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      Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci

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      1 , 2 , 3 , 3 , 4 , 5 , 3 , 4 , 6 , 7 , 5 , 5 , 8 , 5 , 5 , 1 , 3 , 4 , 4 , 4 , 5 , 9 , 9 , 9 , 10 , 10 , 11 , 12 , 1 , 13 , 14 , 15 , 16 , 17 , 18 , 18 , 19 , 3 , 4 , 20 , 21 , 22 , 23 , 24 , 25 , 1 , 5 , 3 , 4 , 7 , *
      PLoS Genetics
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          Abstract

          Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5×10 −8 in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene ( P combined  = 1.2×10 −12), rs864537 near CD247 ( P combined  = 2.2×10 −11), rs2298428 near UBE2L3 ( P combined  = 2.5×10 −10), and rs11203203 near UBASH3A ( P combined  = 1.1×10 −8). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5×10 −8 ( SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.

          Author Summary

          Celiac disease (CD) and rheumatoid arthritis (RA) are two autoimmune diseases characterized by distinct clinical features but increased co-occurrence in families and individuals. Genome-wide association studies (GWAS) performed in CD and RA have identified the HLA region and 26 non-HLA genetic risk loci in each disease. Of the 26 CD and 26 RA risk loci, previous studies have shown that six are shared between the two diseases. In this study we aimed to identify additional shared risk alleles and, in doing so, gain more insight into shared disease pathogenesis. We first empirically investigated the distribution of putative risk alleles from GWAS across both diseases (after removing known risk loci for both diseases). We found that CD risk alleles are non-randomly distributed in the RA GWAS (and vice versa), indicating that CD risk alleles have an increased prior probability of being associated with RA (and vice versa). Next, we performed a GWAS meta-analysis to search for shared risk alleles by combing the RA and CD GWAS, performing both directional and opposite allelic effect analyses, followed by replication testing in independent case-control datasets in both diseases. In addition to the already established six non-HLA shared risk loci, we observed statistically robust associations at eight SNPs, thereby increasing the number of shared non-HLA risk loci to fourteen. Finally, we used gene expression studies and pathway analysis tools to identify the plausible candidate genes in the fourteen associated loci. We observed remarkable overrepresentation of T-cell signaling molecules among the shared genes.

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          STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus.

          Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q. We tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus. A SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81x10(-7); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87x10(-9); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis. A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses. Copyright 2007 Massachusetts Medical Society.
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            TRAF1-C5 as a risk locus for rheumatoid arthritis--a genomewide study.

            Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis. We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1x10(-8)) were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA). We observed associations between disease and variants in the major-histocompatibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P=4x10(-14)). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5). A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis. Copyright 2007 Massachusetts Medical Society.
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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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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                February 2011
                February 2011
                24 February 2011
                : 7
                : 2
                : e1002004
                Affiliations
                [1 ]Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
                [2 ]Complex Genetics Section, Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
                [3 ]Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
                [4 ]Broad Institute, Cambridge, Massachusetts, United States of America
                [5 ]Genetics Department, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands
                [6 ]Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America
                [7 ]Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts, United States of America
                [8 ]Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
                [9 ]Department of Clinical Medicine and Institute of Molecular Medicine, Trinity Centre for Health Sciences, Trinity College, St James's Hospital, Dublin, Ireland
                [10 ]Department of Rheumatology and Clinical Immunology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands
                [11 ]Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
                [12 ]European Laboratory for Food Induced Disease, University of Naples Federico II, Naples, Italy
                [13 ]Unita' di Aterosclerosi e Trombosi, I.R.C.C.S Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Foggia, Italy
                [14 ]Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
                [15 ]Department of Gastroenterology, Hepatology, and Immunology, Children's Memorial Health Institute, Warsaw, Poland
                [16 ]Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland
                [17 ]Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [18 ]Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [19 ]Celera, Alameda, California, United States of America
                [20 ]Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
                [21 ]Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands
                [22 ]The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, United States of America
                [23 ]Arthritis Research Campaign–Epidemiology Unit, The University of Manchester, Manchester, United Kingdom
                [24 ]Department of Medicine, University of Toronto, Mount Sinai Hospital and University Health Network, Toronto, Canada
                [25 ]Rheumatology Unit, Department of Medicine, Karolinska Institutet at Karolinska University Hospital Solna, Stockholm, Sweden
                University of Washington, United States of America
                Author notes

                Conceived and designed the experiments: RM Plenge, C Wijmenga, A Zhernakova, EA Stahl, S Raychaudhuri. Performed the experiments: A Zhernakova, G Trynka, FAS Kurreeman, B Thomson, N Gupta, J Romanos, EF Remmers, Y Li. Analyzed the data: A Zhernakova, EA Stahl, RM Plenge, S Raychaudhuri, L Franke, RSN Fehrmann, EA Festen, FAS Kurreeman, PIW de Bakker, HJ Westra. Contributed reagents/materials/analysis tools: RM Plenge, C Wijmenga, A Zhernakova, R McManus, AW Ryan, G Turner, PK Gregersen, J Worthington, KA Siminovitch, L Klareskog, TWJ Huizinga, EF Remmers, F Tucci, R Toes, E Grandone, MC Mazzilli, A Rybak, B Cukrowska, E Brouwer, MD Posthumus, MJH Coenen, TRDJ Radstake, PLCM van Riel. Wrote the paper: RM Plenge, C Wijmenga, A Zhernakova, EA Stahl, S Raychaudhuri, FAS Kurreeman, G Trynka, R Toes, Y Li, TWJ Huizinga.

                Article
                PGENETICS-D-10-00169
                10.1371/journal.pgen.1002004
                3044685
                21383967
                b67d6f03-a3e5-4adb-9890-16beb3d9cbe4
                This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
                History
                : 19 October 2010
                : 24 December 2010
                Page count
                Pages: 13
                Categories
                Research Article
                Biology
                Computational Biology
                Population Genetics
                Genetics
                Genetics of Disease
                Immunology
                Genetics of the Immune System
                Medicine
                Clinical Genetics
                Clinical Immunology
                Genetics of the Immune System

                Genetics
                Genetics

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