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

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Principal Investigator: Dermot Patrick McGovern
Organization: CEDARS-SINAI MEDICAL CENTER
Fiscal Year: 2024
Award: $546,312
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

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.

Terms: <(TNF)-α><Address><Admixture><African American group><African American individual><African American people><African American population><African Americans><American><Anti-Tumor Necrosis Factor Therapy><Ants><Area><Assay><Bacteria><Bioassay><Biologic Models><Biological Assay><Biological Markers><Biological Models><Biological Response Modifier Therapy><Biological Therapy><Biopsy><Cachectin><Cell Body><Cell Communication and Signaling><Cell Culture System><Cell Line><Cell Signaling><CellLine><Cells><Chronic><Clinical><Code><Coding System><Collaborations><Collection><Complex><Coupled><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><Data><Development><Digestive Diseases><Digestive System Diseases><Digestive System Disorders><Disease><Disease Progression><Disease remission><Disorder><Drugs><Elements><Environment><Environmental Factor><Environmental Risk Factor><Epithelium><European><European ancestry><Expression Signature><GI tract disorder><Gene Expression><Gene Expression Profile><Gene Transcription><Gene variant><Genes><Genetic><Genetic Diversity><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic Transcription><Genetic Variation><Genetic analyses><Genetic propensity><Genetic study><Granulomatous Enteritis><Health Care Costs><Health Care Utilization><Health Costs><Healthcare Costs><Heritability><Hispanic><Hispanic Americans><Hispanic Populations><Hispanic ancestry><Hispanic descent><Hispanic group><Hispanic individual><Hispanic people><Hispanics><Human><Immune><Immune response><Immunes><Immunological response><Incidence><Individual><Individuals from minority><Individuals of minority><Inflammatory><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Infrastructure><Inherited Predisposition><Inherited Susceptibility><Intestinal><Intestines><Intracellular Communication and Signaling><Investigation><Jewish><Judaism><Knowledge><Macrophage-Derived TNF><Maps><Mediating><Medical><Medication><Minority Groups><Minority People><Minority Population><Minority individual><Model System><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Monocyte-Derived TNF><Morbidity><Morbidity - disease rate><Native American Ancestry><Native American genetic ancestry><Native Americans><Operative Procedures><Operative Surgical Procedures><Organoids><Outcome><Pathway interactions><Patients><Peripheral><Persons><Pharmaceutical Preparations><Population><Population Heterogeneity><Predisposition><Predisposition gene><Prevalence><Prospective cohort><QOL><Quality of life><RNA Expression><Recurrence><Recurrent><Remission><Reporting><Research><Research Design><Research Resources><Resources><Science><Serology><Serum Markers><Signal Transduction><Signal Transduction Systems><Signaling><Strains Cell Lines><Study Type><Surgical><Surgical Interventions><Surgical Procedure><Surrogate Markers><Susceptibility><Susceptibility Gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Technology><Testing><Time><Transcription><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Ulcerated Colitis><Ulcerative Colitis><Underrepresented Ethnic Minority><Underrepresented Groups><Underrepresented Minority><Underrepresented Populations><Variant><Variation><Work><admixture mapping><allele variant><allelic variant><anti-TNF therapy><anti-TNF-alpha therapy><bio-markers><biobank><biologic marker><biological signal transduction><biological therapeutic><biological treatment><biologically based therapeutics><biomarker><biorepository><biotherapeutics><biotherapy><bowel><cell bank><cellular targeting><chronic inflammatory disease><clinical remission><cohort><cultured cell line><developmental><digestive disorder><digestive tract disease><diverse populations><drug/agent><effective therapy><effective treatment><eleocolitis><environmental risk><exome sequencing><exome-seq><follower of religion Jewish><gastrointestinal tract disease><gastrointestinal tract disorder><gene expression pattern><gene expression signature><genetic analysis><genetic approach><genetic architecture><genetic etiology><genetic mechanism of disease><genetic strategy><genetic variant><genetic vulnerability><genetically predisposed><genomic variant><health care service use><health care service utilization><healthcare service use><healthcare service utilization><healthcare utilization><heterogeneous population><host microbiome><host response><iPS><iPSC><iPSCs><immune system response><immunoresponse><improved><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><inflammatory disease of the intestine><inflammatory disorder of the intestine><innovate><innovation><innovative><innovative technologies><insight><intestinal autoinflammation><intestinal epithelium><microbial><microbiome><molecular profile><molecular signature><multi-modality><multimodality><new drug treatments><new drugs><new marker><new pharmacological therapeutic><new technology><new therapeutics><new therapy><next generation therapeutics><novel><novel biomarker><novel drug treatments><novel drugs><novel marker><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel technologies><novel therapeutics><novel therapy><pathway><population diversity><predisposing gene><protein expression><proteogenomics><recruit><regional enteritis><resistance mechanism><resistant mechanism><response><social disadvantage><social disparities><social inequality><study design><surgery><surrogate bio-markers><surrogate biomarkers><susceptibility allele><susceptibility locus><susceptibility variant><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptional profile><transcriptional signature><translation strategy><translational approach><translational strategy><treatment strategy><under representation of groups><under represented groups><under represented people><under represented populations><under-representation of minorities><under-represented minority><underrepresentation of groups><underrepresentation of minorities><underrepresented people>