The exposome in development and behaviour of inflammatory bowel disease

In this thesis, the role of environmental and lifestyle factors, the exposome, in etiology as well as course of disease of Inflammatory Bowel Disease (IBD) was examined. After development and validation of the Groningen IBD Environmental questionnaire (GIEQ), a large number of exposome factors was studied by comparing patients with IBD to population-based controls from the Lifelines Cohort study, identifying novel, modifiable, exposome factors possibly involved in disease development, among which prenatal smoke exposure. A large number of exposome factors was also examined for their association with development of disease complications such as the need for biological therapy, IBD-related surgery and development of colorectal neoplasia (CRN). Physical activity for example, was shown to have a beneficial effect, while a high visceral fat volume increased risk of disease-related complications. Also, this thesis shed light on the controversial association of the Mycobacterium Avium Paratuberculosis (MAP) and IBD. While using stringent criteria for test quality and repeatability, this thesis shows an increased use of biological therapy in those with a high immune response to MAP. Finally, cigarette smoke exposure was associated with CRN development in IBD with a clear improvement of risk stratification over the current surveillance guidelines used. These studies have once more shown the importance of the exposome, which offers the possibility of chance. An opportunity that shouldn’t be overlooked by researchers nor clinicians

Genetic risk scores identify genetic aetiology of inflammatory bowel disease phenotypes

Background and Aims: Inflammatory bowel disease [IBD] phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores [GRS] to disentangle the genetic contributions to IBD phenotypes.Methods: Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts [cohort A, n= 1097; cohort B, n= 2156]. Genetic risk scoring [GRS] was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS-phenotype (false-discovery rate [FDR] corrected p<0.05) associations identified in cohort A were put forward for replication in cohort B.Results: Crohn's disease [CD] GRS were associated with fibrostenotic CD [R-2= 7.4%, FDR = 0.02] and ileocaecal resection [R-2 = 4.1%, FDR = 1.6E-03], and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis [UC] GRS [R-2 = 7.1%, FDR = 0.02] and primary sclerosing cholangitis [PSC] GRS [R-2 . 3.6%, FDR = 0.03] were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour [R-2 = 1.7%, FDR = 0.04].Conclusions: Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.Cellular mechanisms in basic and clinical gastroenterology and hepatolog