University of Groningen
Genetic susceptibility for inflammatory bowel disease across ethnicities and diseases
van Sommeren, Suzanne
DOI:
10.33612/diss.100597247
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2019
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Citation for published version (APA):
van Sommeren, S. (2019). Genetic susceptibility for inflammatory bowel disease across ethnicities and
diseases. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.100597247
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CHAPTER
1
9
The inflammatory bowel diseases (IBD) arecharacterised by chronic, relapsing immune mediated inflammation of the gastro- intestinal tract. Although IBD only has two main enti-ties, Crohn’s disease (CD) and ulcerative colitis (UC), it encompasses a heterogeneous clinical disease spectrum with a complex underlying pathogenesis.
Clinical aspects
Patients presenting with idiopathic inflamma-tion in the gastro-intestinal tract are strived to be classified as UC or CD patients mainly accord-ing to clinical and endoscopic features.
Inflammation in UC is restricted to the co-lon, in which the rectum is practically always affected and can extend proximally in a contin-uous fashion. The main classification is based on disease location: at diagnosis the disease is confined to the rectum (proctitis) in 30–60% of patients, extended inflammation till the flexura lienalis (left sided disease) is seen in 16–45% of patients and extended inflammation beyond the flexura lienalis resulting in pancolitis is seen in 15–35% of patients.1,2 Symptoms of ulcerative colitis can be related directly to the inflamma-tion of the colon or colon with (bloody) diar-rhoea as a key symptom. Accompanying abdom-inal pain occurs more often in colitis, urgency occurs more often in proctitis. Because the in-flammation is restricted to the mucosa, UC be-haves in a non-stricturing and non- penetrating fashion; however, the severity of inflammation and thereby the severity of symptoms can vary greatly. In severe cases systemic inflammatory reactions (fever, tachycardia) are seen. The most severe form of UC, acute severe ulcerative colitis, is associated with complications such as gross bleeding, toxic megacolon, in which the colon dilatates, and (micro)perforation, and has a mortality of 1%.3 Furthermore, longstanding inflammation of the colon increases the risk off colorectal cancer (CRC), which necessitates surveillance colonoscopies.4 Next to CRC, the main indications for surgery are medication refractory disease and refractory acute severe
ulcerative colitis, in which case most often a (procto)colectomy is performed. Despite a range of available medical therapies up to 15.6% of patients undergo surgery within 10 years of the diagnosis.5
A typical aspect of CD is the widespread and discontinuous disease location (mouth to anus), mainly affecting the terminal ileum (47%), the colon (28%) or both (21%). In only 3% of the pa-tients the upper gastrointestinal tract is affected (e.g. above the terminal ileum).6 Moreover dis-ease behaviour in CD is more varied compared to UC. A distinction is made between non-stric-turing and non-penetrating (or inflammatory) disease, stricturing disease and penetrating disease. The main classification is based on lo-cation and disease behaviour and is made with the Montreal classification.7 The variance in disease location and behaviour explains the variety of symptoms. Inflammatory disease affecting the colon resembles UC. Inflamma-tion in the terminal ileum can result in vague abdominal pain and loss of weight. Stricturing inflammation results in stenosis with accompa-nying symptoms of nausea, abdominal pain and weight loss. Penetrating disease results through (micro)perforation in abscesses or fistula with skin or other organs. CD often presents with the inflammatory form, the stricturing and pen-etrating forms are relatively rare at diagnosis (only 17% for stricturing disease and 13% for penetrating disease respectively);6 however, through prolonged inflammation strictures, or penetrating complications occur frequently in the course of the disease and they are frequent indications for surgery, with around 50% of pa-tients needing surgery within 10 years of the di-agnosis. Unfortunately, due to the susceptibility of the entire gastrointestinal tract to developing inflammation, CD tends to reoccur, as a result of which one third of the patients require multiple surgeries.8 After multiple resections and with extensive disease, the remaining small intes-tines might not be sufficient to sustain nutri-tional uptake, resulting in intestinal failure.9
Although the characteristics of UC and CD de-scribed seem to be clearly distinctive, it is not always possible to distinguish between the two
10
Chapter 1
entities. If a clear distinction cannot be made, the disease is called undetermined IBD (IBD-U). Sometimes a definite diagnosis can be made through the course of the disease; however, in some patients this remains uncertain. Further-more, rectal sparing or the presence of backwash ileitis in UC might be misinterpreted as CD. On the other hand, 5–10% of the patients diagnosed with UC eventually turn out to have CD.10
The relapsing nature is shared between CD and UC. Although clinical risk factors have been identified to predict a severe disease course or complications (for example young age at diag-nosis, smoking and extensive small intestine disease for CD and pancolitis and deep ulcer-ations in UC )11,12 no individual prognosis can be made.
Adding to the heterogeneity of the disease spectrum are the extraintestinal manifestations (EIM) of IBD, which can affect multiple organ systems and can impact quality of life more than IBD itself. 63.4% of IBD patients suffer from at least one EIM during their lifetime. Some EIMs like erythema nodosum, peripheral arthritis and oral aphthous ulcers occur with active in-testinal disease whereas other EIMs like axial spondylarthropathy/ankylosing spondylitis, uveitis and primary sclerosing cholangitis fol-low their own clinical course.13 It is believed that there is a shared pathogenic mechanism between IBD and its EIMs; however, this link is not yet clarified. One theory suggests activation of the immune response by translocated bacte-ria through the inflamed and leaky intestinal barrier.14 Therefore, a crucial component of the treatment of EIMs is successful treatment of in-testinal inflammation. Furthermore, some con-ditions are frequently seen in IBD patients as a consequence of metabolic abnormalities due to intestinal inflammation. Examples are osteopa-thy, nephrolithiasis or thromboembolic events. A third category of diseases occurs more often in patients with IBD, but is not IBD- specific like the EIM. These associated diseases like insuline- dependent diabetes mellitus, thyroid disease and vitiligo probably share immune mediated pathways with IBD, possibly due to a shared ge-netic background.15
Epidemiology
IBD is a ‘disease of the young’, with the peak age of onset in the second to fourth decade of life.16 The incidence has been rising in recent years; in the Netherlands in 2010 the annual incidence for IBD was 40.36/100,000, for CD 17.49/100,000 and for UC 21.47/100,000. The prevalence of IBD in the Netherlands is high, with 830/100,000 inhabitants (CD: 331/100,000; UC: 475/100,000), and is com-parable to the prevalence in Europe.16,17 IBD has always been considered a disease of indus-trialised countries, with the highest prevalence in Europe and North America. Recently, and simultaneously with the industrialization of developing countries the incidence of IBD is rising in, for example, Asia.16 Since IBD occurs more often in urban areas compared to rural areas18,19 and the fact that children of migrants from low-incidence to high-incidence countries show an increase in incidence this suggests en-vironmental risk factors are driving factors.20,21
Treatment
Because IBD is an immune mediated disease treatment is focused on suppression of the immune system. The first goal is inducing re-mission and because IBD tends to flare up, the next goal is to maintain remission in order to prevent long-term damage and complications. This means that patients might have to take life-long medication. There are multiple definitions of remission and treatment strategies and ther-apy regimes to achieve this. It falls beyond the scope of this introduction to go into great detail, but a key feature of the medication used is that they are not specific in suppressing the immune system, resulting in significant infectious and oncological risks. In order to expand the thera-peutic arsenal and make medication more spe-cific great effort is put into development of new medication. Examples of new biologicals are Vedolizumab, which is a monoclonal antibody that blocks the gut specific a4b7 integrin,22 and Ustekinumab which targets interleukin 12 and
11
interleukin 23.23 Based on new insights indis-ease pathogenesis, new therapy targets and new drugs are still being developed.
One of the biggest clinical challenges in im-proving the therapeutic strategy is to select the right treatment for individual patients (person-alised treatment). Till this day it remains impos-sible to predict the effect of a drug on the disease, the duration of this effect and occurrence of side effects in individual patients. This challenge is further complicated by the unpredictable de-velopment of anti-drug-antibodies that greatly diminish the clinical effect of monoclonal anti-bodies like Infliximab. Furthermore, because the disease course is unpredictable patients of-ten develop a significant flare of disease activ-ity before treatment escalation has taken place. Ideally, clinicians would like to offer individual patients a treatment strategy with a predicted good effectiveness and minimal side-effects at the correct time during the disease course.
Impact
Considering that IBD is a chronic disease, with the impact of symptoms described above, the tense treatment and the erratic prognosis, its in-fluence on daily life can be tremendous, dimin-ishing patients’ quality of life, their ability to participate in society, sexuality and fertility.24 The financial burden of IBD is significant, which is not surprising because IBD often affects young people and their ability to work, and taking into account the considerable costs of medication.25 The costs per patient even exceeds the costs for other chronic diseases like COPD, hypertension and diabetes.26
Pathogenesis
Similar to the complexity of the disease spec-trum is the complexity of the disease patho-genesis. It is believed that IBD is caused by an inappropriate reaction of the immune system in response to commensal gut bacteria in a ge-netic susceptible host. Besides gege-netic factors,
disease susceptibility is thought to be influenced by the gut microbiome and several environmen-tal factors. Furthermore it is believed that there are complex interactions between the different factors.
Environmental factors and the
microbiome
The influence of environmental factors (the ex-posome) has been well established for years,27,28 but has been highlighted by the recent increase in incidence in developing countries that adopt the Western lifestyle. Smoking increases the risk of developing CD29 and is associated with a more severe disease course.30 On the other hand UC occurs more often in former smokers.29 Diet can influence the risk of IBD through dietary macronutrients (fibres,31 saturated fat32), mi-cronutrients (vitamin D,33 zinc34) or by altering the microbiome.35 It is possible that factors like (childhood) antibiotic use36 and hygienic fac-tors during childhood37 also mainly influence disease risk through adjusting the microbiome. The role of the microbiome has only been rec-ognised since a few years, driving a tremendous effort in research in this field. The key feature is a reduction of the diversity of the microbiome in IBD, which is more pronounced in CD than in UC.38–40 As mentioned above, the microbiome is sensitive to influences of numerous external and internal factors, amongst which is the ge-netic background.
Genetic background
Locus identification
The heritability of IBD was demonstrated by seg-regation in families and a higher disease concor-dance in monozygotic twins than in dizygotic twins. Concordance is higher in CD compared to UC, suggesting that the heritable component is higher for CD.41–43 Moreover, it was clear that the heritability of IBD doesn’t behave in a Mendelian fashion and, as is typical for a com-plex disease, multiple genetic factors underlie
12
Chapter 1
disease pathogenesis. Hereafter, tremendous efforts were undertaken to unravel the genetic background of IBD.
Linkage and candidate gene studies
The first IBD gene to be identified in 1996 was
NOD244, after a locus (called IBD1) was found to be associated with Crohn’s disease. It was iden-tified by a linkage study, in which genetic mark-ers are tested for cosegregation (linkage) with disease status in affected families. In 2001 three causal mutations (R702W, G908R and L1007fs) in NOD2 were found.45,46 The NOD2 locus still remains the locus with the greatest risk in caus-ing disease (or effect size): heterozygotes have an odds ratio (OR) of 2–4, homozygotes have an OR of 20–40.45,46 By means of linkage studies mul-tiple loci were identified; however many of them failed replication. Besides NOD2 IBD5/5q31 (harboring SLC22A4, SLC22A5), IBD3/6p21 (HLA region) showed consistent replication.47
Results from candidate gene studies also suffered from replication issues. In candidate gene studies markers in genes with suspected in-volvement in disease pathogenesis are selected. In case of the IBD studies candidate genes have roles in the innate or adaptive immune system or the intestinal mucosal barrier. Only a few associations, like CARD9 and IL18RAP, were consistently replicated,48 and some tested loci that would later turn out to be associated, like the IL10 locus, were missed.49
Genome-wide association studies
With the development of genotyping arrays, the research of IBD genetics took a new turn. In ge-notyping arrays genetic markers (by means of single nucleotide polymorphisms – SNPs) are strategically selected based on linkage disequi-librium (LD) patterns, enabling the coverage of the majority of the genome by a relatively small selection of SNPs. In a genome-wide association study (GWAS) these SNPs are tested in a large selection of cases and controls to find SNPs that are significantly associated. This study design enables hypothesis-free testing and testing ge-netic variants with modest to small effect sizes, which wasn’t possible with the linkage and
candidate gene studies. In order to correct for the multiple statistical tests done in a GWAS stringent criteria have to be met to claim an association.
Interestingly, the first GWAS in IBD was per-formed in a Japanese CD population.50 Later studies were primarily focused on European (derived) populations. Therefore, there has re-mained a relative gap of knowledge in the ge-netic background of IBD in non-European pop-ulations. At the start of the research presented in this thesis in 2010 17 GWAS were published, nine in CD,50–58 six in UC59–64 and two in early- onset IBD.65,66 As could be expected, many of the candidate genes in associated loci play roles in the innate (CARD9, MST1) or adaptive im-mune system (PTPN22, ICOSLG) or the intes-tinal mucosal barrier (CDH1, HNF4α, LAMB1,
MUC19). Interestingly, candidate genes in
path-ways that were not implicated in the pathogen-esis of IBD before turned out to be associated, like IRGM and ATG16L1 in CD, which together with NOD2 play crucial roles in autophagy. Au-tophagy is the process of degradation of dam-aged cytoplasmic components by the lysosome and has been studied in the context of CD after genetic association became apparent.67,68 The importance of certain pathways is stressed by the large enrichment of candidate genes found to be associated. The Th17/IL23 pathway is such an example with many key genes residing in IBD associated loci (IL23R, IL12B, JAK2, STAT3,
IL17REL, CCR6).
Because the first studies included relatively small sample sizes, they first picked up the ‘low-hanging fruit’: the loci with relatively large effect sizes like TNFSF15 in the Japanese pop-ulation (OR 2.17)50 and IL23R in a combined Jewish and non-Jewish European collection (OR 2.2–3.8).51 As it became clear that most genetic variants had much smaller effect sizes, with ORs below 1.5, it became more important to increase statistical power by increasing sample sizes. Therefore, the next effort was combining GWAS data in meta-analyses. Shortly after starting this research, two large meta-analyses in CD and UC were published, increasing the total number of IBD associated loci to 99.69,70 It turned out that
13
many loci associated with CD or UC were shared,implicating large overlap in disease pathogene-sis. Also, many genetic loci are shared with other immune mediated diseases. This led with the combined effort of multiple research groups to the development of a customised genotyping platform that primarily targets genetic loci in-volved in 11 immune mediated diseases, the Immunochip. In 2012, a large meta-analysis of previously reported GWAS data, combined with an extra cohort of individuals genotyped on the Immunochip was published.71 In total, 75,000 individuals were analysed, which gave enough statistical power to increase the num-ber of IBD associated loci with 71 (to a total of 163 loci). Two-third of these loci are shared be-tween CD and UC, 30 seem to be CD specific and 23 seem to be UC specific.
Uncovering functional implications
Although the GWASs and meta-analyses where very successful in identifying disease risk loci, many challenges remained. GWAS platforms were designed to cover large stretches of the ge-nome, the SNPs that act as genetic markers are (mostly) not causal variants but tag causal ants through LD. For some risk loci causal vari-ants have been found, for example the NOD2 and IRGM loci;45,46,72,73 however, for most of the loci the causal variants remain unknown. The dense coverage of loci on the Immunochip aids in solving this problem. Another possible solution is sequencing the locus.
The next challenge is to determine the effect of causal variants and which genes are influenced by genetic variation. The most obvious expla-nation through which genetic risk variants can influence disease pathogenesis is by influencing gene expression. Many associated SNPs have a strong correlation with gene expression, the so-called eQTL effect.74 And although this par-ticular SNP is not likely to cause a disruption in gene expression itself, the eQTL effect can point out the candidate gene for a locus and we can learn more about a genetic risk factor if we un-derstand how gene expression is influenced by that risk factor. Other approaches use network analyses (based on for example gene ontology or
protein-protein interaction) to find enrichment of certain pathways in the entire set of genes residing within associated loci.75,76 These meth-ods were used mostly to select candidate genes in the published GWAS.
Finally a correlation will have to be made be-tween genetic risk factor, the gene(s) influenced by genetic variation, it’s role in a signalling path-way and the influence of this pathpath-way on disease pathogenesis.
Aim and outline of the thesis
The complexity of the clinical disease spectrum and the response to treatment are probably a reflection of (subtle) differences in disease pathogenesis. In order to gain insight into the disease development and disease course and improve quality of life by realising personalised treatment, we need to gain full insight in the pathogenesis of IBD.In this thesis we focus on expanding knowl- edge about the genetic basis of disease patho- genesis.
Part I starts by describing our research fo-cussed on identification of genetic risk loci and candidate genes and explains how the effect of genetic variation on gene expression plays a role.
Chapter 2 is a replication study of three
previ-ously reported associated loci resulting from a genome-wide association study (GWAS) per-formed in ulcerative colitis (UC). The candidate genes residing in the loci (CDH1, HNF4A and
LAMB1) play roles in the intestinal mucosal
barrier integrity. We analysed these loci in an independent Dutch UC cohort. Chapter 3 de-scribes the largest meta-analysis published at the time, containing nearly 100,000 individuals including a substantial proportion of individu-als from East-Asian, Indian and Iranian descent. This study plays two roles: identifying new IBD risk loci and investigating the overlap in genetic background of IBD across populations.
Next we focus on the role of gene expression. In the study presented in chapter 4 we selected SNPs with known influence on gene expres-sion from GWAS results that did not reach the
14
Chapter 1
genome wide significant threshold before. We hypothesised that these genetic loci were more likely to be truly associated to IBD because they have functional consequences. We performed a replication study in an independent Crohn’s disease (CD) cohort. In the research presented in
chapter 5, we investigated the effect of genetic
risk on gene expression of genes in the Th17/ IL23 pathway. This pathway is very import-ant in IBD from both a biological and genetic perspective.
In part II, we focus on shared genetics with other diseases. The clinical spectrum of IBD is broad and includes several extraintestinal manifestations. Chapter 6 presents the over-lap in genetic factors and sharing of biological pathways between IBD and its extraintestinal manifestations. In chapter 7 we focus on a dis-ease occurring after allogeneic hematopoietic cell transplantation and clinically resembling Crohn’s disease: gastro-intestinal graft-vs.-host disease. We identify risk loci and examine wether there is overlap with IBD.
Chapter 8 gives an overview of the results of
the work presented and provides a general dis-cussion and future perspectives.
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