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      Investigation of type 1 diabetes and coeliac disease susceptibility loci for association with juvenile idiopathic arthritis

      research-article
        1 , 1 , 1 , 1 , 2 , 1 , Childhood Arthritis Prospective Study (CAPS), UKRAG Consortium, BSPAR study group, 1 , 1
      Annals of the Rheumatic Diseases
      BMJ Group

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          Abstract

          Background

          There is strong evidence suggesting that juvenile idiopathic arthritis (JIA) shares many susceptibility loci with other autoimmune diseases.

          Objective

          To investigate variants robustly associated with type 1 diabetes (T1D) or coeliac disease (CD) for association with JIA.

          Methods

          Sixteen single-nucleotide polymorphisms (SNPs) already identified as susceptibility loci for T1D/CD were selected for genotyping in patients with JIA (n=1054) and healthy controls (n=3129). Genotype and allele frequencies were compared using the Cochrane–Armitage trend test implemented in PLINK.

          Results

          One SNP in the LPP gene, rs1464510, showed significant association with JIA (p trend=0.002, OR=1.18, 95% CI 1.06 to 1.30). A second SNP, rs653178 in ATXN2, also showed nominal evidence for association with JIA (p trend=0.02, OR=1.13, 95% CI 1.02 to 1.25). The SNP, rs17810546, in IL12A showed subtype-specific association with enthesitis-related arthritis (ERA) subtype (p trend=0.005, OR=1.88, 95% CI 1.2 to 2.94).

          Conclusions

          Evidence for a novel JIA susceptibility locus, LPP, is presented. Association at the SH2B3/ATXN2 locus, previously reported to be associated with JIA in a US series, also supports this region as contributing to JIA susceptibility. In addition, a subtype-specific association of IL12A with ERA is identified. All findings will require validation in independent JIA cohorts.

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          Most cited references15

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          Shared and distinct genetic variants in type 1 diabetes and celiac disease.

          Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared. We evaluated the association between type 1 diabetes and eight loci related to the risk of celiac disease by genotyping and statistical analyses of DNA samples from 8064 patients with type 1 diabetes, 9339 control subjects, and 2828 families providing 3064 parent-child trios (consisting of an affected child and both biologic parents). We also investigated 18 loci associated with type 1 diabetes in 2560 patients with celiac disease and 9339 control subjects. Three celiac disease loci--RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12, and TAGAP on chromosome 6q25--were associated with type 1 diabetes (P<1.00x10(-4)). The 32-bp insertion-deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81x10(-8)) and was also associated with celiac disease, along with PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33, bringing the total number of loci with evidence of a shared association to seven, including SH2B3 on chromosome 12q24. The effects of the IL18RAP and TAGAP alleles confer protection in type 1 diabetes and susceptibility in celiac disease. Loci with distinct effects in the two diseases included INS on chromosome 11p15, IL2RA on chromosome 10p15, and PTPN22 on chromosome 1p13 in type 1 diabetes and IL12A on 3q25 and LPP on 3q28 in celiac disease. A genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles. These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens, may be etiologic features of both diseases. 2008 Massachusetts Medical Society
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            Newly identified genetic risk variants for celiac disease related to the immune response.

            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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              Rheumatoid arthritis association at 6q23.

              The Wellcome Trust Case Control Consortium (WTCCC) identified nine single SNPs putatively associated with rheumatoid arthritis at P = 1 x 10(-5) - 5 x 10(-7) in a genome-wide association screen. One, rs6920220, was unequivocally replicated (trend P = 1.1 x 10(-8)) in a validation study, as described here. This SNP maps to 6q23, between the genes oligodendrocyte lineage transcription factor 3 (OLIG3) and tumor necrosis factor-alpha-induced protein 3 (TNFAIP3).
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                Author and article information

                Journal
                Ann Rheum Dis
                annrheumdis
                ard
                Annals of the Rheumatic Diseases
                BMJ Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0003-4967
                1468-2060
                1 December 2010
                20 July 2010
                : 69
                : 12
                : 2169-2172
                Affiliations
                [1 ]Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester, UK
                [2 ]Haywood Hospital, University Hospital of North Staffordshire, Stoke on Trent, Staffordshire, ST4 7LN
                Author notes
                Correspondence to Dr Anne Hinks, Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, Stopford Building, The University of Manchester, Manchester M13 9PT, UK; anne.hinks@ 123456manchester.ac.uk
                Article
                annrheumdis126938
                10.1136/ard.2009.126938
                3002762
                20647273
                f43591f3-af5f-4844-8b76-0ecff8786af0
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

                History
                : 25 June 2010
                Categories
                Clinical and Epidemiological Research
                1506
                Concise report
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                Immunology
                Immunology

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