Celiac Disease

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

Celiac disease (CD) 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. The prevalence of CD 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 CD 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 CD 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, CD 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 CD encoded by different combinations of DQA1 and DQB1 alleles.

The close association between CD 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 1:100

Figure 1: CD 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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