University of Groningen
Genomic medicine in inflammatory bowel disease
Voskuil, Michiel
DOI:
10.33612/diss.136307453
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Publication date: 2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Voskuil, M. (2020). Genomic medicine in inflammatory bowel disease. University of Groningen. https://doi.org/10.33612/diss.136307453
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SUMMARY
Michiel D. Voskuil
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
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The aim of this thesis is to translate the large amount of genomic information that is now available into improved clinical outcomes for patients with inflammatory bowel disease (IBD). Below, we summarise the main results and provide answers to the thesis objectives.
In the first part of this thesis (Aetiology), we focused on genomic factors contributing to the aetiology of IBD. In chapter 2, we reviewed the progress that has been made in IBD genomic research. While many genomic regions have been found to be associated with the risk of IBD, a causal genetic variant driving the association has been identified for only a few of these genomic regions. We highlight these causal genetic variants and focus on their downstream effects on protein function. The mechanisms by which the genetic variants contribute to pathogenesis remain largely unknown, but downstream analyses point to a major role for T cells in the pathogenesis of Crohn’s disease (CD). In chapter 3, we used single-cell RNA sequencing to characterise transcriptional signatures of T cells from patients with CD. We identified marked differences between intestinal mucosal T cells and peripheral blood T cells and demonstrate that mucosal T- helper 17 cells, mucosal cytotoxic T cells, and T regulatory cells are enriched for transcribed CD risk genes. This emphasises the cell-type-specific context in which CD risk genes may contribute to pathogenesis, and may provide promising targets for future cell-type-specific therapies for CD.
In the second part of this thesis (Disease course), we focused on the disease course of IBD. The heterogeneous character of IBD suggests that there are different biological mechanisms leading to disease, but genetic determinants of clinical heterogeneity remain largely unknown. In chapter 4, we constructed genetic risk scores for thirteen traits and correlated these genetic risk scores to IBD phenotypes. The composite genetic risk of CD susceptibility is associated with CD disease behaviour. Moreover, genetic risk of ulcerative colitis is associated with CD disease location. These results contribute to our understanding of the genetic contributions to IBD phenotypes.
In the final part of this thesis (Therapy), we focused on the identification and clinical implementation of genetic variants that predict adverse drug responses. In chapter 5, we review well-established pharmacogenetic interactions relevant for the management of IBD. We discuss the potential of pre-treatment genetic testing in the context of IBD management, but also the challenges associated with its clinical implementation into IBD management guidelines. In chapter 6, we set out to identify additional genetic determinants of thiopurine-induced myelosuppression (TIM) in European patients with IBD. Using whole-exome sequencing studies, we identified NUDT15 as an important genetic determinant of TIM. We show that TPMT, NUDT15, and thiopurine dose are all independent predictors of TIM. We also show that patients with genetic variants in either NUDT15 or TPMT had faster onset of TIM, more severe TIM, and a greater need for granulocyte colony-stimulating factor rescue therapy. These results suggest the potential benefit of genotyping
NUDT15 prior to initiation of thiopurine therapy.
Summary
In chapter 7, we present on-going work aimed at identification of genetic determinants of four clinically-relevant adverse responses to thiopurines. Using the largest cohort to date of well-characterised patients with IBD for whom we have exome sequencing data, we validate TPMT and NUDT15 as genetic predictors of TIM in patients with IBD of European ancestry. In addition, our preliminary results suggest ZNF516 to be associated with the risk of thiopurine-induced hepatotoxicity, although this finding still needs to be validated via Sanger sequencing and replicated in an independent cohort.
To aid timely implementation of pre-treatment genetic testing into clinical IBD management, we have designed an “IBD pharmacogenetic passport”, which we introduce in chapter 8 . We have combined multiple pharmacogenetic interactions relevant for the management of IBD and show that only 24 patients need to be genotyped to prevent one adverse drug response. Implementation of pre-treatment genetic testing would offer personalised therapeutic recommendations based on patient genotype and lead to a reduction in adverse events and treatment failures.
The work presented in chapter 9 is focused on COVID-19 in the context of IBD. We report increased expression of SARS-CoV-2 host protease TMPRSS2 in intestinal mucosal biopsies of older patients, of male patients, with mucosal inflammation, and in patients using TNFα-antagonists or aminosalicylates. This in turn might contribute to a more severe course of COVID-19, but this hypothesis is yet to be confirmed in follow-up studies.
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