Genetic Background of Celiac Disease and Its Clinical Implications

Victorien M. Wolters, M.D.; Cisca Wijmenga, Ph.D.


Am J Gastroenterol. 2008;103(1):190-195. 

In This Article

Abstract and Introduction

Celiac disease (CD) is a complex genetic disorder with multiple contributing genes. Linkage studies have identified several genomic regions that probably contain CD susceptibility genes. The most important genetic factors identified are HLA-DQ2 and HLA-DQ8, which are necessary but not sufficient to predispose to CD. The associations found in non-HLA genomewide linkage and association studies are much weaker. This might be because a large number of non-HLA genes contributes to the pathogenesis of CD. Hence, the contribution of a single predisposing non-HLA gene might be quite modest. Practically all CD patients carry HLA-DQ2 or HLA-DQ8, while the absence of these molecules has a negative predictive value for CD close to 100%. Genetic risk profiles for CD would be helpful in clinical practice for predicting disease susceptibility and progression.

Celiac disease (CD) is a common enteropathy with a strong genetic risk. It is characterized by a permanent intolerance for gluten proteins present in dietary wheat, rye, and barley. It affects approximately 1:100-300 individuals,[1,2,3] although only 1 person in ~8 is aware of being affected because the symptoms may be mild or nonspecific.[4] Environmental, genetic, and immunologic factors are important in the pathogenesis of CD.

Genes play a key role in CD and considerable progress has been made in identifying some of those responsible for CD. The roles of HLA-DQ2 and HLA-DQ8 are well known as almost all patients carry the genes encoding these heterodimers.[5,6] Non-HLA genes also contribute to the development of CD, but these associations are less evident. Genetic linkage analyses have identified susceptibility loci on various chromosomes, such as 2, 5, 6, 9, 15, and 19, revealing the complexity of CD.[7,8,9,10,11,12,13,14,15,16]

Gluten is the most important environmental factor. Gluten proteins provoke the disease as the high proline content of gluten is relatively resistant to proteolytic digestion in the intestinal tract.[17,18] The undigested gluten peptides are deamidated by tissue transglutaminase, which results in a better binding capacity to the pocket of HLA-DQ2 or HLA-DQ8 molecules on antigen-presenting cells (see Figure 1). This complex is presented to CD4+ T cells and the ensuing immune response causes inflammation and intestinal tissue damage. A direct response of the epithelium via the innate immune system also plays a role.

Pathogenesis of celiac disease: Gliadin is absorbed into the lamina propria and presented in conjunction with HLA-DQ2 or HLA-DQ8 cell-surface antigens by antigen-presenting cells, probably dendritic cells, to sensitized T cells expressing the α/ß-cell receptor. Tissue transglutaminase deamidates gliadin peptides, generating acidic, negatively charged residues of glutamic acid from neutral glutamines. Because negatively charged residues are preferred in positions 4, 6, and 7 of the antigen-binding groove of HLA-DQ2, deamidated gliadin elicits a stronger T-cell response (with permission of Farrell RJ, Kelly CP in N Engl J Med 2002;346:180-8).


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