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Caroline Montén

In search of the missing heritability of celiac disease, from genome-wide linkage & associaiton to a candidate gene approach

Celiac diseasd ia a gluten dependent enteropathy of the small intestine, associated with the HLA DQ2 and DQ8 haplotypes and tissue transglutaminase autoantibodies (tTGA). About 40% of the population carries these HLA risk haplotypes, but only 1-3% develoops celias disease. A majority of the heritabolity of celiac disease is therefore most likely unexplained. The aim of this thesis was to identify new candidate genes involved in celiac disease mechanisms using a whole genome linkage and associaiton approach, followed by small intestinal biopsy and peripheral blood gene expression as well as blood plasma analyses in children with celiac disease. The agreement of duodenal biopsy interpretation at four different university hospitals in Sweden was also evaluated.

In Paper I, a new genome wide significant locus was identified on chromosome I in Scandinavian families with celias disease at low HLA risk. The applied transmission disequlibrium test proposed new candidate genes and disease mechanisms based on four functional categories; 1) cell proliferation and apoptosis 2) intestinal smooth muscle function 3) nutrient and energy homeostasis and 4) the innate and adaptivve immune system.

In Paper II, four suggested risk gene variants from paper 1 affected expression of teh GLX, NCALD, INSR and KIF13A genes in the small intestine of children with celiac disease or controls. A differential gene expression between celiac cases and controls of genes involved in smooth muscle contraction and nutrient signaling was detected in the small bowel. The NTS transcript was down-regulated almost 4-fold in the celiac small bowed.

In Paper III, the pro-NT precursor protein of NTS was increased in plamsa from children with celiac disease and reflected the severity of small intestinal inflammation and plasma levels of tTGA.

In paper IV, the reproductibility of biopsy interpretation at university hospitals and its impact om biopsy-proven celiac disease diagnosis was dependent on local procedures at the clinic, such as the number and location of collected biopsies, as well as access to tTGA results and clinical information for the pathologist.

A novel risk locus and new potential candidate genes in celiac diseae were identified and suggest disturbance of nutrient signalin and smooth muscle function in pathogenesis of celiac disease. Plasma Pro-NT was identified as a potential diagnostic marker of inflammation in celiac disease. Access to clinical and endoscopic information as well as tTGA results for the pathologists are useful to complement the biopsy evalutation in dubious cases.

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