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A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides
  1. L Bossini-Castillo1,
  2. C de Kovel2,
  3. H Kallberg3,4,
  4. R van ‘t Slot2,
  5. A Italiaander2,
  6. M Coenen5,
  7. P P Tak6,
  8. M D Posthumus7,
  9. C Wijmenga8,
  10. T Huizinga9,
  11. A H M van der Helm-van Mil9,
  12. G Stoeken-Rijsbergen9,
  13. Luis Rodriguez-Rodriguez10,
  14. Alejandro Balsa11,
  15. Isidoro González-Álvaro12,
  16. Miguel Ángel González-Gay13,
  17. Carmen Gómez-Vaquero14,
  18. B Franke5,
  19. LifeLines Cohort Study,
  20. S Vermeulen5,
  21. IE van der Horst-Bruinsma15,
  22. B A C Dijkmans15,
  23. G J Wolbink16,
  24. R A Ophoff2,
  25. M T Maehlen17,
  26. P van Riel18,
  27. M Merriman19,
  28. L Klareskog3,
  29. B A Lie17,
  30. T Merriman19,
  31. J B A Crusius20,
  32. E Brouwer7,
  33. J Martin1,
  34. N de Vries6,
  35. R Toes9,
  36. L Padyukov3,
  37. B P C Koeleman2
  1. 1Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain
  2. 2Department of Medical Genetics, UMCU, Utrecht, The Netherlands
  3. 3Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
  4. 4Institute of Environmental Medicine, Karolinska Institutet, Sweden
  5. 5Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  6. 6Division of Clinical Immunology and Rheumatology, AMC, University of Amsterdam, Amsterdam, The Netherlands
  7. 7Department of Rheumatology, UMCG, Groningen, The Netherlands
  8. 8Department of Medical Genetics, UMCG, Groningen, The Netherlands
  9. 9Department of Rheumatology, LUMC, Leiden, The Netherlands
  10. 10Rheumatology Service, Hospital Clínico San Carlos, Madrid, Spain
  11. 11Rheumatology Service, Hospital Universitario La Paz, Madrid, Spain
  12. 12Rheumatology Service, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
  13. 13Rheumatology Service, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain
  14. 14Rheumatology Service, Hospital Universitari Bellvitge, Barcelona, Spain
  15. 15Department of Rheumatology, VUMC, Amsterdam, The Netherlands
  16. 16Jan van Breemen Research Institute, Amsterdam, The Netherlands
  17. 17Department of Medical Genetics; University of Oslo and Oslo University, hospital, Oslo, Norway; K. G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway
  18. 18Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  19. 19Department of Biochemistry, University of Otago, New Zealand
  20. 20Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands


Introduction 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.

  • Ant-CCP
  • Gene Polymorphism
  • Rheumatoid Arthritis

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