Genetic susceptibility for inflammatory bowel disease across ethnicities and diseases

The inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), have a broad disease spectrum and disease course and response to therapy are unpredictable. We need to understand the aetiology and the influence of genetic risk factors. This thesis contributes to this by identifying 38 new genetic risk factors. We show that the majority of genetic risk factors are shared between populations. A small proportion differs between populations, possibly environmental factors underlie this. Furthermore we replicated a few UC associated loci, which encode genes with functions in the intestinal barrier. We also developed a method to select genetic risk factors based on their relationship with gene expression, hypothesis that these represent biologically relevant signals. In this way we identified 2 new CD loci.In order to make a translation to biologically relevant processes we investigated the influence of genetic risk factors on gene expression in the Th17/IL23 pathway, a pathway that is important in IBD pathogenesis. We didn’t find a correlation and we expect this is due to the fact that gene expression is cell specific and we used a mix of cells. Lastly, we investigated the overlap in genetic risk factors between IBD and a group of diseases that occur often with IBD: the extra-intestinal manifestations and with a disease that occurs after allogeneic cell transplantation and resembles CD: gastro-intestinal graft-.vs.-host disease. We find substantial overlap, not only based on genetic factors, but also based on co-expression of genes and protein-protein interaction

Turbulent buoyant convection from a maintained source of buoyancy in a narrow vertical tank

We describe new experiments to examine the buoyancy-induced mixing which results from the injection of a small constant volume flux of fluid of density at the top of a long narrow vertical tank with square cross-section which is filled with fluid of density . The injected fluid vigorously mixes with the less dense fluid which initially occupies the tank, such that a dense mixed region of turbulent fluid propagates downwards during the initial mixing phase of the experiment. For an ideal source of constant buoyancy flux , we show that the height of the mixed region grows as and that the horizontally averaged reduced gravity at the top of tank increases as , where is the width of the tank. Once the mixed region reaches the bottom of the tank, the turbulent mixing continues in an intermediate mixing phase, and we demonstrate that the reduced gravity at each height increases approximately linearly with time. This suggests that the buoyancy flux is uniformly distributed over the full height of the tank. The overall density gradient between the top and bottom of the mixed region is hence time-independent for both the mixing phases before and after the mixed region has reached the bottom of the tank. Our results are consistent with previous models developed for the mixing of an unstable density gradient in a confined geometry, based on Prandtl’s mixing length theory, which suggest that the turbulent diffusion coefficient and the magnitude of the local turbulent flux are given by the nonlinear relations and , respectively. The constant relates the width of the tank to the characteristic mixing length of the turbulent eddies. Since the mixed region is characterized by a time-independent overall density gradient, we also tested the predictions based on a linear model in which the turbulent diffusion coefficient is approximated by a constant . We solve the corresponding nonlinear and linear turbulent diffusion equations for both mixing phases, and show a good agreement with experimental profiles measured by a dye attenuation technique, in particular for the solutions based on the nonlinear model

De bediening van navigatie-ondersteuning voor blinden en slechtzienden - naar een generieke interface

Zelfstandige navigatie en oriëntatie voor blinden en slechtzienden kan worden ondersteund met hiervoor geëigende systemen. Bestaande systemen zijn echter vaak niet toegerust met een bruikbare interface. In het huidige onderzoek zijn drie interfaces voor een routegeleidingssysteem voor blinden en slechtzienden getest. Hoewel één variant een beter algemeen resultaat bood dan de twee anderen was het resultaat zodanig dat een integratie van de positieve aspecten van de verschillende interfacevarianten aan te bevelen is

Complex host genetics influence the microbiome in inflammatory bowel disease

Background: Human genetics and host-associated microbial communities have been associated independently with a wide range of chronic diseases. One of the strongest associations in each case is inflammatory bowel disease (IBD), but disease risk cannot be explained fully by either factor individually. Recent findings point to interactions between host genetics and microbial exposures as important contributors to disease risk in IBD. These include evidence of the partial heritability of the gut microbiota and the conferral of gut mucosal inflammation by microbiome transplant even when the dysbiosis was initially genetically derived. Although there have been several tests for association of individual genetic loci with bacterial taxa, there has been no direct comparison of complex genome-microbiome associations in large cohorts of patients with an immunity-related disease. Methods: We obtained 16S ribosomal RNA (rRNA) gene sequences from intestinal biopsies as well as host genotype via Immunochip in three independent cohorts totaling 474 individuals. We tested for correlation between relative abundance of bacterial taxa and number of minor alleles at known IBD risk loci, including fine mapping of multiple risk alleles in the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene exon. We identified host polymorphisms whose associations with bacterial taxa were conserved across two or more cohorts, and we tested related genes for enrichment of host functional pathways. Results: We identified and confirmed in two cohorts a significant association between NOD2 risk allele count and increased relative abundance of Enterobacteriaceae, with directionality of the effect conserved in the third cohort. Forty-eight additional IBD-related SNPs have directionality of their associations with bacterial taxa significantly conserved across two or three cohorts, implicating genes enriched for regulation of innate immune response, the JAK-STAT cascade, and other immunity-related pathways. Conclusions: These results suggest complex interactions between genetically altered host functional pathways and the structure of the microbiome. Our findings demonstrate the ability to uncover novel associations from paired genome-microbiome data, and they suggest a complex link between host genetics and microbial dysbiosis in subjects with IBD across independent cohorts. Electronic supplementary material The online version of this article (doi:10.1186/s13073-014-0107-1) contains supplementary material, which is available to authorized users

Differential association of two PTPN22 coding variants with Crohn’s disease and ulcerative colitis

2 páginas.-- Póster presentado al 5º European Workshop on Immune-Mediated Inflammatory Diseases celebrado en Sitges (Barcelona) dxel 1 al 3 de Diciembre de 2010.-- et al.The PTPN22 gene is an important risk factor for human autoimmunity. Two PTPN22 missense-SNPs, both with functional influence, the R620W (1858C>T, rs2476601) in exon 14 and the R263Q (788G>A, rs33996649) in exon 10 have been associated with autoimmune diseases [1-4].Peer reviewe

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases