University of Groningen
Genomic medicine in inflammatory bowel disease
Voskuil, Michiel
DOI:
10.33612/diss.136307453
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Voskuil, M. (2020). Genomic medicine in inflammatory bowel disease. University of Groningen. https://doi.org/10.33612/diss.136307453
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GENERAL INTRODUCTION AND OUTLINE
OF THE THESIS
Michiel D. Voskuil
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
General introduction and outline of this thesis
Inflammatory bowel disease (IBD) comprises a range of heterogeneous disorders characterised by chronic relapsing inflammation and ulceration of the gut mucosa, of which Crohn’s disease (CD) and ulcerative colitis (UC) are the two major clinical forms. In UC, the disease is generally limited to the colon, whereas in CD, inflammation can occur in the entire gastrointestinal tract[1,2]. Patients
with UC have continuous inflammation limited to the mucosal layer. In CD, the inflammation is discontinuous and involves all layers of the gut. IBD affects approximately 1 in 1,000 individuals, and its incidence is increasing. Clinical symptoms of IBD include recurrent episodes of abdominal pain, diarrhoea, bloody stools, and weight loss.
Although the exact pathogenesis is unknown, IBD is believed to result from an aberrant immune response to enteric microbiota in genetically susceptible individuals. Inflammatory responses to enteric microbiota are a feature of a normal gut. What distinguishes IBD from the inflammatory responses seen in the normal gut is an inability to down-regulate those responses. Multiple genetic, environmental and microbial factors contribute to the risk of IBD, which classifies IBD as a complex disease.
Genomic studies have greatly increased our understanding of the pathogenesis of IBD, but this has not yet been translated into improved clinical outcomes for patients with IBD. There is no cure for IBD; treatment is aimed at maintaining periods of disease remission and long-term prevention of disease complications such as hospitalisation and surgery. Despite increasing therapeutic options, it remains challenging to change the course the disease takes over time. Long-term surgery rates have not declined over the last decade, and up to a third of patients with IBD still require surgical intervention within the first ten years after diagnosis[3,4].
Aetiology
Genome-wide association studies (GWAS) have identified around 240 genetic risk loci, or genetic regions, associated with the risk of IBD[5]. For the majority of these genetic regions, the
disease-associated genes or the causal genetic variants remain unknown. In chapter 2, we review the progress that has been made in IBD genomic research and focus on the genetic risk loci for which the causal genetic variant driving the association has been identified. We discuss causal genetic variants in the well-studied IBD risk genes: NOD2, ATG16L1, IRGM, IL23R, CARD9, RNF186, and PRDM1. We further describe their downstream effects on protein function and their effects on the gut immune system.
Mechanisms by which the associated genetic variants contribute to CD pathogenesis remain largely unknown. Subsequent analyses of genetic risk loci point to a major role for T cells in the characteristic CD pattern of enhanced inflammation combined with the release of pro-inflammatory cytokines that is aggravated by an impaired negative feedback mechanism[6,7].
Because of the constant interaction between intestinal mucosal T cells and luminal microbial products, intestinal mucosal T cells are modified by adaptations that reflect a unique niche and the functional demand of the intestinal environment.
In efforts to develop more effective treatments for CD, one would ideally target its unique disease site, the local effector cells, and the corresponding disease pathways. Characterisation of gene expression signatures, referred to as transcriptomes, of intestinal mucosal T cells can further our understanding of the molecular processes that lead to enhanced mucosal inflammation, and pinpoint new targets for drug development.
Single-cell RNA sequencing technologies allow unbiased identification of cell-type-specific transcriptomes at high resolution[8]. In chapter 3, we characterise T cells from peripheral blood
and ileal mucosa from patients with CD using single-cell RNA sequencing. Using this technique allowed us to functionally interrogate T cells based on gene expression signatures. We hypothesise that T cells expressing CD risk genes are likely to be involved in CD pathogenesis. We further show which T cells express which CD risk genes, exerting their function, and are thus potential drug targets.
Disease course
One of the most challenging aspects of IBD from a clinical perspective is the unpredictable and heterogeneous clinical course the disease may take over time. Some patients will have long periods of disease remission without even the need for therapy. However, a significant proportion of patients experience frequent relapse of inflammation or progression to a complicated CD disease behaviour such as fibrostenotic or penetrating disease. This latter group of patients often require treatment escalation with potent immunosuppressive therapy, hospitalisation, or surgical resection.
The heterogeneous character of IBD suggests there are different biological mechanisms leading to inflammation, and subgroups of patients may have different effector mechanisms that contribute to their disease phenotypes. Identification of these patient-specific biological mechanisms could aid drug development and allow for personalised diagnostic workup or treatment. Although similar patterns of disease phenotypes have been observed within families, genetic determinants of these clinical aspects of disease, beyond disease susceptibility, remain largely unknown[9,10,11].
Several factors may contribute to the largely unexplained genetic contribution to IBD phenotypes. First, the genetic contribution to phenotype might be distinct from that which confers disease susceptibility[12]. Second, previous genotype–phenotype studies often used Immunochip data,
and therefore lacked genome-wide coverage[11]. Third, single variant effect-sizes might be too
small to capture with conventional GWAS.
Genetic risk scores aggregate the effects of thousands of trait-associated genetic variants discovered in GWASs. By combining the effects of many genetic variants with small effects sizes, genetic risk scores are powerful tools to identify genetic contributions to phenotypes[13,14]. Genetic
risk scores also have the potential to identify pleiotropic effects of genetic variants, which may aid drug discovery or drug repurposing. Moreover, genetic risk scores may help to identify patients at risk for specific clinical aspects of IBD. In chapter 4, we construct genetic risk scores for thirteen
traits, both related and unrelated to IBD, to uncover genetic determinants that contribute to IBD phenotypes.
For this study, we make use of novel genome-wide genetic array data with the potential to capture regions of the genome that were not covered by the earlier Immunochip platform.
Therapy
Therapeutic options for the management of IBD have rapidly expanded over the last two decades. Beyond conventional therapies such as aminosalicylates, corticosteroids and thiopurines, the development of biological therapies has revolutionised the management of IBD. Although all of these therapies are effective, it is well known that the inter-individual variability in therapy response is high with respect to both toxicity and efficacy. As a consequence, particular groups of patients are needlessly exposed to (expensive) drugs that are either ineffective or harmful. This is associated with increased costs, morbidity and mortality. Better patient stratification is needed to maximise patient benefit and minimise the harm caused by adverse events. In turn, this will decrease the burden of unnecessary costs for healthcare systems.
Genetic variation can affect individual responses to drugs in terms of both therapeutic and adverse effects. Pre-treatment genotyping allows patient stratification based on this genetic variation. In chapter 5, we review genetic variants predictive of response to therapies used in the management of IBD. Furthermore, we discuss the challenges and future perspectives associated with the implementation of pre-treatment genetic testing in clinical care of IBD.
Thiopurine therapy in patients with IBD has great potential to benefit from pre-treatment genetic testing. Thiopurines are the mainstay of treatment for many patients with IBD, but their use is limited by commonly occurring adverse events[15]. Thiopurine-induced myelosuppression (TIM) is
one of the most common adverse events, and TIM often necessitates drug withdrawal and may lead to opportunistic infections. Genetic variants in TPMT may lead to a deficient TPMT enzyme and increase the risk of TIM. However, genetic variants in TPMT explain only 25% of TIM in patients of European ancestry, implicating additional (genetic) determinants of TIM[16]. Indeed, genetic
variation in NUDT15 has been associated to TIM in patients from Asian ancestry, but the relevance of NUDT15 genetic variation in European patients with IBD remains unknown[17]. In chapter 6,
we perform both genome-wide and exome-wide association studies to identify genetic variants associated with TIM in European patients with IBD.
Next to TIM, induction of pancreatitis, hepatotoxicity, or flu-like illness often preclude patients from continuing thiopurine therapy, and these adverse events are associated with significant morbidity. Genetic variation at HLA-DQA1-HLA-DRB1 has been identified as a genetic determinant of thiopurine-induced pancreatitis, but explains only a minority of the variation[18]. No genetic
determinations of thiopurine-induced hepatotoxicity or flu-like illness have been identified thus far. In chapter 7, we describe exome-wide association studies to identify genetic variation associated with thiopurine-induced pancreatitis, hepatotoxicity, and flu-like illness. Moreover, we
General introduction and outline of this thesis
meta-analyse existing exome sequencing data and aim to identify additional genetic variants predictive of TIM.
Pre-treatment genetic testing allows for better patient stratification and optimisation of therapeutic outcomes. However, the uptake of this testing into IBD management guidelines and clinical practice has been challenging. Studies investigating the clinical efficacy of pre-treatment genetic testing can highlight its necessity by showing its potential to reduce adverse drug events and/or increase efficacy. In chapter 8, we combine all the known predictive genetic variants that are relevant for drugs used in the management of IBD into an “IBD pharmacogenetic passport”. We then explore the clinical efficacy of this IBD pharmacogenetic passport, which will hopefully aid timely implementation of pre-treatment genetic testing into IBD management guidelines.
COVID-19 and IBD
While Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become pandemic, currently little is known about COVID-19 in the context of IBD and the use of immunomodulating drugs like TNFα-antagonists[19,20]. In chapter 9,
we interrogate intestinal expression of genes that mediate SARS-CoV-2 viral transmission in patients with IBD.
Aim and objectives
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 IBD. While genomic medicine has great potential to provide novel diagnostic and therapeutic solutions for patients with IBD, the process of translating results from the first genomic association studies into genomics-based diagnostics or therapeutics has proven long and challenging. In this thesis, we focus on three different objectives that reflect different stages of this translational process. The first part of this thesis (Aetiology) focuses on the genomic factors contributing to the aetiology of IBD. The second part (Disease course) explores genetic determinants of IBD phenotypes. The final part (Therapeutic outcomes) aims to identify genetic variants predictive of adverse drug responses and show the potential of pre-treatment genetic testing in patients with IBD.
In chapter 10, we summarise results from the previous chapters. In chapter 11, we discuss these results and we will explore future directions for IBD research and clinical care.
Cohorts
Four different cohorts were used for this thesis. For chapter 3, we designed the GEID (Gastro-Intestinal Expression profiles in Immune-mediated Diseases) study, which was approved by the ethical board of the University Medical Center Groningen (UMCG). The GEID study prospectively collects peripheral blood, intestinal biopsies, and faecal samples in combination with questionnaire data of patients with IBD treated at the UMCG in order to establish comprehensive multi-omics profiles. This study allows for detailed interrogation of intestinal cells, including the generation of human intestinal organoids. Inclusion of patients and prospective collection of samples are currently ongoing.
Chapters 8 and 9 make use of data from the 1000IBD cohort. In short, the 1000IBD cohort consists of over 1,215 patients with IBD treated at the UMCG for whom prospective data is being collected for the generation of multi-omics profiles[21]. In chapter 4, we have combined data
from the 1000IBD cohort and the Dutch IBD Biobank (Parelsnoer). The Dutch IBD Biobank is a biobank of patients with IBD treated at one of the eight Dutch university medical centres[22]. Both
the 1000IBD cohort and the Dutch IBD Biobank had been established prior to initiation of the work presented in this thesis.
Chapters 6 and 7 make use of data generated with the International IBD Genetics Consortium (IIBDGC), and results obtained in these chapters would not have been possible without strong international collaboration. The IIBDGC has focused on collecting very large genomic datasets from a diverse set of countries via world-wide collaboration[23]. The IIBDGC has been able to
generate genome-wide genetic array data and whole-exome sequencing data for over 50,000 and 20,000 patients with IBD, respectively. Exome sequencing efforts are currently ongoing, and the number of sequenced exomes is still increasing.
Acknowledgements
This manuscript was edited for language and formatting by Kate Mc Intyre, Scientific Editor in the Department of Genetics, University Medical Center Groningen.
Conflicts of interest
The author has no (potential) financial relationships with any organisations that might have an interest with the work and no other relationships or activities that could appear to have influenced the work.
General introduction and outline of this thesis
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