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.

背景：炎症性肠病（IBD）是胃肠道的慢性炎症疾病 与生活质量差有关的道。 IBD无法治愈，大多数人都需要终身 免疫抑制药物，也经常需要手术。克罗恩病（CD）和 IBD的两种最常见形式的溃疡性结肠炎（UC）尚不清楚，但已广泛认为它们是 在响应最引人注目的环境因素的一般易感人群中发展 证据是微生物组。传统上被认为是北欧（EUA）和Ashkenazi的疾病 犹太血统IBD的患病率在诸如西班牙裔和非洲人等少数民族中迅速上升 美国人口的研究不足。我们研究的目标包括： 西班牙裔人群中IBD遗传建筑的描述；描述基因 - 微生物组 西班牙裔的互动；了解对最多反应的基本分子原因 IBD中广泛使用的生物疗法；重要的是，将决定一些功能效应的工作 这些遗传变异。我们将通过解决以下特定目标来实现这些目标。在目标1中 我们将破译IBD的遗传结构，并使用生物标志物研究宿主 - 微生物组相互作用 基于推理方法。在AIM 2中，我们将使用先进的技术研究基因和蛋白质表达 在肠壁中的单个细胞中，以识别与药物反应相关的特征。在目标3中 我们将使用人类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：在合作中，我们将建立最大的西班牙血统IBD主题集合 使用最先进的遗传方法来识别与IBD发展相关的遗传信号。我们 预计这些信号中的一些会与我们在EUA主题中观察到的信号重叠，而其他信号将是 西班牙裔人口独有。由于北部有美国原住民血统的大量混合 美国人口，我们预计我们还将确定一些对本地的遗传信号 美国人。很少有研究研究非欧盟种群中的宿主 - 微生物组相互作用 我们将通过调查血清标记物来解决这一问题，这些标记是微生物组的替代物，从而允许 我们第一次研究西班牙裔遗传变异与微生物组之间的相互作用 人群。同时，我们将研究来自肠道活检中的基因表达特征，以确定 分子特征是我们最有效的无反应的非常重要的临床问题的基础 药物。最后，我们使用模型系统来确定遗传变异的功能后果 我们已经确定了。我们将使用我们已经收集的非常大的细胞系列库 并使用创新的方法将其转换为肠状上皮器官。细胞系将优先考虑 基于我们在包括西班牙裔研究在内的大型遗传研究中发现的遗传变异。

项目成果

Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function.

• DOI: 10.1038/s41598-021-98120-7
• 发表时间: 2021-09-29
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Yang T;Jackson VE;Smith AV;Chen H;Bartz TM;Sitlani CM;Psaty BM;Gharib SA;O'Connor GT;Dupuis J;Xu J;Lohman K;Liu Y;Kritchevsky SB;Cassano PA;Flexeder C;Gieger C;Karrasch S;Peters A;Schulz H;Harris SE;Starr JM;Deary IJ;Manichaikul A;Oelsner EC;Barr RG;Taylor KD;Rich SS;Bonten TN;Mook-Kanamori DO;Noordam R;Li-Gao R;Jarvelin MR;Wielscher M;Terzikhan N;Lahousse L;Brusselle G;Weiss S;Ewert R;Gläser S;Homuth G;Shrine N;Hall IP;Tobin M;London SJ;Wei P;Morrison AC
• 通讯作者: Morrison AC

Myeloid ATG16L1 Facilitates Host-Bacteria Interactions in Maintaining Intestinal Homeostasis.

• DOI: 10.4049/jimmunol.1601293
• 发表时间: 2017-03-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Zhang H;Zheng L;McGovern DP;Hamill AM;Ichikawa R;Kanazawa Y;Luu J;Kumagai K;Cilluffo M;Fukata M;Targan SR;Underhill DM;Zhang X;Shih DQ
• 通讯作者: Shih DQ

Fine-mapping inflammatory bowel disease loci to single-variant resolution.

• DOI: 10.1038/nature22969
• 发表时间: 2017-07-13
• 期刊: Nature
• 影响因子: 64.8
• 作者: Huang H;Fang M;Jostins L;Umićević Mirkov M;Boucher G;Anderson CA;Andersen V;Cleynen I;Cortes A;Crins F;D'Amato M;Deffontaine V;Dmitrieva J;Docampo E;Elansary M;Farh KK;Franke A;Gori AS;Goyette P;Halfvarson J;Haritunians T;Knight J;Lawrance IC;Lees CW;Louis E;Mariman R;Meuwissen T;Mni M;Momozawa Y;Parkes M;Spain SL;Théâtre E;Trynka G;Satsangi J;van Sommeren S;Vermeire S;Xavier RJ;International Inflammatory Bowel Disease Genetics Consortium;Weersma RK;Duerr RH;Mathew CG;Rioux JD;McGovern DPB;Cho JH;Georges M;Daly MJ;Barrett JC
• 通讯作者: Barrett JC

Increased Prevalence of Inflammatory Bowel Disease in Patients with Mutations in Genes Encoding the Receptor Subunits for TGFβ.

• DOI: 10.1097/mib.0000000000000872
• 发表时间: 2016-09
• 期刊: Inflammatory bowel diseases
• 影响因子: 4.9
• 作者: Guerrerio AL;Frischmeyer-Guerrerio PA;Huang C;Wu Y;Haritunians T;McGovern DPB;MacCarrick GL;Brant SR;Dietz HC
• 通讯作者: Dietz HC

Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.

• DOI: 10.1053/j.gastro.2015.07.065
• 发表时间: 2015-11
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Huang C;Haritunians T;Okou DT;Cutler DJ;Zwick ME;Taylor KD;Datta LW;Maranville JC;Liu Z;Ellis S;Chopra P;Alexander JS;Baldassano RN;Cross RK;Dassopoulos T;Dhere TA;Duerr RH;Hanson JS;Hou JK;Hussain SZ;Isaacs KL;Kachelries KE;Kader H;Kappelman MD;Katz J;Kellermayer R;Kirschner BS;Kuemmerle JF;Kumar A;Kwon JH;Lazarev M;Mannon P;Moulton DE;Osuntokun BO;Patel A;Rioux JD;Rotter JI;Saeed S;Scherl EJ;Silverberg MS;Silverman A;Targan SR;Valentine JF;Wang MH;Simpson CL;Bridges SL;Kimberly RP;Rich SS;Cho JH;Rienzo AD;Kao LWH;McGovern DPB;Brant SR;Kugathasan S
• 通讯作者: Kugathasan S