差异 患有IBD的西班牙裔美国人。我们将教化基因和环境如何相互作用，从而产生不同的表型 炎症性肠病的表现。我们的团队对以前绘制精细地图的方法具有特殊的专业知识和兴趣 确定风险基因座并了解当地遗传血统对基因-血统相互作用的影响 以识别具有功能意义的遗传变异为目标。我们的 拟议的研究将扩大对IBD疾病表型和遗传基础的了解 西班牙裔群体，希望开发预防和改进治疗方法。 我们将利用两个PI的互补优势来推动发现，并实现 NIDDK IBD遗传学联盟(IBDGC)在美国扩大拉美裔IBD患者的集合。

PROJECT SUMMARY 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. Approximately, 1% of the US population is affected. The causes of Crohn's disease (CD) and ulcerative colitis (UC) lie in the interplay between host response genes and a microbiome with pathogenic properties. IBD incidence has leveled off in the developed world and rising in the newly industrialized world. In the US, we are witnessing a rising incidence in immigrants from low-risk parts of the world, particularly Hispanics. This provides an opportunity for discovery of disease pathogenesis towards a goal of prevention and improved therapies. Unfortunately, most genetic studies of IBD, including from the IBDGC, have focused on individuals of European ancestry from North America and Europe. Moreover, most clinical trials of IBD medications include too few Hispanics or Blacks and thus do not represent the totality of the affected population. Our group has a dedicated research interest on IBD in Latin-American immigrants and American-born Hispanic patients. We have published highly-cited studies of the genotype and phenotype of IBD in the Hispanic population of South Florida. We have also described disparities in medication usage and surgical rates. Important for the notion that IBD is caused by a gene-environment interaction, we have found that IBD is occurring faster in the last 20 years in immigrants from Latin-America. We have been very successful in our collection efforts because of our location and our commitment and engagement in the Hispanic community. We have a unique opportunity and obligation to study this disease within the Hispanic population. Miami-Dade County is over 50% Hispanic. The state of Florida has the 3rd largest Hispanic population and the most diverse in terms of countries of origin. We are poised with the support of an IBDGC grant to expand our collection efforts to the broader state of Florida. Genome-wide association studies (GWAS) have facilitated the discovery of previously unrecognized genes and pathways in IBD and provided the opportunity for unbiased exploration of the genomes of patients with IBD. We will explore genetic variation in a large set of US-born and foreign-born Hispanic IBD cases by focusing on targeted genomic, transcriptomic, and epigenetic differences between immigrant and first-generation Hispanic-Americans with IBD. We will edify how genes and environment interact to result in diverse phenotypic manifestations of IBD. Our group has particular expertise and interest in methods to fine-map previously identified risk loci and access the impact of local genetic ancestry on genotype-ancestry interactions in relation to phenotypic characteristics, with the goal of identifying genetic variation of functional significance. Our proposed studies will expand knowledge of disease phenotype and genetic underpinnings in IBD in this growing Hispanic cohort in the hopes of developing prevention and improved treatment approaches. We will use the complementary strengths of the two PIs to catapult discoveries and meet the goals of the NIDDK IBD Genetics Consortium (IBDGC) to expand the collection of Hispanic IBD patients in the US.