Eguzkine Ochoa1, José-Ezequiel Martin2, Shervin Assasi3, Lorenzo Beretta4, Patricia Carreira5, Alfredo Guillén6, Carmen Pilar Simeón6, Eugénie Koumakis7, Philippe Dieude8, Yannick Allanore7, Francisco J García-Hernández9, Gerard Espinosa10, Ivan Castellví11, Jose Luis Trapiella12, Luis Rodriguez13, Miguel Ángel González-Gay14, María Victoria Egurbide15, Luis Sáez16, Jose Luis Callejas-Rubio17, Jose Antonio Vargas-Hitos18, Nicolas Hunzelmann19, Gabriela Riemekasten20, Torsten Witte21, Jörg H W Distler22, Alexander Kreuter23, Claudio Lunardi24, Alessandro Santaniello4, Filemon K Tan3, Paul G Shiels25, Ariane Herrick26, Jane Worthington26, Madelon C Vonk27, Bobby P Koeleman28, Timothy R D J Radstake29, Maureen D Mayes3, Javier Martin2. 1. Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain. eguzki8A@gmail.com. 2. Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain. 3. The University of Texas Health Science Center-Houston, Houston, TX, USA. 4. Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggioire Policlinico di Milano, Milan, Italy. 5. Department of Rheumatology, Hospital 12 de Octubre, Madrid, Spain. 6. Department of Internal Medicine, Hospital Valle de Hebrón, Barcelona, Spain. 7. INSERM, Institut Cochin, Cochin Hospital, AP-HP, INSERM U1016, Sorbonne Paris Cité, and Paris Descartes University, Paris, France. 8. Paris Diderot University, INSERM U699, and Hôpital Bichat Claude Bernard, AP-HP, Paris, France. 9. Department of Internal Medicine, Hospital Virgen del Rocío, Sevilla, Spain. 10. Department of Internal Medicine, Autoimmune Diseases Unit, Hospital Clínico, Barcelona, Spain. 11. Department of Rheumatology, Hospital Universitario de la Santa Creu y Sant Pau, Barcelona, Spain. 12. Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain. 13. Department of Rheumatology, Hospital Clínico Universitario San Carlos, Madrid, Spain. 14. Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain. 15. Department of Internal Medicine, Hospital Universitario Cruces, Barakaldo, Spain. 16. Department of Internal Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitario Miguel Servet, Zaragoza, Spain. 17. Department of Systemic Autoimmune Diseases, Hospital Clínico Universitario San Cecilio, Granada, Spain. 18. Department of Internal Medicine, Hospital Virgen de las Nieves, Granada, Spain. 19. Department of Dermatology, University of Cologne, Cologne, Germany. 20. Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany. 21. Department of Clinical Immunology, Hannover Medical School, Hannover, Germany. 22. Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany. 23. Department of Dermatology, Venereology, and Allergology, Ruhr-University Bochum, Bochum, Germany. 24. Department of Medicine, Università degli Studi di Verona, Verona, Italy. 25. Section of Epigenetics, Institute of Cancer Sciences, MVLS, University of Glasgow, Glasgow, UK. 26. Arthritis Research UK Epidemiology Unit and NIHR Manchester Musculoskeletal Biomedical Research Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. 27. Department of Rheumatology, Radboud University, Nijmegen Medical Centre, Nijmegen HC, The Netherlands. 28. Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 29. Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, The Netherlands.
Abstract
OBJECTIVES: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. METHODS: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. RESULTS: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88x10(-2), OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89x10(-2), OR=1.13; p=1.69x10(-2), OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00x10(-4), OR=1.16) comparing with healthy controls. CONCLUSIONS: Our work confirms the association of CCR6 gene and ATA+ SSc patients.
OBJECTIVES: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. METHODS: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. RESULTS: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88x10(-2), OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89x10(-2), OR=1.13; p=1.69x10(-2), OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00x10(-4), OR=1.16) comparing with healthy controls. CONCLUSIONS: Our work confirms the association of CCR6 gene and ATA+ SSc patients.