Determining genomic and host-environment contributions to IBD phenotypes

Cedars-Sinai Medical Center, West Hollywood CA

Investigators

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Abstract

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. IBD is rapidly rising in all populations and across all geographic regions. The objectives of our study include: the delineation of the genetic architecture of IBD across all US populations; describe the gene (host) and microbiome (environment) interactions that lead to an increase in IBD across US populations; an understanding of the underlying molecular causes of lack of response to the most widely used advanced 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 ‘global’ gene and protein expression as well as expression in individual cells in blood and 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 continue to build large datasets from IBD subjects from across the US and using state of the art genetic approaches, we will identify genetic signals associated with development of IBD. We will investigate the overlap in signals across US populations and use these resources to dig deep into the genetic structure to identify ‘causative’ genetic variants. Studies investigating host-environment interactions in the development of IBD have been lacking and we will address this by investigation of serum markers that are surrogates for the microbiome thereby allowing us, for the first time, to interrogate interactions between genetic variation and the microbiome across US populations. In parallel, we will look at gene and protein expression signatures from blood and 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 will use model systems to determine the functional consequences of the genetic variants that we have identified. We will do 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-scale genetic studies outlined above.