Clinical genomics
Celiac Disease Genetics: Current Concepts and Practical Applications

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Celiac disease is a multifactorial disease with complex genetics. Both HLA and non-HLA genes contribute to the genetic component, but recent findings suggest that the importance of non-HLA genes might have been overestimated. No susceptibility genes other than HLA-DQ have yet been identified in celiac disease. In contrast to the meager knowledge regarding non-HLA genes, we have acquired a detailed understanding about which HLA genes are predisposing for disease, and how they are involved in the pathogenesis. This knowledge might pave the road for novel treatments for the disease. The role of HLA as a necessary, but not sufficient, genetic factor can moreover be used for diagnostic purposes to exclude a celiac disease diagnosis. The applicability of HLA genotyping is particularly useful for excluding celiac disease in family members or risk groups with fairly unbiased distribution of HLA alleles (ie, patients with Turner syndrome and patients with Down syndrome) and in patients with a clinical suspicion of celiac disease.

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Celiac Disease Is a Multifactorial Disorder With Complex Genetics

The celiac enteropathy develops as a result of an interplay between genetic and environmental factors (Figure 1). Gluten (consisting of the gliadin and glutenin subcomponents) is clearly a critical environmental component, and both HLA and non-HLA genes are thought to be predisposing genetic factors. The importance of genetic factors is illustrated by a high degree of familial clustering, with about 10% of first-degree relatives being affected,1 and by the high concordance rate (∼75%) among

Genetic Diagnostic Tests

The final diagnosis of celiac disease is based on the findings of typical histologic alterations of the small intestinal mucosa of patients eating gluten. A clinical response on a gluten exclusion diet is also considered to be of importance. Serologic tests, particularly measuring IgA antibodies to TG2, are very useful tools to predict the disease and to select patients for subsequent endoscopic examination. Recent recommendations also include HLA genotyping as a diagnostic adjunct.56 In this

Future Therapy and Disease Prevention

Many patients cope with the gluten-free diet easily. Others find that the dietary restrictions are laborious, negatively influencing their quality of life. Compliance with the gluten-free diet is often incomplete among celiac disease patients, and there is a need for alternative treatments. Encouragingly, the new insight into the molecular mechanisms of celiac disease has uncovered novel targets for therapy.60

The activation of the CD4 gluten-reactive T cells seems to be a critical checkpoint in

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    Supported by grants from the Research Council of Norway, the European Community (BHM4-CT98-3087, QLK1-CT-1999-00037, and QLK1-CT-2000-00657), the Norwegian Cancer Society, the Juvenile Diabetes Foundation International (3-2000-515 and 1-2004-793), the NIH (DK65965; together with C. Khosla), and EXTRA funds from the Norwegian Foundation for Health and Rehabilitation.

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