Overview
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] 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.
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%.
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.[3, 4, 5]
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.[6]
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.[7] 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.[8]
A GWAS on follow-up samples from three independent European CD databases identified seven previously unknown genetic regions that significantly contribute toward disease risk.[9] 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,[10] 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.
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.
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.
The following companies are currently offering testing for HLA-DQ2 and HLA-DQ8:
Kimball Genetics (http://www.kimballgenetics.com)
LabCorp (http://www.labcorp.com)
Quest Diagnostics (http://www.questdiagnostics.com)
Specialty Laboratories (http://www.specialtylabs.com)
Resources
More information about celiac disease and HLA-DQ2/DQ8 can be found in Medscape's Celiac Disease Resource Center as well as in the eMedicine article on Celiac Sprue.
Kumar V, Wijmenga C. Celiac disease: update from the 14th International Celiac Disease Symposium 2011. Expert Rev Gastroenterol Hepatol. Dec 2011;5(6):685-7. [Medline].
Kurppa K, Salminiemi J, Ukkola A, Saavalainen P, Löytynoja K, Laurila K, et al. Utility of the New ESPGHAN Criteria for the Diagnosis of Celiac Disease in at-Risk Groups: A Large Family-Based Cohort Study. J Pediatr Gastroenterol Nutr. Nov 14 2011;[Medline].
Wolters VM, Wijmenga C. Genetic background of celiac disease and its clinical implications. Am J Gastroenterol. Jan 2008;103(1):190-5. [Medline].
Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A, et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet. Nov 6 2011;43(12):1193-201. [Medline]. [Full Text].
da Silva EM, W Achatz MI, Martel-Planche G, Montagnini AL, Olivier M, Prolla PA, et al. TP53 mutation p.R337H in gastric cancer tissues of a 12-year-old male child: evidence for chimerism involving a common mutant founder haplotype: case report. BMC Cancer. Oct 17 2011;11:449. [Medline]. [Full Text].
Wapenaar MC, Monsuur AJ, van Bodegraven AA, Weersma RK, Bevova MR, Linskens RK, et al. Associations with tight junction genes PARD3 and MAGI2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitis. Gut. Apr 2008;57(4):463-7. [Medline].
van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M, et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet. Jul 2007;39(7):827-9. [Medline].
Zhernakova A, Alizadeh BZ, Bevova M, van Leeuwen MA, Coenen MJ, Franke B, et al. Novel association in chromosome 4q27 region with rheumatoid arthritis and confirmation of type 1 diabetes point to a general risk locus for autoimmune diseases. Am J Hum Genet. Dec 2007;81(6):1284-8. [Medline].
Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet. Apr 2008;40(4):395-402. [Medline].
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. Jun 7 2007;447(7145):661-78. [Medline].
Csizmadia CG, Mearin ML, Oren A, Kromhout A, Crusius JB, von Blomberg BM, et al. Accuracy and cost-effectiveness of a new strategy to screen for celiac disease in children with Down syndrome. J Pediatr. Dec 2000;137(6):756-61. [Medline].
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