Alternative titles; symbols
Other entities represented in this entry:
DO: 10608;
Cytogenetic location: 4q27 Genomic coordinates (GRCh38) : 4:119,900,001-122,800,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q27 | {Autoimmune disease, susceptibility to, 5} | 611598 | 2 | |
| {Celiac disease, susceptibility to, 6} | 611598 | 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.
For a discussion of autoimmunity, see 109100.
A susceptibility to celiac disease (CELIAC6) and to autoimmunity (AIS5) has been mapped to the 4q27 region, within a linkage disequilibrium (LD) block encompassing the KIAA1109 (611565), TENR (ADAD1), IL2 (147680), and IL21 (605384) genes.
Celiac Disease Susceptibility
In a genomewide study to identify predisposing factors in celiac disease (CD), Van Heel et al. (2007) identified genetic variation in a linkage disequilibrium (LD) block encompassing the KIAA1109, TENR (ADAD1), IL2, and IL21 genes as a susceptibility factor for CD. Using 310,605 genomewide SNPs in 778 individuals from the United Kingdom (UK) with CD and 1,422 UK controls, they achieved the most significant linkage outside the HLA region (see 146880) at rs13119723 (P = 2.0 x 10(-7)) in the KIAA1109 gene (611565) on chromosome 4q27. The association was confirmed in 2 further collections, 508 Dutch CD patients and 929 controls and 483 Irish CD patients and 560 controls (metaanalysis P = 4.8 x 10(-11)). The strongest association overall was achieved at rs6822844 (metaanalysis P = 1.3 x 10(-14)) located 25 kb 5-prime of the IL21 gene. Van Heel et al. (2007) concluded that genetic variation at chromosome 4q27, in an LD block spanning the KIAA1109, TENR (ADAD1), IL2, and IL21 genes, predisposes to CD. The authors stated that because of extensive LD the causal variant associated with CD in the 4q27 region could not be determined.
In a separate replication sample comprising 1,643 celiac cases and 3,406 controls from 3 independent European celiac disease collections, Hunt et al. (2008) found that rs6822844 showed a strong association with celiac disease (P overall = 2.82 x 10(-13)).
In an Italian cohort involving 538 patients with celiac disease and 593 healthy controls, Romanos et al. (2009) confirmed association at rs6822844 (p = 0.0253).
Autoimmune Disease Susceptibility
Zhernakova et al. (2007) hypothesized that the KIAA1109/TENR/IL2/IL21 CD susceptibility region reported by van Heel et al. (2007) may represent a general risk locus for multiple autoimmune diseases. They tested rs6822844 for association with disease in 350 type 1 diabetes (T1D; see 222100)-affected and 1,047 rheumatoid arthritis (RA; 180300)-affected Dutch patients and 929 controls. A decrease in the frequency of the T allele was observed in both T1D (12.7%) and RA (14.1%) groups compared with controls (18.5%). The association was significant in both T1D (P = 0.0006, OR = 0.64, 95% CI 0.50-0.83) and RA (P = 0.0002, OR = 0.72, 95% CI 0.61-0.86). The Wellcome Trust Case Control Consortium (2007) had reported a locus on 4q27 containing the KIAA1109/TENR/IL2/IL21 region in a genomewide association study of T1D; the follow-up replication study of Todd et al. (2007) indicated moderate association of SNPs in the KIAA1109/TENR/IL2/IL21 region with T1D. Zhernakova et al. (2007) found that the most T1D-associated SNP in the Wellcome Trust Case Control Consortium (2007) study, rs3136534, was in complete LD with one of the SNPs identified by van Heel et al. (2007), rs4505848. Zhernakova et al. (2007) found a slight increase in the G allele of rs4505848 in patients with T1D and RA compared with controls. Overall, Zhernakova et al. (2007) found that the T allele of the rs6822844 SNP was a perfect proxy for a haplotype, AATGG, that showed consistent association with the majority of the decreased risk for CD, T1D, and RA and was therefore the best proxy for the disease variant, which could not be determined because of extensive linkage disequilibrium.
Psoriatic Arthritis Susceptibility
In a genomewide association study of 223 U.S. patients with psoriasis, including 91 with psoriatic arthritis, and 519 European controls, followed by replication in a U.K. cohort of 576 patients with psoriatic arthritis and 480 controls, Liu et al. (2008) found evidence for a locus on chromosome 4q27, which harbors the IL2 (147680) and IL21 (605384) genes. The most significant association in the discovery set was with rs13151961 (p = 4 x 10(-5)); rs13151961, rs7684187, and rs6822844 showed association with psoriatic arthritis in the replication cohort (p values from 0.001 to 0.008). Liu et al. (2008) noted that this region overlaps with the PSORS3 locus (601454) and the CELIAC6 locus.
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]
Liu, Y., Helms, C., Liao, W., Zaba, L. C., Duan, S., Gardner, J., Wise, C., Miner, A., Malloy, M. J., Pullinger, C. R., Kane, J. P., Saccone, S., Worthington, J., Bruce, I., Kwok, P.-Y., Menter, A., Krueger, J., Barton, A., Saccone, N. L., Bowcock, A. M. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 4: e1000041, 2008. Note: Electronic Article. [PubMed: 18369459] [Full Text: https://doi.org/10.1371/journal.pgen.1000041]
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]
Todd, J. A., Walker, N. M., Cooper, J. D., Smyth, D. J., Downes, K., Plagnol, V., Bailey, R., Nejentsev, S., Field, S. F., Payne, F., Lowe, C. E., Szeszko, J. S., and 30 others. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39: 857-864, 2007. [PubMed: 17554260] [Full Text: https://doi.org/10.1038/ng2068]
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., Alizadeh, B. Z., Bevova, M., van Leeuwen, M. A., Coenen, M. J. H., Franke, B., Franke, L., Posthumus, M. D., van Heel, D. A., van der Steege, G., Radstake, T. R. D. J., Barrera, P., Roep, B. O., Koeleman, B. P. C., Wijmenga, C. 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. 81: 1284-1288, 2007. [PubMed: 17999365] [Full Text: https://doi.org/10.1086/522037]