Lieke M. Spekhorst

Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease

Objective Patients with IBD display substantial heterogeneity in clinical characteristics. We hypothesise that individual differences in the complex interaction of the host genome and the gut microbiota can explain the onset and the heterogeneous presentation of IBD. Therefore, we performed a case–control analysis of the gut microbiota, the host genome and the clinical phenotypes of IBD. Design Stool samples, peripheral blood and extensive phenotype data were collected from 313 patients with IBD and 582 truly healthy controls, selected from a population cohort. The gut microbiota composition was assessed by tag-sequencing the 16S rRNA gene. All participants were genotyped. We composed genetic risk scores from 11 functional genetic variants proven to be associated with IBD in genes that are directly involved in the bacterial handling in the gut: NOD2, CARD9, ATG16L1, IRGM and FUT2. Results Strikingly, we observed significant alterations of the gut microbiota of healthy individuals with a high genetic risk for IBD: the IBD genetic risk score was significantly associated with a decrease in the genus Roseburia in healthy controls (false discovery rate 0.017). Moreover, disease location was a major determinant of the gut microbiota: the gut microbiota of patients with colonic Crohns disease (CD) is different from that of patients with ileal CD, with a decrease in alpha diversity associated to ileal disease (p=3.28×10−13). Conclusions We show for the first time that genetic risk variants associated with IBD influence the gut microbiota in healthy individuals. Roseburia spp are acetate-to-butyrate converters, and a decrease has already been observed in patients with IBD.

Identification of Clinical and Genetic Parameters Associated with Hidradenitis Suppurativa in Inflammatory Bowel Disease

Background:Hidradenitis suppurativa (HS) has recently been associated with inflammatory bowel disease (IBD). The objective of this study is to investigate the prevalence of HS in IBD and to identify clinical and genetic parameters associated with HS in IBD. Methods:A questionnaire, validated for HS, was sent to 1969 patients suffering from IBD. Results:The prevalence of HS in our IBD cohort (1260 participating patients) was significantly higher than in the general population (6.8%–10.6% versus 1%–2%). IBD patients with HS were affected by IBD significantly earlier and more often treated with anti-TNF-&agr; therapy and surgical resection compared to IBD without HS. Female gender, smoking, a higher body mass index, and younger age were independent associated parameters for HS. Within cases allelic association analysis was performed for 59 cases (IBD with HS) and 293 controls (IBD without HS). We observed 2 promising new associations in genomic regions harboring ELOVL7 (rsnumber 10057395 P = 7.15 × 10−5, odds ratio = 0.4), and in the intergenic region between SULT1B1 and SULT1E1 (rsnumber 2014777 P = 7.48 × 10−5, odds ratio = 2.3). Conclusions:HS is present in 6.8% to 10.6% of IBD patients. Co-morbid HS is associated with an early onset of IBD in which anti–tumor necrosis factor-&agr; therapy and surgical resections are often needed. We identified a suggestive protective association with ELOVL7 and suggestive risk association with the genes SULT1B1 and SULT1E1 for HS, in the context of IBD. These genetic associations need further exploration and replication in additional independent cohorts.

Down the line from genome-wide association studies in inflammatory bowel disease: the resulting clinical benefits and the outlook for the future

Inflammatory bowel disease (IBD), consisting of Crohn’s disease and ulcerative colitis, is a chronic inflammatory disease of the gut. The etiology of IBD is complex, involving genetic as well as environmental factors. Genetic studies have identified 163 genetic risk loci for IBD, which have led to new insights into the biological mechanisms of the disease. The currently known IBD risk loci show an almost 75% overlap with genetic risk loci for other immune mediated diseases. Current studies are focused on the translation of the identified risk loci to clinical practice. The first steps towards this translation are being taken with the identification of genetic risk factors for drugs toxicity, specific disease course and response to therapy. In this review we will discuss how the IBD genetic risk loci were identified and how this knowledge can be translated towards clinical practice.

Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

Sex-Related Differences in Patients With Inflammatory Bowel Disease: Results of 2 Prospective Cohort Studies

Background The understanding of gender differences in inflammatory bowel disease (IBD) patients is an important step towards tailored treatment for the individual patient. The aim of this study was to compare disease phenotype, clinical manifestations, disease activity, and healthcare utilization between men and women with Crohns disease (CD) and ulcerative colitis (UC). Methods Two multicenter observational cohort studies with a prospective design were used to explore the differences between men and women regarding demographic and phenotypic characteristics and healthcare utilization. Detailed data on IBD-phenotype was mainly available from the Dutch IBD Biobank, while the COIN cohort provided healthcare utilization data. Results In the Dutch IBD Biobank study, 2118 CD patients and 1269 UC patients were analyzed. Female CD patients were more often current smokers, and male UC patients were more often previous smokers. Early onset CD (<16 years) was more frequently encountered in males than in females (20% versus 12%, P < 0.01). Male CD patients were more often diagnosed with ileal disease (28% versus 20%, P < 0.01) and underwent more often small bowel and ileocecal resection. Extraintestinal manifestations (EIMs) were more often encountered in female IBD patients. In the COIN study, 1139 CD patients and 1213 UC patients were analyzed. Male CD patients used prednisone more often and suffered more often from osteopenia. IBD-specific healthcare costs did not differ between male and female IBD patients. Conclusions Sex differences in patients with IBD include age of onset, disease location, and EIM prevalence. No large differences in therapeutic management of IBD were observed between men and women with IBD. 10.1093/ibd/izy004_video1izy004_Video_15786481854001.

Prevalence of- and risk factors for work disability in Dutch patients with inflammatory bowel disease

AIM To determine the prevalence of work disability in inflammatory bowel disease (IBD), and to assess risk factors associated with work disability. METHODS For this retrospective cohort study, we retrieved clinical data from the Dutch IBD Biobank on July 2014, containing electronic patient records of 3388 IBD patients treated in the eight University Medical Centers in the Netherlands. Prevalence of work disability was assessed in 2794 IBD patients and compared with the general Dutch population. Multivariate analyses were performed for work disability (sick leave, partial and full disability) and long-term full work disability (> 80% work disability for > 2 years). RESULTS Prevalence of work disability was higher in Crohn’s disease (CD) (29%) and ulcerative colitis (UC) (19%) patients compared to the general Dutch population (7%). In all IBD patients, female sex, a lower education level, and extra-intestinal manifestations, were associated with work disability. In CD patients, an age > 40 years at diagnosis, disease duration > 15 years, smoking, surgical interventions, and anti-TNFα use were associated with work disability. In UC patients, an age > 55 years, and immunomodulator use were associated with work disability. In CD patients, a lower education level (OR = 1.62, 95%CI: 1.02-2.58), and in UC patients, disease complications (OR = 3.39, 95%CI: 1.09-10.58) were associated with long-term full work disability. CONCLUSION The prevalence of work disability in IBD patients is higher than in the general Dutch population. Early assessment of risk factors for work disability is necessary, as work disability is substantial among IBD patients.

The Impact of Ethnicity and Country of Birth on Inflammatory Bowel Disease Phenotype: A Prospective Cohort Study

Background and Aims The number of patients with inflammatory bowel disease [IBD], of non-Caucasian descent in Western Europe, is increasing. We aimed to explore the impact of ethnicity and country of birth on IBD phenotype. Methods IBD patients treated in the eight University Medical Centers in The Netherlands [Dutch IBD Biobank] were divided into two groups according to their ethnicity: 1] Caucasian patients of Western and Central European descent [CEU]; and 2] patients of non-Caucasian descent [non-CEU]. The non-CEU group was subdivided according to country of birth, into: born in The Netherlands or Western Europe [non-CEU European born]; or born outside Western-Europe who migrated to The Netherlands [non-CEU non-European born]. Both comparisons were analysed for phenotype differences [by chi-square test]. Results The Dutch IBD Biobank included 2921 CEU patients and 233 non-CEU patients. Non-CEU Crohns disease [CD] patients more often had upper gastro-intestinal disease [16% vs 8%, p = 0.001] and anal stenosis [10% vs 4%, p = 0.002] than CEU CD patients. The use of anti-tumour necrosis factor [TNF] agents and immunomodulators was higher in non-CEU IBD patients than in CEU IBD patients [45% vs 38%, p = 0.042] and [77% vs 66%, p = 0.001], respectively. Non-CEU IBD patients born in Europe [n = 116] were diagnosed at a lower age than non-CEU IBD patients born outside Europe [n = 115] [at 22.7 vs 28.9 years old, p < 0.001]. Conclusion Non-Caucasians had more severe disease behaviour than Caucasians. Non-CEU patients born in Europe were diagnosed at a lower age with IBD than those born outside Europe who migrated to The Netherlands.

Cohort profile: design and first results of the Dutch IBD Biobank: a prospective, nationwide biobank of patients with inflammatory bowel disease

Purpose The Dutch IBD Biobank aims to facilitate the discovery of predictors for individual disease course and treatment response in patients with inflammatory bowel disease (IBD). In this paper, we aim to describe the establishment of the Dutch IBD Biobank, including the facilitators and barriers to establishment. Moreover, we aim to provide a complete overview of the content of the Dutch IBD Biobank. Participants Since 2007, every patient with IBD treated in one of the eight Dutch university medical centres is asked to participate in the Dutch IBD Biobank in which 225 standardised IBD-related data items and biomaterials, such as serum, DNA, biopsies and a stool sample, are collected. Findings to date As of June 2014, the Dutch IBD Biobank had enrolled 3388 patients with IBD: 2118 Crohn’s disease (62.5%), 1190 ulcerative colitis (35.1%), 74 IBD-unclassified (2.2%) and 6 IBD-indeterminate (0.2%). The inclusion of patients with IBD is ongoing. The quality of the biomaterials is good and serum, DNA and biopsies have been used in newly published studies. Future plans The genotyping (750 000 genetic variants) of all participants of the Dutch IBD Biobank is currently ongoing, enabling more genetic research. In addition, all participants will start reporting disease activity and outcome measures using an online platform and mobile app.