L Bossini-Castillo1, C de Kovel2, H Kallberg3, R van 't Slot2, A Italiaander2, M Coenen4, P P Tak5, M D Posthumus6, C Wijmenga7, T Huizinga8, A H M van der Helm-van Mil8, G Stoeken-Rijsbergen8, Luis Rodriguez-Rodriguez9, Alejandro Balsa10, Isidoro González-Álvaro11, Miguel Ángel González-Gay12, Carmen Gómez-Vaquero13, B Franke4, S Vermeulen4, Ie van der Horst-Bruinsma14, B A C Dijkmans14, G J Wolbink15, R A Ophoff2, M T Maehlen16, P van Riel17, M Merriman18, L Klareskog19, B A Lie16, T Merriman18, J B A Crusius20, E Brouwer6, J Martin1, N de Vries5, R Toes8, L Padyukov19, B P C Koeleman2. 1. Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain. 2. Department of Medical Genetics, UMCU, Utrecht, The Netherlands. 3. Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden Institute of Environmental Medicine, Karolinska Institutet, Sweden. 4. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 5. Division of Clinical Immunology and Rheumatology, AMC, University of Amsterdam, Amsterdam, The Netherlands. 6. Department of Rheumatology, UMCG, Groningen, The Netherlands. 7. Department of Medical Genetics, UMCG, Groningen, The Netherlands. 8. Department of Rheumatology, LUMC, Leiden, The Netherlands. 9. Rheumatology Service, Hospital Clínico San Carlos, Madrid, Spain. 10. Rheumatology Service, Hospital Universitario La Paz, Madrid, Spain. 11. Rheumatology Service, Hospital Universitario La Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain. 12. Rheumatology Service, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain. 13. Rheumatology Service, Hospital Universitari Bellvitge, Barcelona, Spain. 14. Department of Rheumatology, VUMC, Amsterdam, The Netherlands. 15. Jan van Breemen Research Institute, Amsterdam, The Netherlands. 16. Department of Medical Genetics; University of Oslo and Oslo University, hospital, Oslo, Norway; K. G. Jebsen Inflammation Research Centre, University of Oslo, Oslo, Norway. 17. Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 18. Department of Biochemistry, University of Otago, New Zealand. 19. Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. 20. Laboratory of Immunogenetics, Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands.
Abstract
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. 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.
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 RApatients 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 RApatients 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. 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.
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