Carlo Catassi; Alessio Fasano


Curr Opin Gastroenterol. 2008;24(6):687-691. 

In This Article

The Genetics of Celiac Disease is Complex

Genetic predisposition plays a key role in celiac disease and considerable progress has been made recently in identifying genes that are responsible for celiac disease predisposition. It is well known that celiac disease is strongly associated with specific HLA class II genes known as HLA-DQ2 and HLA-DQ8 located on chromosome 6p21. Most celiac disease patients (around 95%) express HLA-DQ2 and the remaining patients are usually HLA-DQ8 positive. The HLA-DQ2 allele is common and is carried by approximately 30% of Caucasian individuals. Thus, HLA-DQ2 or HLA-DQ8 is necessary for disease development, but not sufficient, as its estimated risk effect is only 36-53%. Non-HLA genes contribute more than HLA to the celiac disease genetic background; however, this predisposition depends on a multitude of genes, each of them adding only a modest contribution to disease development. Due to small effect size and genetic heterogeneity between populations, the search for non-HLA celiac disease predisposing genes is like looking for a needle in a haystack. However, this process has been facilitated by the recent application of genome-wide association studies (GWAS), a hypothesis-free approach that can test thousands of single nucleotide polymorphisms (SNPs) across the whole genome for association.[6••]

A provisional list of celiac disease predisposing loci includes CELIAC1 on chromosome 6 (HLA-DQ2 and HLA-DQ8), CELIAC2 on chromosome 5q31-33, CELIAC3 on chromosome 2q33 (containing the T-lymphocyte regulatory genes CD28, CTLA4, and ICOS), and CELIAC4 (the myosin IXB gene, MYO9XB) on chromosome 19p13.1. MYO9B encodes an unconventional myosin molecule that may have a role in actin remodeling of epithelial enterocytes. It has been hypothesized that this genetic variant might lead to an impaired intestinal barrier, which might allow the passage of immunogenic gluten peptides.[7] Although the MYO9B association has not been replicated in some European populations, it was a puzzling finding that MYO9B genetic variants predispose also to inflammatory bowel disease. These data imply shared causal mechanisms underlying intestinal inflammatory diseases.[8] Genetic variation in MYO9B was found to be associated also with systemic lupus erythematosus and rheumatoid arthritis, suggesting that MYO9B is a general risk factor for autoimmunity.[9] Furthermore, associations with tight junction genes PARD3 and MAGI2 has been reported in Dutch patients affected with either celiac disease or ulcerative colitis, again suggesting a common defect of the intestinal barrier in these two conditions.[10•]

The first GWAS in a large cohort of UK celiac disease patients and controls identified risk variants in the 4q27 region harboring IL2 and IL21 genes.[11] IL-2, secreted in an autocrine fashion by antigen-stimulated T cells, is a key cytokine for T-cell activation and proliferation. Another T-cell-derived cytokine, IL-21, enhances B-cell, T-cell, and natural killer cell proliferation and IFN-Υ production. Both cytokines are implicated in the mechanism of other autoimmune conditions, namely T1D and rheumatoid arthritis, suggesting that the 4q27 region might represent a general autoimmune disease risk locus.[12] A further GWAS on follow-up samples from three independent European celiac disease collections identified seven previously unknown regions contributing significantly toward disease risk.[13••] These seven newly identified regions, together with IL2-IL21, explained 3-4% of the heritability of celiac disease. Six out of seven regions harbored genes controlling immune responses, for example leukocyte signaling in response to IL-18 and IFN-Υ production. Together with other recent GWAS reports,[14] these findings suggested possible common mechanisms between celiac disease and T1D at the SH2B3 region and the 3p21 CCR gene region, and between celiac disease and Crohn's disease at the IL18RAP region.

To summarize, it appears that the genetic predisposition to celiac disease depends on one gene with a large effect (HLA-DQ2/DQ8) on the adaptive immune response to gluten peptides and many other genes influencing different aspects of innate and adaptive immune reactions, intestinal permeability, and general predisposition to autoimmunity.


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