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

项目摘要 炎症性肠病（IBD）是一种常见的破坏性免疫介导的疾病， 粘膜免疫系统异常识别肠细菌植物群，导致慢性炎症。 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组之间的相互作用。IBD 发达国家的发病率趋于平稳，而新兴工业化国家的发病率则在上升。在美国，我们 来自世界低风险地区的移民，特别是西班牙裔移民的发病率正在上升。这提供 这是发现疾病发病机制的机会，从而实现预防和改进治疗的目标。 不幸的是，大多数IBD的遗传研究，包括来自IBDGC的研究，都集中在欧洲人的个体上。 祖先来自北美和欧洲。此外，大多数IBD药物的临床试验包括太少 西班牙裔或黑人，因此不代表受影响人口的全部。 我们的小组对拉丁美洲移民和美国出生的IBD有专门的研究兴趣。 西班牙裔患者我们已经发表了关于西班牙人IBD基因型和表型的高引用研究， 南佛罗里达的人口。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这一观点，我们发现IBD的发生速度更快， 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西班牙裔社区的承诺和参与。我们有一个独特 在西班牙裔人群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拥有第三大西班牙裔人口，并且在国家方面最多样化 混元我们准备在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。全基因组关联研究（GWAS）促进了以前未被发现的 IBD的基因和途径，并提供了无偏见的探索患者的基因组的机会， 关于IBD我们将通过以下方式探索大量美国出生和外国出生的西班牙裔IBD病例的遗传变异： 专注于移民和第一代之间有针对性的基因组，转录组和表观遗传差异 患有IBD的美国人我们将启发如何基因和环境相互作用，导致不同的表型 IBD的表现。我们的团队对先前精细映射的方法具有特殊的专业知识和兴趣 确定风险位点，并访问当地遗传祖先对基因型-祖先相互作用的影响， 表型特征，目的是鉴定具有功能意义的遗传变异。我们 拟议的研究将扩大对IBD疾病表型和遗传基础的认识， 西班牙裔队列，希望开发预防和改善治疗方法。 我们将利用这两个PI的互补优势来推动发现并实现 NIDDK IBD Genetics Consortium（IBDGC），以扩大美国西班牙裔IBD患者的收集。

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.