Genetic Background of Celiac Disease and Its Clinical Implications

Genetic Linkage Studies in CD

The CELIAC1 locus on chromosome 6p21 contains HLA class II molecules.^[22] It is unequivocal that CD is strongly associated with specific HLA class II genes known as HLA-DQ2 and HLA-DQ8.^[23] HLA-DQ molecules are heterodimers consisting of an α and ß chain. Particularly the combination of alleles encoding for the α chain DQA1*05 and ß chain DQB1*02 of the HLA-DQ2 heterodimer are associated with CD. Most CD patients (~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 whites.^[23] However, only ~3% of individuals in the general population who carry HLA-DQ2 will develop CD.^[24] It is noteworthy that individuals homozygous for the DQ2 molecule comprise approximately 2% of the European population but make up approximately 25% of all CD patients.^[5] Thus, HLA-DQ2 or HLA-DQ8 is necessary for disease development but not sufficient as its estimated risk effect is only 36-53%.^[25] Thus, non-HLA genes may well contribute more than HLA. The importance of non-HLA genes is supported by the difference in concordance rates seen among HLA identical siblings (~30%).^[19,26,27] However, linkage peaks observed in non-HLA regions are much lower and not consistent compared to HLA. This might be because many non-HLA genes contribute to the pathogenesis of CD. Hence, the contribution of a single predisposing non-HLA gene might be modest.

The support for linkage to the CELIAC2 locus on chromosome 5q31-33 was first identified by Greco et al.^[7,8] Replication of this locus has not been universal and no disease-causing functional gene could be identified. This region contains a cytokine gene cluster and it might play a role in immune regulation and inflammation.

The CELIAC3 locus on chromosome 2q33 has shown linkage to CD and was replicated by a few but not all the studies performed.^{[9,28,29,30,31,32,33]} The CELIAC3 locus contains the T lymphocyte regulatory genes CD28, CTLA4, and ICOS.

CTLA4 (cytotoxic T lymphocyte-associated antigen 4) is a negative costimulatory molecule of the T-cell response and CTLA4 was already pinpointed as a candidate gene based on this known function before the era of genomewide linkage studies. No evidence for a single mutation in CTLA4 specific to CD has been found but a strong association was suggested at the haplotype level.^[34] The genetic variants in the CTLA4 gene in CD were extensively studied in several populations but with opposite results.^[35]

A genomewide scan by our group identified a region of significant linkage at chromosome 19p13.1.^[11] Further association analysis showed association to the myosin IXB gene (MYO9B). Interestingly, MYO9B is a good candidate gene for CD because of its function; it encodes an unconventional myosin molecule that may have a role in actin remodeling of epithelial enterocytes. It is hypothesized that this genetic variant might lead to an impaired intestinal barrier, which might allow the passage of immunogenic gluten peptides. This could be a factor involved in the early mucosal events preceding the inflammatory response in CD. However, in CD populations in the United Kingdom, Spain, Italy, and Scandinavia this association could not be replicated.^{[36,37,38,39]} Furthermore, it is unlikely that the SNP itself is the causing mutation as it is located deep in the intron, which means that it has no function in coding for protein synthesis. Most probably, the SNP is rather a disease marker, an allele "hitchhiking" (in linkage disequilibrium) with the true causative variant.

Chromosome 19p13 was also shown to have significant linkage to inflammatory bowel disease (IBD6) and recently our group showed an association of ulcerative colitis with MYO9B and Morbus Crohn, albeit weaker.^[40,41] This suggests that MYO9B might also promote susceptibility to other intestinal inflammatory diseases, although the precise mechanism of how gene variants in MYO9B can lead to altered gut function is unclear.

A strong association to MYO9B was also reported in patients with a complicated form of CD, known as refractory CD type II (RCDII). In this group, the enteropathy persists despite adherence to a gluten-free diet or it recurs after an initially good response to the diet. RCDII patients are characterized by the presence of aberrant intraepithelial lymphocytes in the small bowel mucosa.

Cite this: Genetic Background of Celiac Disease and Its Clinical Implications - Medscape - Jan 01, 2008.

Evidence for Genetic Susceptibility to Celiac Disease
Ethnic differences in disease incidence/prevalence	(21)
Familial aggregation	5-15% first-degree relatives of affected individuals are also affected
Familial aggregation	30% HLA identical sibs
Twin studies concordance rates	Monozygotic twins 83-86%
Twin studies concordance rates	Dizygotic twins 11%
Identification of susceptibility loci by genome screening	Chromosomes 2, 5, 6, 9, 15, 19
Genetic association studies of functional candidate genes	CTLA4
Association found with genetic syndromes	Down syndrome (57,58)
	Turner syndrome (59-62)
	Williams syndrome (63)

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