title: Confirmation of CCR6 as a risk factor for anti-topoisomerase I antibodies in systemic sclerosis.
abstract: OBJECTIVE
  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.
authors: Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain. eguzki8A@gmail.com.
authors: Eguzkine
authors: E
authors: Ochoa
authors: Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain.
authors: José-Ezequiel
authors: JE
authors: Martin
authors: The University of Texas Health Science Center-Houston, Houston, TX, USA.
authors: Shervin
authors: S
authors: Assasi
authors: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggioire Policlinico di Milano, Milan, Italy.
authors: Lorenzo
authors: L
authors: Beretta
authors: Department of Rheumatology, Hospital 12 de Octubre, Madrid, Spain.
authors: Patricia
authors: P
authors: Carreira
authors: Department of Internal Medicine, Hospital Valle de Hebrón, Barcelona, Spain.
authors: Alfredo
authors: A
authors: Guillén
authors: Department of Internal Medicine, Hospital Valle de Hebrón, Barcelona, Spain.
authors: Carmen Pilar
authors: CP
authors: Simeón
authors: INSERM, Institut Cochin, Cochin Hospital, AP-HP, INSERM U1016, Sorbonne Paris Cité, and Paris Descartes University, Paris, France.
authors: Eugénie
authors: E
authors: Koumakis
authors: Paris Diderot University, INSERM U699, and Hôpital Bichat Claude Bernard, AP-HP, Paris, France.
authors: Philippe
authors: P
authors: Dieude
authors: INSERM, Institut Cochin, Cochin Hospital, AP-HP, INSERM U1016, Sorbonne Paris Cité, and Paris Descartes University, Paris, France.
authors: Yannick
authors: Y
authors: Allanore
authors: Department of Internal Medicine, Hospital Virgen del Rocío, Sevilla, Spain.
authors: Francisco J
authors: FJ
authors: García-Hernández
authors: Department of Internal Medicine, Autoimmune Diseases Unit, Hospital Clínico, Barcelona, Spain.
authors: Gerard
authors: G
authors: Espinosa
authors: Department of Rheumatology, Hospital Universitario de la Santa Creu y Sant Pau, Barcelona, Spain.
authors: Ivan
authors: I
authors: Castellví
authors: Department of Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors: Jose Luis
authors: JL
authors: Trapiella
authors: Department of Rheumatology, Hospital Clínico Universitario San Carlos, Madrid, Spain.
authors: Luis
authors: L
authors: Rodriguez
authors: Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain.
authors: Miguel Ángel
authors: MÁ
authors: González-Gay
authors: Department of Internal Medicine, Hospital Universitario Cruces, Barakaldo, Spain.
authors: María Victoria
authors: MV
authors: Egurbide
authors: Department of Internal Medicine, Systemic Autoimmune Diseases Unit, Hospital Universitario Miguel Servet, Zaragoza, Spain.
authors: Luis
authors: L
authors: Sáez
authors: Department of Systemic Autoimmune Diseases, Hospital Clínico Universitario San Cecilio, Granada, Spain.
authors: Jose Luis
authors: JL
authors: Callejas-Rubio
authors: Department of Internal Medicine, Hospital Virgen de las Nieves, Granada, Spain.
authors: Jose Antonio
authors: JA
authors: Vargas-Hitos
authors: Department of Dermatology, University of Cologne, Cologne, Germany.
authors: Nicolas
authors: N
authors: Hunzelmann
authors: Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany.
authors: Gabriela
authors: G
authors: Riemekasten
authors: Department of Clinical Immunology, Hannover Medical School, Hannover, Germany.
authors: Torsten
authors: T
authors: Witte
authors: Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Jörg H W
authors: JH
authors: Distler
authors: Department of Dermatology, Venereology, and Allergology, Ruhr-University Bochum, Bochum, Germany.
authors: Alexander
authors: A
authors: Kreuter
authors: Department of Medicine, Università degli Studi di Verona, Verona, Italy.
authors: Claudio
authors: C
authors: Lunardi
authors: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggioire Policlinico di Milano, Milan, Italy.
authors: Alessandro
authors: A
authors: Santaniello
authors: The University of Texas Health Science Center-Houston, Houston, TX, USA.
authors: Filemon K
authors: FK
authors: Tan
authors: Section of Epigenetics, Institute of Cancer Sciences, MVLS, University of Glasgow, Glasgow, UK.
authors: Paul G
authors: PG
authors: Shiels
authors: Arthritis Research UK Epidemiology Unit and NIHR Manchester Musculoskeletal Biomedical Research Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors: Ariane
authors: A
authors: Herrick
authors: Arthritis Research UK Epidemiology Unit and NIHR Manchester Musculoskeletal Biomedical Research Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors: Jane
authors: J
authors: Worthington
authors: Department of Rheumatology, Radboud University, Nijmegen Medical Centre, Nijmegen HC, The Netherlands.
authors: Madelon C
authors: MC
authors: Vonk
authors: Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Bobby P
authors: BP
authors: Koeleman
authors: Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, The Netherlands.
authors: Timothy R D J
authors: TR
authors: Radstake
authors: The University of Texas Health Science Center-Houston, Houston, TX, USA.
authors: Maureen D
authors: MD
authors: Mayes
authors: Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain.
authors: Javier
authors: J
authors: Martin
mesh_terms: D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D004264:DNA Topoisomerases, Type I / Q000276:immunology*; D005060:Europe; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054399:Receptors, CCR6 / Q000235:genetics*; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; C106311:CCR6 protein, human; D054399:Receptors, CCR6; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human