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A multicenter study confirms CD226 gene association with systemic sclerosis-related pulmonary fibrosis

Lara Bossini-Castillo1*, Carmen P Simeon2, Lorenzo Beretta3, Jasper C Broen4, Madelon C Vonk4, Raquel Ríos-Fernández5, Gerard Espinosa6, Patricia Carreira7, María T Camps8, Maria J Castillo9, Miguel A González-Gay10, Emma Beltrán11, María del Carmen Freire12, Javier Narváez13, Carlos Tolosa14, Torsten Witte15, Alexander Kreuter16, Annemie J Schuerwegh17, Anna-Maria Hoffmann-Vold18, Roger Hesselstrand19, Claudio Lunardi20, Jacob M van Laar21, Meng May Chee22, Ariane Herrick23, Bobby PC Koeleman24, Christopher P Denton25, Carmen Fonseca25, Timothy RDJ Radstake26, Javier Martin1 and the Spanish Scleroderma Group

Author Affiliations

1 Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Avenida del Conocimiento s/n, Granada, 18100, Spain

2 Servicio de Medicina Interna, Hospital Valle de Hebron, Passeig de la Vall d'Hebron, 119-129, Barcelona, 08035, Spain

3 IRCCS Fondazione Policlinico-Mangiagalli-Regina Elena and University of Milan, Allergy, Clinical Immunology and Rheumatology, Via Francesco Sforza 28, Milan, 20122, Italy

4 Department of Rheumatology, Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 10, Nijmegen, 6525 GA, The Netherlands

5 Servicio de Medicina Interna, Hospital Clínico Universitario, Avenida Doctor Olóriz 16, Granada, 18012, Spain

6 Servicio de Enfermedades Autoinmunes, Hospital Clinic, C/Villarroel, 170, Barcelona, 08036, Spain

7 Servicio de Reumatología, Hospital 12 de Octubre, Avenida de Córdoba, s/n, Madrid, 28041, Spain

8 Servicio de Medicina Interna, Hospital Carlos Haya, Avenida Carlos Haya s/n, Málaga, 29010, Spain

9 Servicio de Medicina Interna, Hospital Virgen del Rocío, Avenida Manuel Siurot s/n, Sevilla, 41013, Spain

10 Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla, IFIMAV, Avenida Valdecilla 25, Santander, 39008, Spain

11 Servicio de Reumatología, Hospital del Doctor Peset Aleixandre, Avenida Gaspar Aguilar 90, Valencia, 46017, Spain

12 Unidad Trombosis y Vasculitis, Servicio de Medicina Interna, Hospital Xeral-Complexo Hospitalario Universitario de Vigo, Rua Pizarro 22, Vigo, 36204, Spain

13 Servicio de Reumatología, Hospital Universitario de Bellvitge, C/Feixa Llarga s/n, 08907, Barcelona, Spain

14 Servicio de Medicina Interna, Hospital Parc Taulí, Parc del Taulí s/n, Sabadell, 08208, Spain

15 Hannover Medical School, Carl-Neuberg-Straße 1, Hannover, 30625, Germany

16 Ruhr University of Bochum, Universitätsstraße 150, Bochum, 44801, Germany

17 Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands

18 Department of Rheumatology, Rikshospitalet, Oslo University Hospital, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, 0027, Norway

19 Department of Rheumatology, Lund University, Paradisgatan 2, Lund, SE-221 00, Sweden

20 Department of Medicine, Università degli Studi di Verona, Via dell'Artigliere, 19, Verona 37129, Italy

21 Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon Tyne, Newcastle, NE2 4HH, UK

22 Centre for Rheumatic Diseases, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

23 Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Stopford Building, Oxford Road, Manchester, M13 9PT, UK

24 Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, Utrecht, 3584 CG, The Netherlands

25 Centre for Rheumatology, Royal Free and University College Medical School, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 PF, UK

26 Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands

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Arthritis Research & Therapy 2012, 14:R85  doi:10.1186/ar3809

Published: 24 April 2012



CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population.


A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays.


Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (PBonf = 3.18E-02 OR 1.27 (1.05 to 1.54)).


Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis.