Celiac Disease

DQ2/DQ8 AND HLA-DQ Risk Assessment for Celiac Disease

Celiac Disease is a chronic gluten-intolerance that occurs in genetically predisposed individuals. In gluten-sensitive individuals, the ingestion of gluten causes chronic inflammation of the small intestinal mucosa leading to villous atrophy and nutrient malabsorption.  Celiac Disease DNA Testing can assess the genetic risk for developing the condition. The prevalence of Celiac Disease is estimated at about 1:100 in Caucasians, and it occurs more often in females with a gender ratio of about two-to-one. Furthermore, gluten intolerance is more frequent in at-risk groups, such as first-degree relatives of patients as well as individuals with specific genetic syndromes (Down, Turner, Williams) or autoimmune diseases (type I diabetes, thyroiditis and multiple sclerosis).

Clinical Utility

Celiac disease is a multifactorial disorder in which specific HLA-DQA1 and HLA-DQB1 alleles represent the major genetic predisposition. HLA typing allows a patient assessment of their relative risk. This means a positive test is indicative of genetic susceptibility but does not necessarily mean the disease is actively developing. A negative test result for Celiac Disease is just as informative, because gluten intolerance rarely occurs in the absence of specific HLA predisposing alleles. Approximately 90% of Celiac Disease patients possess DQA1*05 and DQB1*02(DQ2.5); 5-10% carry DQA1*03 and DQB1*0302 (DQ8); while about 5% of patients possess DQ2.x molecules, encoded by the DQB1*02 at-risk allele in the absence of the DQA1*05; and very rarely, Celiac Disease patients carry different DQ molecules (DQX.x). Chart 1, shown below, identifies the risks with celiac-associated DQ markers. Figure 1, also shown below, illustrates the at-risk heterodimers for Celiac Disease encoded by different combinations of DQA1 and DQB1 alleles.

The close association between Celiac Disease and these HLA alleles is due to the fact that these disease-associated HLA-DQ molecules expressed on antigen-presenting cells specifically bind gluten-derived peptides that are modified by the enzyme tissue transglutaminase (tTG) and present them to intestinal CD4+ T cells. The resulting T cell response leads to the production of auto-antibodies directed against tTG and to the secretion of pro-inflammatory cytokines (mainly TNF-α and IFN-γ) with consequent mucosa atrophy and clinical manifestations.

Chart 1, Figure 1 and the information on this page are adopted from various publications referenced below.Chart 1: Risk gradient, considering a disease prevalence of 1:100. Refer to Figure 1 for nomenclature (from Megiorni F et al, 2009).
Risk gradient, considering a disease prevalence of 1:100Figure 1: Celiac Disease at-risk heterodimers encoded by different combinations of DQA1 and DQB1 alleles (from Megiorni and Pizzuti, 2012).
CD at-risk heterodimers encoded by different combinations of DQA1 and DQB1 alleles

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