Hunt, K.A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395-402

Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK.
Nature Genetics (Impact Factor: 29.35). 04/2008; 40(4):395-402. DOI: 10.1038/ng.102
Source: PubMed


Our genome-wide association study of celiac disease previously identified risk variants in the IL2-IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non-HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions (P < 5 x 10(-7)). Six regions harbor genes controlling immune responses, including CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504) and TAGAP. Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2-IL21, CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.

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    • "Low levels of IL-10 have been associated with anti-tissue transglutaminase (anti tTG) antibodies in CD patients [6] and Salvati et al. [7] have also observed a suppression of gliadin-specific T cell activation using recombinant human IL-10 (rhIL-10). The IL10 gene maps on the long arm of chromosome 1 (1q31–q32) a locus previously identified by different genome wide association studies as possibly involved in CD [8] [9] [10]. Three single nucleotide polymorphisms (SNPs) at positions À1082 (A>G), À819 (T>C) and À592 (A>C) in the promoter region of the gene may affect the IL10 gene expression [11] [12] [13] [14]; previous studies have analyzed the influence of the three IL10 SNPs on CD susceptibility with discordant results [15] [16] [17]. "
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    • "Common to many other autoimmune disorders, the two alleles are often present in the cis conformation on the DR3 haplotype [8]; HLA-DQ2 and HLA-DQ8 are necessary but not sufficient for the development of CD. Genome wide association studies indicated 39 non-HLA loci to be predisposing to CD [9] [10] [11]. Altogether, the nonHLA loci explain only 5% of the risk for CD [6], while the HLA loci account for 35% of the risk [7]. "
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    • "As yet, these specific triggers remain incompletely understood. Furthermore , while HLA-DQ is clearly the main genetic determinant of susceptibility to CD, additional gene polymorphisms have also been shown to contribute to susceptibility to CD, many of which may contribute to enhanced T-cell reactivity (Hunt et al., 2008; Tjon et al., 2010). To date, at least 40 genomic regions containing 64 candidate genes for CD susceptibility have been identified, although these loci are thought to contribute only a small proportion of the genetic heritability of the disease (Abadie et al., 2011). "
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