Genomics of Coeliac Disease - Molecular Signatures of the Pathogenesis

摘要: Coeliac disease, the intolerance for dietary gluten common in Western populations, is a multifactorial disorder, meaning that it caused by interaction of environmental factors and multiple susceptibility genes. The aim this thesis was to gain insight into pathogenesis means genomics approach. We carried out integrated genetic analysis gene expression studies identify, better understanding genes mechanisms behind pathology etiology coeliac disease. In introducing chapter we review on disease introduce new methods profiling. First, examined whether tissue heterogeneity (‘patchiness’) may have an effect measurements performed duodenal biopsies. observed mucosal inflammation differentiation (represented IFNG TM4SF4 expression, respectively) were inversely correlated, depending extent restructuring. However, variance similar cases controls, thus independent lesion severity. Consequently, proposed model where mosaicism duodenum might result (‘patchiness’). Second, applied microarrays study genome-wide duodenums patients. Alterations induced pointed enhanced cell proliferation mucosa arrested terminal enterocytes. This impaired affected uptake processing lipids, sterols, sugars, peptides, iron. These deficiencies contribute wide variety clinical features also detoxification system, previously described inflammatory bowel (IBD). suggests that, like IBD characterized defect. Third, analyzed tight junction network using genetics pattern claudin family appeared been evolutionary conserved over 75 million years. Three pairs claudins showed co-regulation. Patients variable patterns marked extreme outliers. Particularly involved signal transduction regulation cytoskeleton trends changed expression. Genetic association based use single nucleotide polymorphisms (SNPs) information linkage disequilibrium from International HapMap Consortium. identified two associated with lesser IBD. suggested both gastrointestinal disorders, share barrier Fourth, candidate families immune pathways. Both (pivotal Th1 adaptive response), SPINK4 (expressed goblet cells) differential correlated well remodeling. Weak only INFG Dutch population, but not positional SPINK1, -2, -4, –5. Finally, General Discussion, evaluate our approach interpretations data, which are than incorporated possible models