^{Using a combination of genome-wide association, fine mapping, DNA sequencing and transcriptomic studies we aim to identify causal genes, their protective and predisposing variants, and biological contexts in which they exert their influences.  (images from PMID: 25559196, 29420262, 36038634).}

We aim to define the rare and common variants, both coding and non-coding, that influence an individual’s probability of developing one of the inflammatory bowel diseases (IBD) known as Crohn’s disease (CD) and ulcerative colitis (UC).

It is important to identify protective and predisposing genetic variants for multiple reasons: 

(1) to develop genetic tools such as polygenic risk scores that can aid in diagnosis; 

(2) to increase success rates of drug development efforts; and 

(3) to obtain a more comprehensive understanding of pathophysiologic mechanisms. 

While some IBD genes may be ubiquitously expressed, many are enriched in specific cells and tissues. We therefore aim to identify the appropriate biological context in which to study IBD genes and their causal variants, for example the relevant tissues and cell types.

Selected Publications:

Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility. Sazonovs A, et al. Nat Genet. 2022 Sep;54(9):1275-1283. doi: 10.1038/s41588-022-01156-2. Epub 2022 Aug 29.PMID: 36038634

Fine-mapping inflammatory bowel disease loci to single-variant resolution. Huang H, et al. Nature. 2017 Jul 13;547(7662):173-178. doi: 10.1038/nature22969. Epub 2017 Jun 28. PMID: 28658209 

High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis. Goyette P, et al. Nat Genet. 2015 Feb;47(2):172-9. doi: 10.1038/ng.3176. Epub 2015 Jan 5. PMID: 25559196 

^{Patient blood, Lymphoblastoid cell lines (LCLs), or skin fibroblast cells are reprogrammed into hiPSC, and then differentiated in a stepwise fashion either into monocyte or macrophage cultures (top) or into 2D and 3D intestinal epithelial cultures (bottom). These models are used to evaluate the impact of genetic variants on structural and functional characteristics.}

We aim to use the information from our IBD genetic studies to guide and prioritize our functional studies.  We will focus this work on genes that are expressed in intestinal epithelial cells and/or in monocyte/macrophages.  Epithelial cells and monocyte/macrophages are important players in IBD, and we have developed significant expertise in developing and studying genetics disease models including patient-derived human induced pluripotent cell (hiPSC) models of intestinal epithelial cells (2D and 3D) and/or in monocyte/macrophages and their functions.  These models can be gene- (knock down/over expression) or genotype-specific (e.g. genotype-specific hiPSC, CRISPR, etc.).

^{Models, culturing approaches and assays used for our studies of intestinal barrier functions.}  

Selected publications:

Prostaglandins and calprotectin are genetically and functionally linked to the Inflammatory Bowel Diseases. Karaky M, et al. .PLoS Genet. 2022 Sep 26;18(9):e1010189. doi: 10.1371/journal.pgen.1010189. Online ahead of print.PMID: 36155972

IBD-associated G protein-coupled receptor 65 variant compromises signalling and impairs key functions involved in inflammation. Mercier V, et al. .Cell Signal. 2022 May;93:110294. doi: 10.1016/j.cellsig.2022.110294. Epub 2022 Feb 24.PMID: 35218908

Functional screen of inflammatory bowel disease genes reveals key epithelial functions. Ntunzwenimana JC, et al. Genome Med. 2021 Nov 11;13(1):181. doi: 10.1186/s13073-021-00996-7.PMID: 34758847

C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions. Mohanan V, et al. Science. 2018 Mar 9;359(6380):1161-1166. doi: 10.1126/science.aan0814. Epub 2018 Feb 1.PMID: 29420262 

We aim to unravel the biological heterogeneity of CD and UC using genetic, genomic and immunologic profiling of patient blood and stool samples and a subset with intestinal biopsies/surgical specimens, with a particular focus on incident cases of CD and in longitudinal studies of response to therapy in CD and UC. This enables us to look at “baseline” heterogeneity as well as heterogeneity in the context of a “stimulus” – molecularly targeted therapies – and to identify and validate genetic, genomic, immunologic markers with predictive potential.

^{Genetic risk scores developed in ~35,000 IBD patients demonstrate that that ileal and colonic Crohn’s disease are at least as genetically distinct from each other as they are from ulcerative colitis (Left Panel).  Serum proteomics support the hypothesis that disease location is an intrinsic aspect of a patient’s disease (in part genetically determined) and the complex set of circulating cytokines, chemokines, growth factors etc.associated with CD reflect the complex interactions between immune, epithelial and mesenchymal cells (Middle Panel). Serum metabolomics in the same patients has enabled the identification of a set of six lipid metabolites that is sufficient to build a model with very beneficial sensitivity and specificity performance. (Right Panel)}

Selected publications:

Serum Analyte Profiles Associated With Crohn’s Disease and Disease Location.  Boucher G, et al. Inflamm Bowel Dis. 2021 Jun 9:izab123. doi: 10.1093/ibd/izab123.. PMID: 34106269

Comprehensive and Reproducible Untargeted Lipidomic Workflow Using LC-QTOF Validated for Human Plasma Analysis.  Forest A, et al. J Proteome Res. 2018 Nov 2;17(11):3657-3670. doi: 10.1021/acs.jproteome.8b00270. Epub 2018 Oct 10. PMID: 30256116 

Biomarker-guided stratification of autoimmune patients for biologic therapy. Ivison S, et al. Curr Opin Immunol. 2017 Dec;49:56-63. doi: 10.1016/j.coi.2017.09.006. Epub 2017 Oct 17. PMID: 29053992 

Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study.  Cleynen I, Boucher G, et al. Lancet. 2016 Jan 9;387(10014):156-67. doi: 10.1016/S0140-6736(15)00465-1. Epub 2015 Oct 18. PMID: 26490195