Understanding genetic architecture and host-microbiome interactions in Inflammatory bowel disease in under-represented minority populations and in patients with unmet medical need.

了解代表性不足的少数群体和医疗需求未得到满足的患者中炎症性肠病的遗传结构和宿主-微生物组相互作用。

• 批准号: 10707113
• 负责人: Dermot Patrick McGovern
• 金额: $ 56.91万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707113
• 关键词: Address; Admixture; African American population; American; Anti-Tumor Necrosis Factor Therapy; Ants; Area; Bacteria; Biological Assay; Biological Markers; Biological Models; Biological Response Modifier Therapy; Biopsy; Cell Culture System; Cell Line; Cells; Chronic; Clinical; Code; Collaborations; Collection; Complex; Coupled; Crohn' s disease; Data; Development; Digestive System Disorders; Disease; Disease Progression; Disease remission; Elements; Environment; Environmental Risk Factor; Epithelium; European; European ancestry; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genetic Variation; Genetic study; Health Care Costs; Heritability; Hispanic; Hispanic Americans; Hispanic Populations; Hispanic ancestry; Human; Immune; Immune response; Incidence; Individual; Inflammatory; Inflammatory Bowel Diseases; Infrastructure; Intestines; Investigation; Knowledge; Maps; Mediating; Medical; Minority Groups; Molecular; Molecular Profiling; Morbidity - disease rate; Native American Ancestry; Native Americans; Operative Surgical Procedures; Organoids; Outcome; Pathway interactions; Patients; Peripheral; Persons; Pharmaceutical Preparations; Population; Population Heterogeneity; Predisposition; Prevalence; Prospective cohort; Quality of life; Recurrence; Reporting; Research; Research Design; Resources; Science; Serology; Serum Markers; Signal Transduction; Surrogate Markers; Susceptibility Gene; TNF gene; Technology; Testing; Time; Ulcerative Colitis; Underrepresented Minority; Underrepresented Populations; Variant; Work; admixture mapping; biobank; cell bank; cellular targeting; chronic inflammatory disease; clinical remission; cohort; effective therapy; exome sequencing; follower of religion Jewish; genetic analysis; genetic approach; genetic architecture; genetic variant; health care service utilization; host microbiome; improved; induced pluripotent stem cell; innovation; innovative technologies; insight; intestinal epithelium; microbial; microbiome; multimodality; new technology; novel; novel marker; novel therapeutics; protein expression; proteogenomics; recruit; resistance mechanism; response; social disparities; targeted treatment; translational approach; treatment strategy

Background: The inflammatory bowel diseases (IBD) are a chronic inflammatory disease of the gastrointestinal tract that are associated with a poor quality of life. There is no cure for IBD, and most people require lifelong immunosuppressive medication and also frequently need surgery. The cause of Crohn’s disease (CD) and ulcerative colitis (UC), the two most common forms of IBD, are unknown but it is widely accepted that they develop in genetically susceptible individuals in response to environmental factors for which the most compelling evidence is the microbiome. Traditionally regarded as diseases of Northern European (EUA) and Ashkenazi Jewish ancestry the prevalence of IBD is rapidly rising in minority populations such as Hispanic and African American populations who have been under-represented in research. The objectives of our study include: the delineation of the genetic architecture of IBD in Hispanics populations; describe the gene-microbiome interactions in Hispanics; an understanding of the underlying molecular causes of lack of response to the most widely used biologic therapies in IBD; and importantly, work that will determine some of the functional effects of these genetic variants. We will achieve these objectives by addressing the following specific aims. In aim 1 we will decipher genetic architecture of IBD and investigate host-microbiome interactions using a biomarker- based inference approach. In aim 2 we will use advanced technology investigating gene and protein expression in individual cells in the lining of the gut to identify signatures associated with response to medication. In aim 3 we will use human intestinal epithelial cell culture systems to screen for function of new IBD susceptibility genes. Research Design: in collaboration we will build the largest collection of IBD subjects of Hispanic ancestry and use state of the art genetic approaches to identify genetic signals associated with development of IBD. We anticipate that some of these signals will overlap with those we’ve observed in EUA subjects and others will be unique to the Hispanic population. Since there is significant admixture of Native American ancestry in the North American population, we anticipate that we will also identify some genetic signals that are ‘peculiar’ to Native Americans. There have been few studies investigating host-microbiome interactions in Non-EUA populations and we will address this by investigation serum markers that are surrogates for the microbiome thereby allowing us, for the first time, to investigate interactions between genetic variation and the microbiome in Hispanic populations. In parallel we will look at gene expression signatures in biopsies from the gut to determine the molecular signature that underlies a very important clinical issue of non-response to our most effective medications. Finally, we use model systems to determine the functional consequences of the genetic variants that we have identified. We will due this using the very large bank of cell lines that we have already collected and use innovative approaches to convert these to gut-like epithelium organoids. The cell lines will be prioritized based on the genetic variants that we discover in our large genetic studies including the Hispanic studies.

【摘要】：背景:炎症性肠病(IBD)是一种慢性胃肠道炎症性疾病。 IBD 无法治愈，大多数人需要终生治疗。 免疫抑制药物，并且还经常需要手术治疗克罗恩病 (CD) 和 溃疡性结肠炎 (UC) 是 IBD 的两种最常见形式，目前尚不清楚，但人们普遍认为它们 遗传易感个体对环境因素的反应而发展，其中最引人注目的 证据是微生物组，传统上被认为是北欧（EUA）和德系犹太人的疾病。 犹太血统的 IBD 患病率在西班牙裔和非洲裔等少数群体中迅速上升 研究中代表性不足的美国人群我们的研究目标包括： 描述西班牙裔人群 IBD 的遗传结构；描述基因-微生物组； 西班牙裔人之间的相互作用；了解对大多数问题缺乏反应的根本分子原因。 IBD 中广泛使用的生物疗法；重要的是，这些工作将确定一些功能效应 我们将通过实现目标 1 中的以下具体目标来实现这些目标。 我们将破译 IBD 的遗传结构，并使用生物标志物研究宿主-微生物组的相互作用- 在目标 2 中，我们将使用先进的技术研究基因和蛋白质表达。 在目标 3 中，研究人员在肠道内壁的单个细胞中识别与药物反应相关的特征。 我们将利用人肠上皮细胞培养系统来筛选新的IBD易感基因的功能。 研究设计：通过合作，我们将建立最大的西班牙裔 IBD 受试者集合 我们使用最先进的遗传方法来识别与 IBD 发展相关的遗传信号。 预计其中一些信号将与我们在 EUA 受试者中观察到的信号重叠，而其他信号将与我们在 EUA 受试者中观察到的信号重叠 这是西班牙裔人口所独有的，因为北部有大量美洲原住民血统的混合。 在美国人口中，我们预计我们还将识别出一些原住民“特有”的遗传信号 美国人很少有研究调查非 EUA 人群中的微生物组相互作用。 我们将通过研究作为微生物组替代物的血清标志物来解决这个问题，从而允许 我们首次研究西班牙裔遗传变异与微生物组之间的相互作用 与此同时，我们将观察肠道活检中的基因表达特征，以确定 分子特征是对我们最有效的药物无反应这一非常重要的临床问题的基础 最后，我们使用模型系统来确定遗传变异的功能后果。 我们将使用我们已经收集的大量细胞系来解决这一问题。 并使用创新方法将它们转化为肠样上皮类器官，这些细胞系将被优先考虑。 基于我们在大型遗传研究（包括西班牙裔研究）中发现的遗传变异。

项目成果

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

通过测量和预测的基因表达对溃疡性结肠炎进展为结肠切除术的风险进行分层。

• DOI: 10.1016/j.ajhg.2021.07.013
• 发表时间: 2021-08-24
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: A. Mo;Sini Nagpal;K. Gettler;T. Haritunians;M. Giri;Y. Haberman;Rebekah A. Karns;J. Prince;D. Arafat;Nai;Ling;C. Argmann;A. Kasarskis;M. Suárez;Nathan M Gotman;E. Mengesha;S. Venkateswaran;P. Rufo;S. Baker;Cary G. Sauer;J. Markowitz;M. Pfefferkorn;J. Rosh;B. Boyle;D. Mack;R. Baldassano;Sapana R. Shah;N. LeLeiko;M. Heyman;A. Griffiths;A. Patel;J. Noe;Sonia Davis Thomas;B. Aronow;T. Walters;D. McGovern;J. Hyams;S. Kugathasan;Judy H. Cho;L. Denson;G. Gibson
• 通讯作者: G. Gibson

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis.

3p 染色体以基因为中心的关联图谱表明 MST1 在 IBD 发病机制中发挥着重要作用。

• 发表时间: 2008-03
• 影响因子: 8
• 作者: Goyette, P;Lefebvre, C;Ng, A;Brant, S R;Cho, J H;Duerr, R H;Silverberg, M S;Taylor, K D;Latiano, A;Aumais, G;Deslandres, C;Jobin, G;Annese, V;Daly, M J;Xavier, R J;Rioux, J D
• 通讯作者: Rioux, J D

Genome wide association (GWA) predictors of anti-TNFalpha therapeutic responsiveness in pediatric inflammatory bowel disease.

儿科炎症性肠病抗 TNFα 治疗反应的全基因组关联 (GWA) 预测因子。

• 发表时间: 2010-08
• 影响因子: 4.9
• 作者: Dubinsky, Marla C;Mei, Ling;Friedman, Madison;Dhere, Tanvi;Haritunians, Talin;Hakonarson, Hakon;Kim, Cecilia;Glessner, Joseph;Targan, Stephan R;McGovern, Dermot P;Taylor, Kent D;Rotter, Jerome I
• 通讯作者: Rotter, Jerome I

Ileal Gene Expression Data from Crohn's Disease Small Bowel Resections Indicate Distinct Clinical Subgroups.

克罗恩病小肠切除术的回肠基因表达数据表明不同的临床亚组。

• 发表时间: 2019-08-14
• 作者: Potdar, Alka A;Li, Dalin;Haritunians, Talin;VanDussen, Kelli L;Fiorino, Marie F;Liu, Ta;Stappenbeck, Thaddeus S;Fleshner, Phillip;Targan, Stephan R;McGovern, Dermot P B;Bilsborough, Janine
• 通讯作者: Bilsborough, Janine

Perianal Crohn's Disease is Associated with Distal Colonic Disease, Stricturing Disease Behavior, IBD-Associated Serologies and Genetic Variation in the JAK-STAT Pathway.

肛周克罗恩病与远端结肠疾病、限制疾病行为、IBD 相关血清学和 JAK-STAT 途径的遗传变异有关。

• 发表时间: 2016-04
• 影响因子: 4.9
• 作者: Kaur, Manreet;Panikkath, Deepa;Yan, Xiaofei;Liu, Zhenqiu;Berel, Dror;Li, Dalin;Vasiliauskas, Eric A;Ippoliti, Andrew;Dubinsky, Marla;Shih, David Q;Melmed, Gil Y;Haritunians, Talin;Fleshner, Phillip;Targan, Stephan R;McGovern, Dermot P B
• 通讯作者: McGovern, Dermot P B