Genetics of Celiac Disease

Updated: Nov 10, 2016
  • Author: Alessio Fasano, MD; Chief Editor: Karl S Roth, MD  more...
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Celiac disease (CD) is an immune-mediated disease of the intestines that is triggered by the ingestion of gluten in genetically susceptible individuals. Gluten is the major protein component of wheat, rye, and barley. [1]

Genetic predisposition plays a key role in CD and considerable progress has been made recently in identifying genes that are responsible for CD predisposition. [2, 3] It is well known that CD is strongly associated with specific HLA class II genes known as HLA-DQ2 and HLA-DQ8 located on chromosome 6p21. [3, 4, 5, 6, 7]

Approximately 95% of CD patients express HLA-DQ2, and the remaining patients are usually HLA-DQ8 positive. However, 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 is not sufficient for disease development; its estimated risk effect is only 36-53%.

The majority of patients with CD have been found to carry the HLA DQA1*05 and DQB1*02 alleles, which encode the DQ2.5 molecule, and the expression of DQ2.5 genes is an important risk factor in CD. The DQ2.5 genes establish the different intensities of anti-gluten immunity, depending on whether they are in a homozygous or a heterozygous configuration. [4]

Trynka et al comprehensively surveyed the genetic architecture of all known risk loci previously associated with immune-mediated diseases in 12,041 patients with celiac disease and 12,228 controls. They identified 13 new celiac disease risk loci reaching genome-wide significance, some being present in single genes or regulatory genes. Even if each of the identified genes have little "weight" in defining a celiac disease genetic trait, they add to the growing pieces (now approximately 40 genes) of the celiac disease genetic puzzle. [8]

Guidelines for CD diagnosis from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) propose the option to omit the duodenal biopsy in the diagnosis of CD if all 4 of the following criteria are met in children and adolescents [9, 10, 11, 12] :

  1. Signs and symptoms suggestive of CD
  2. Anti-transglutaminase type 2 antibody (anti-TG2) levels more than 10 times the upper limit of normal
  3. Positive confirmation tests of anti-endomysium-IgA antibodies (EMA)
  4. At-risk HLA-DQ2 or HLA-DQ8

According to Nevoral et al, intestinal biopsies for CD could be omitted in 28% of patients when ESPGHAN guidelines (European Society for Pediatric Gastroenterology, Hepatology and Nutrition) are applied. The authors found that because of the high accuracy of serologic tests and clinical symptoms of CD, the new guidelines seem applicable even without HLA testing. Of the 345 biopsied children, 213 (62%) had anti-TG titers greater than 10 times the upper limit of normal and positive EMA antibodies. Ninety-nine (29%) of the patients also had symptoms suggestive of CD in addition to EMA positivity and elevated titers of anti-TG greater than 10 times the upper limit of normal. [11]


Clinical Implications

Non-HLA genes contribute more to the CD genetic background than do the HLA genes, but each adds only a modest contribution to disease development. The search for these additional genes 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 across the whole genome for association. [13, 14, 15]

A provisional list of CD-predisposing genetic 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. Associations with tight junction genes PARD3 and MAGI2 have been reported in Dutch patients with either CD or ulcerative colitis, suggesting a common defect of the intestinal barrier in these two conditions. [16]

The first GWAS in a large cohort of CD patients and controls in the United Kingdom identified risk variants in the 4q27 region harboring IL2 and IL21 genes. [17] IL-2 is a key cytokine for T-cell activation and proliferation. IL-21, also a T-cell derived cytokine, enhances B-cell, T-cell and NK-cell proliferation and interferon-gamma production. Of note, both cytokines are implicated in the mechanism of other autoimmune conditions, namely type 1 diabetes and rheumatoid arthritis, suggesting that the 4q27 region might represent a general autoimmune disease risk locus. [18, 19]

A GWAS on follow-up samples from three independent European CD databases identified seven previously unknown genetic regions that significantly contribute toward disease risk. [20] These seven newly identified regions, together with IL2 and IL21, explained approximately 3-4% of the heritability of CD. Six out of seven regions harbored genes controlling immune responses, eg, leukocyte signaling in response to IL-18 and interferon-gamma production. This report, together with another recent GWAS report, [21] suggest possible common mechanisms between CD and type 1 diabetes at the SH2B3 region and the 3p21 CCR gene region, as well as between CD and Crohn's disease at the IL18RAP region.

Certain gene polymorphisms of IL2/IL21 (rs6822844 and rs6840978) and SH2B3 (rs3184504) may influence susceptibility to CD, although the effects remain unclear. [19]

To summarize, it appears that the genetic predisposition to CD depends largely on the effect of HLA-DQ2/DQ8 on the adaptive immune response to gluten peptides, as well as on many other genes influencing different aspects of innate and adaptive immune reactions, intestinal permeability, and a general predisposition to autoimmunity.

Therefore, based on their contribution to CD heritability, the HLA genes are the only genes for which testing is currently recommended, as most patients with CD carry the HLA-DQ alleles associated with CD. Because the presence of symptoms alone does not necessarily predict which individuals might have CD, select individuals with potential CD in high risk groups, such as first-degree relatives of CD patients, those with Down syndrome, and/or those with autoimmune diseases, could consider genetic diagnostic testing. Serology screening once in a lifetime might be not enough to detect CD, so an accurate, two-step strategy for screening consisting of HLA-DQ typing and longitudinal serologic CD-screening only in subjects positive for HLA DQ2 and/or DQ8 has been suggested by some groups. [4]


Genetic Testing

HLA tests for the class II heterodimers DQ2 and DQ8 are commercially available. Note that while the DQ2 or DQ8 genotype is considered necessary to develop CD, the presence of either one does not confirm the diagnosis. Conversely, the absence of both HLA types has a negative predictive value of over 99% and virtually excludes the diagnosis of CD. [4, 7]

In a study that included 1494 women and 1540 men from the general Australian population, along with 356 volunteers who had biopsy-confirmed celiac disease, Anderson et al assessed the ability of HLA-DQ genotyping and serology to estimate the prevalence of celiac disease.  Of those with biopsy-confirmed celiac disease, 91.3% had HLA-DQ2.5, 5.3% had HLA-DQ8 but not HLA-DQ2.5, and 2.0% had HLA-DQ2.2 but not HLA-DQ2.5 or HLA-DQ8; 5 patients lacked all 3, but 4 were found to have normal small bowel histology despite prolonged gluten challenge. [22]

The prevalence of celiac disease in the general community, on the basis of the presence of 1 of these HLA-DQ types and positive tissue transglutaminase (TG)-2 serology, was approximately 1.3% in both women and men. Confirmatory testing yielded positive results in 26 subjects (13 women and 13 men) with elevated TG-2 IgA levels, all of whom had HLA-DQ2.5. In addition, test results were positive in all 21 subjects (10 women and 11 men) with raised levels of TG-2 IgA, deamidated gliadin peptide (DGP) IgG, and DGP IgA, all of whom had HLA-DQ2.5. [23, 22]



More information about celiac disease and HLA-DQ2/DQ8 can be found in Medscape's Celiac Disease Resource Center as well as in the Medscape Reference article on Celiac Sprue.