title: A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides.
abstract: BACKGROUND
  Rheumatoid arthritis (RA) patients can be classified based on presence or absence of anticitrullinated peptide antibodies (ACPA) in their serum. This heterogeneity among patients may reflect important biological differences underlying the disease process. To date, the majority of genetic studies have focused on the ACPA-positive group. Therefore, our goal was to analyse the genetic risk factors that contribute to ACPA-negative RA.
  
  
  METHODS
  We performed a large-scale genome-wide association study (GWAS) in three Caucasian European cohorts comprising 1148 ACPA-negative RA patients and 6008 controls. All patients were screened using the Illumina Human Cyto-12 chip, and controls were genotyped using different genome-wide platforms. Population-independent analyses were carried out by means of logistic regression. Meta-analysis with previously published data was performed as follow-up for selected signals (reaching a total of 1922 ACPA-negative RA patients and 7087 controls). Imputation of classical HLA alleles, amino acid residues and single nucleotide polymorphisms was undertaken.
  
  
  RESULTS
  The combined analysis of the studied cohorts resulted in identification of a peak of association in the HLA-region and several suggestive non-HLA associations. Meta-analysis with previous reports confirmed the association of the HLA region with this subset and an observed association in the CLYBL locus remained suggestive. The imputation and deep interrogation of the HLA region led to identification of a two amino acid model (HLA-B at position 9 and HLA-DRB1 at position 11) that accounted for the observed genome-wide associations in this region.
  
  
  CONCLUSIONS
  Our study shed light on the influence of the HLA region in ACPA-negative RA and identified a suggestive risk locus for this condition.
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain.
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authors.affiliation: Department of Medical Genetics, UMCU, Utrecht, The Netherlands.
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authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden Institute of Environmental Medicine, Karolinska Institutet, Sweden.
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authors.affiliation: Department of Medical Genetics, UMCU, Utrecht, The Netherlands.
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authors.affiliation: Department of Medical Genetics, UMCU, Utrecht, The Netherlands.
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authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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authors.affiliation: Division of Clinical Immunology and Rheumatology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
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authors.affiliation: Department of Rheumatology, UMCG, Groningen, The Netherlands.
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authors.affiliation: Department of Medical Genetics, UMCG, Groningen, The Netherlands.
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authors.affiliation: Department of Rheumatology, LUMC, Leiden, The Netherlands.
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authors.affiliation: Department of Rheumatology, LUMC, Leiden, The Netherlands.
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authors.lastname: van der Helm-van Mil
authors.affiliation: Department of Rheumatology, LUMC, Leiden, The Netherlands.
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authors.affiliation: Rheumatology Service, Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Luis
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authors.lastname: Rodriguez-Rodriguez
authors.affiliation: Rheumatology Service, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Alejandro
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authors.lastname: Balsa
authors.affiliation: Rheumatology Service, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain.
authors.forename: Isidoro
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authors.lastname: González-Álvaro
authors.affiliation: Rheumatology Service, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain.
authors.forename: Miguel Ángel
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authors.affiliation: Rheumatology Service, Hospital Universitari Bellvitge, Barcelona, Spain.
authors.forename: Carmen
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authors.lastname: Gómez-Vaquero
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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authors.lastname: Franke
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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authors.lastname: Vermeulen
authors.affiliation: Department of Rheumatology, VUMC, Amsterdam, The Netherlands.
authors.forename: Ie
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authors.lastname: van der Horst-Bruinsma
authors.affiliation: Department of Rheumatology, VUMC, Amsterdam, The Netherlands.
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authors.lastname: Dijkmans
authors.affiliation: Jan van Breemen Research Institute, Amsterdam, The Netherlands.
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authors.affiliation: Department of Medical Genetics, UMCU, Utrecht, The Netherlands.
authors.forename: R A
authors.initials: RA
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authors.affiliation: Department of Medical Genetics; University of Oslo and Oslo University, hospital, Oslo, Norway; K. G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
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authors.lastname: Maehlen
authors.affiliation: Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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authors.lastname: van Riel
authors.affiliation: Department of Biochemistry, University of Otago, New Zealand.
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authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
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authors.lastname: Klareskog
authors.affiliation: Department of Medical Genetics; University of Oslo and Oslo University, hospital, Oslo, Norway; K. G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway.
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authors.affiliation: Department of Biochemistry, University of Otago, New Zealand.
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authors.affiliation: Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands.
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authors.lastname: Crusius
authors.affiliation: Department of Rheumatology, UMCG, Groningen, The Netherlands.
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authors.lastname: Brouwer
authors.affiliation: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain.
authors.forename: J
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authors.lastname: Martin
authors.affiliation: Division of Clinical Immunology and Rheumatology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
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authors.lastname: de Vries
authors.affiliation: Department of Rheumatology, LUMC, Leiden, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Toes
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
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authors.affiliation: Department of Medical Genetics, UMCU, Utrecht, The Netherlands.
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mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D016022:Case-Control Studies; D002956:Citrulline / Q000276:immunology; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D010455:Peptides / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies; D006680:HLA Antigens; D015235:HLA-B Antigens; D059811:HLA-DRB1 Chains; D010455:Peptides; D002956:Citrulline
keywords: Ant-CCP; Gene Polymorphism; Rheumatoid Arthritis