Alternative titles; symbols
DO: 10608;
Cytogenetic location: 2q11-q12 Genomic coordinates (GRCh38) : 2:93,900,001-108,700,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q11-q12 | {Celiac disease, susceptibility to, 8} | 612006 | 2 |
Celiac disease, also known as celiac sprue and gluten-sensitive enteropathy, is a multifactorial disorder of the small intestine that is influenced by both environmental and genetic factors. It is characterized by malabsorption resulting from inflammatory injury to the mucosa of the small intestine after the ingestion of wheat gluten or related rye and barley proteins (summary by Farrell and Kelly, 2002).
For additional information and a discussion of genetic heterogeneity of celiac disease, see 212750.
The form of susceptibility to celiac disease here designated CELIAC8 is influenced by genetic variation in the 2q11-q12 region, within a linkage disequilibrium (LD) block encompassing the IL18RAP (604509) and IL18R1 (604494) genes.
To identify risk variants contributing to celiac disease susceptibility other than those in the HLA-DQ region (see CELIAC1, 212750), Hunt et al. (2008) genotyped 1,020 of the most strongly associated non-HLA markers identified by van Heel et al. (2007) in an additional 1,643 cases of celiac disease and 3,406 controls. Two significantly associated single-nucleotide polymorphisms (SNPs), rs917997 (p overall = 8.49 x 10(-10)) and rs13015714, both in LD, map to an approximately 400-kb LD block. This region was also identified in the Wellcome Trust Case Control Consortium (2007) (WTCCC) study of Crohn disease (see 266600). This LD block contains 4 genes, 2 of which, IL18RAP (604509) and IL18R1 (604494), encode the receptor for the IL18 protein. The IL18 pathway is highly relevant, as mature IL18 induces T cells to synthesize interferon-gamma (147570), a key cytokine involved in the mucosal inflammation of celiac disease. IL18 (600953) binds to targeted cells through a receptor comprising an alpha chain (IL18R1) and a beta chain (IL18RAP). Salvati et al. (2002) found that mature IL18 is expressed in intestinal mucosa of active, treated, and latent celiac cases, but not in healthy controls. Hunt et al. (2008) found that IL18RAP is strongly expressed in unstimulated T cells and natural killer cells and is expressed in small intestinal biopsies. The authors observed a large cis effect of rs917997 genotypes on the level of IL18RAP mRNA expression in whole blood from treated individuals with celiac disease, accounting for 16.1% of the population variants in IL18RAP expression. They observed a significant allele dosage effect on expression (post hoc regression testing for linear trend P less than 0.0001). Individuals homozygous for the minor rs917997 A allele, which was more common in individuals with celiac disease than in control subjects, expressed the lowest levels of IL18RAP mRNA; heterozygotes expressed intermediate levels, and homozygotes for the G allele expressed the highest levels.
Zhernakova et al. (2008) found strong association between rs917997 and both Crohn disease and ulcerative colitis (see IBD1, 266600).
In an Italian cohort involving 538 patients with celiac disease and 593 healthy controls, Romanos et al. (2009) found no association with the rs917997 SNP previously reported by Hunt et al. (2008). The authors noted that this was the first celiac disease association study in a southern European cohort, and suggested that there may be population differences across Europe regarding the loci contributing to celiac disease.
Koskinen et al. (2009) tested 2 previously indicated risk variants at the IL18RAP locus (rs13015714 and rs917997) for genetic association in 1,638 patients with celiac disease and 1,385 control individuals from Finnish, Hungarian, and Italian populations. Protein expression level of IL18RAP was compared between risk allele carriers and noncarriers by Western blotting, and immunohistochemical analysis was performed to study IL18RAP protein expression in small intestinal biopsies of untreated and treated celiac patients and controls. The authors confirmed genetic association and dosage effects of the IL18RAP SNPs with celiac disease in the Hungarian population. The GA haplotype of the rs13015714 and rs917997 SNPs showed the strongest association (p = 0.0001, odds ratio = 1.475). Koskinen et al. (2009) identified 2 putative isoforms of IL18RAP and suggested that the ratios and total levels of these isoforms may contribute to the etiology of celiac disease.
In a study of 722 Spanish celiac patients and 794 ethnically matched controls, Dema et al. (2009) did not detect a significant association with {dbSNP 917997}; they did observe a dosage effect similar to that found in the study by Koskinen et al. (2009), although it was nonsignificant. A metaanalysis combining the Spanish data with that of previous negative studies reached borderline significance (p = 0.044; OR = 1.12). Dema et al. (2009) suggested that the initial odds ratio of 1.34 reported by Hunt et al. (2008) was slightly overestimated and that the real situation might be the existence of a genuine but weak risk factor, which generates statistical power limitations.
Castellanos-Rubio et al. (2016) studied LNC13 (617071), a long noncoding RNA that overlaps the IL18RAP gene and encompasses the CELIAC8 haplotype block that includes rs917997. Quantitative analysis of intestinal biopsies from celiac patients showed significant downregulation of LNC13 compared to controls, specifically in lymphocytes of the lamina propria. Expression of 4 inflammation-associated genes, TRAF2 (601895), STAT1 (600555), IL1RN (147679), and MYD88 (602170), was significantly increased in patient biopsies, and that expression was inversely associated with levels of LNC13; however, expression of IL18RAP and IL15 (600554) did not change with LNC13 levels, suggesting that LNC13 affects expression of only a subset of celiac-associated genes. Castellanos-Rubio et al. (2016) demonstrated that LNC13 regulates expression of those genes through interaction with chromatin and HNRNPD (601324), and observed that the interaction between LNC13 and HNRNPD was significantly decreased with the disease-associated 'T' allele of rs917997 compared to wildtype 'C' allele. In addition, they showed that LNC13 is degraded by DCP2 (609844) after NFKB (see 164011) activation. The authors concluded that LNC13 plays a role in maintenance of intestinal mucosal immune homeostasis and that dysregulation of LNC13 expression and function contributes to inflammation in autoimmune disorders such as celiac disease.
Zhernakova et al. (2010) assessed signatures of natural selection for 10 confirmed celiac disease loci in several genomewide data sets comprising 8,154 controls from 4 European populations and 195 individuals from a North African population and found consistent signs of positive selection for disease-associated alleles at 3 loci, with rs917997 from the IL18RAP locus showing a borderline-significant signature for the European and North African populations.
Castellanos-Rubio, A., Fernandez-Jimenez, N., Kratchmarov, R., Luo, X., Bhagat, G., Green, P. H. R., Schneider, R., Kiledjian, M., Bilbao, J. R., Ghosh, S. A long noncoding RNA associated with susceptibility to celiac disease. Science 352: 91-95, 2016. [PubMed: 27034373] [Full Text: https://doi.org/10.1126/science.aad0467]
Dema, B., Martinez, A., Fernandez-Arquero, M., Maluenda, C., Polanco, I., de la Concha, E. G., Urcelay, E., Nunez, C. Association of IL18RAP and CCR3 with coeliac disease in the Spanish population. (Letter) J. Med. Genet. 46: 617-619, 2009. [PubMed: 19542083] [Full Text: https://doi.org/10.1136/jmg.2009.067041]
Farrell, R. J., Kelly, C. P. Celiac sprue. New Eng. J. Med. 346: 180-188, 2002. [PubMed: 11796853] [Full Text: https://doi.org/10.1056/NEJMra010852]
Hunt, K. A., Zhernakova, A., Turner, G., Heap, G. A. R., Franke, L., Bruinenberg, M., Romanos, J., Dinesen, L. C., Ryan, A. W., Panesar, D., Gwilliam, R., Takeuchi, F., and 25 others. Newly identified genetic risk variants for celiac disease related to the immune response. Nature Genet. 40: 395-402, 2008. [PubMed: 18311140] [Full Text: https://doi.org/10.1038/ng.102]
Koskinen, L. L. E., Einarsdottir, E., Dukes, E., Heap, G. A. R., Dubois, P., Korponay-Szabo, I. R., Kaukinen, K., Kurppa, K., Ziberna, F., Vatta, S., Not, T., Ventura, A., and 9 others. Association study of the IL18RAP locus in three European populations with coeliac disease. Hum. Molec. Genet. 18: 1148-1155, 2009. [PubMed: 19103669] [Full Text: https://doi.org/10.1093/hmg/ddn438]
Romanos, J., Barisani, D., Trynka, G., Zhernakova, A., Bardella, M. T., Wijmenga, C. Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease. J. Med. Genet. 46: 60-63, 2009. [PubMed: 18805825] [Full Text: https://doi.org/10.1136/jmg.2008.061457]
Salvati, V. M., MacDonald, T. T., Bajaj-Elliott, M., Borrelli, M., Staiano, A., Auricchio, S., Troncone, R., Monteleone, G. Interleukin 18 and associated markers of T helper cell type 1 activity in coeliac disease. Gut 50: 186-190, 2002. [PubMed: 11788557] [Full Text: https://doi.org/10.1136/gut.50.2.186]
van Heel, D. A., Franke, L., Hunt, K. A., Gwilliam, R., Zhernakova, A., Inouye, M., Wapenaar, M. C., Barnardo, M. C. N. M., Bethel, G., Holmes, G. K. T., Feighery, C., Jewell, D., and 16 others. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nature Genet. 39: 827-829, 2007. [PubMed: 17558408] [Full Text: https://doi.org/10.1038/ng2058]
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661-678, 2007. [PubMed: 17554300] [Full Text: https://doi.org/10.1038/nature05911]
Zhernakova, A., Elbers, C. C., Ferwerda, B., Romanos, J., Tryunka, G., Dubois, P. C., de Kovel, C. G. F., Francke, L., Oosting, M., Barisani, D., Bardella, M. T., Finnish Celiac Disease Study Group, Joosten, L. A. B., Saavalainen, P., van Heel, D. A., Catassi, C., Netea,, M. G., Wijmenga, C. Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection. Am. J. Hum. Genet. 86: 970-977, 2010. [PubMed: 20560212] [Full Text: https://doi.org/10.1016/j.ajhg.2010.05.004]
Zhernakova, A., Festen, E. M., Franke, L., Trynka, G., van Diemen, C. C., Monsuur, A. J., Bevova, M., Nijmeijer, R. M., van't Slot, R., Heijmans, R., Boezen, H. M., van Heel, D. A., van Bodegraven, A. A., Stokkers, P. C. F., Wijmenga, C., Crusius, J. B. A., Weersma, R. K. Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP. Am. J. Hum. Genet. 82: 1202-1210, 2008. [PubMed: 18439550] [Full Text: https://doi.org/10.1016/j.ajhg.2008.03.016]