Abstract
Celiac disease is characterized by a chronic immune reaction in the small intestine to the gluten proteins that are present in the grains eaten in a Western diet. Its prevalence is around 1% although many patients are in fact never diagnosed. Celiac disease patients suffer from all kinds of symptoms
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related to a malfunctioning of the small intestine, but it is now becoming increasingly apparent that the disorder is also systemic. Celiac disease is caused by alterations in multiple genes (susceptibility) combined with environmental factors. It is known that some variants of the HLA-DQA1 and -DQB1 genes, e.g. DQ2.5, DQ7 and DQ8, form proteins that are involved in celiac disease because they have the ability to present gluten to the cells of the immune system. Although these particular gene variants are important - they are in fact present in over 25% of the general population - there must also be other gene variants necessary to induce celiac disease. We searched extensively for these other genes and found that the gene myosin IXB is involved in celiac disease, probably by enhancing the permeability of the intestinal barrier. After finding this gene we decided to search for other genes involved in the intestinal barrier, the so-called tight-junction genes. We searched in over 40 genes and found two that also showed association to celiac disease. We have increased our understanding in complex genetic disorders in general since we noticed that some disorders show an overlap in the causal genes. We therefore tested myosin IXB and the two tight-junction genes for their involvement in two other intestinal disorders, Crohn's disease and ulcerative colitis and found that the three celiac disease genes are also involved in ulcerative colitis. Besides searching for new genes involved in celiac disease we also looked at the known HLA variants. Since celiac disease is widely under diagnosed, we consider it would be good to screen the relatives of patients, or may be even the whole population, for celiac disease genes. The first step would be to test for the HLA variants and thereby exclude those not at risk (˜75% of population). The tests for the HLA variants are not simple but we have developed a new, simple and cost-effective method to screen for these variants, using SNPs that are in linkage disequilibrium with the risk variants. Our next goal is to learn more about the function of myosin IXB and the other two genes in order to pinpoint possible new therapies for celiac disease. In addition, we need to search for more of the genes involved in celiac disease and discover how they interact with each other. We hope that our new test for the HLA variants will expand testing for celiac disease and reduce the number of undiagnosed patients.
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