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Celiac disease is an autoimmune disorder of the small intestine that affects about 1% of the U.S. population and 2.5-5.2% of the people in Europe. 1,2 Approximately 1% of the world population suffers from the disease.3,4. By the age of 40 most patients will have developed symptoms, which are characterized by inflammation and destruction of the small intestine resulting in villous atrophy and malabsorption. As the disease progresses the villous atrophy develops into a nodular fibrosis called "focal villous atrophy". At this stage the patients are no longer able to tolerate gluten-containing foods and malabsorption of nutrients occurs. 5-7
Celiac disease is a chronic inflammatory disease of the small intestine that is mediated by a dysregulated immune response against ingested gluten.8-10 The hallmarks of celiac disease are: 1) the presence of small intestinal villous atrophy; 2) crypt hyperplasia; 3) increased intraepithelial lymphocytes; and 4) the presence of various autoantibodies.11-13
The disease has been reported to be genetically transmitted in both the HLA class II and class I regions and has also been reported in patients without HLA alleles predisposing to celiac disease.14-16 HLA is the most widely recognized genetic marker for celiac disease.12 The HLA-DQ2 and -DQ8 genes are the most common alleles associated with celiac disease, accounting for about 75% of celiac disease cases.17,18,19,20 However, the use of HLA alleles to predict the risk of developing celiac disease in relatives is limited as these alleles alone do not fully account for the genetic risk of the disease.21
Since the identification of a strong association between celiac disease and HLA-DQ2 and -DQ8, the majority of studies on celiac disease focused on the investigation of the role of these two genes. Genetic analysis of families with multiple cases of celiac disease, among whom at least two individuals had positive HLA DQ2 or DQ8 serology, revealed HLA-DQ alleles in 12%-40% of celiac disease patients,14,15,22,23,24,25,26,27 suggesting that HLA-DQ2 and -DQ8 are associated with celiac disease in over 40% of patients. Indeed, in ser 0b46394aab
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