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Identification of novel genetic markers associated with the clinical phenotypes of systemic sclerosis through a genome wide association strategy

  • O Gorlova1,
  • J M Martin2,
  • B Rueda2,
  • BPC Koeleman3,
  • J Ying1,
  • M Teruel2,
  • L M Diaz-Gallo2,
  • J C Broen4,
  • M C Vonk4,
  • C P Simeon5,
  • B Z Alizadeh6,
  • MJH Coenen7,
  • A E Voskuyl8,
  • A J Schuerwegh9,
  • PLCM van Riel4,
  • M Vanthuyne10,
  • R van ‘t Slot3,
  • A Italiaander3,
  • R A Ophoff3,
  • N Hunzelmann11,
  • V Fonollosa5,
  • N Ortego-Centeno12,
  • M A González-Gay13,
  • F J García-Hernández14,
  • M F González-Escribano15,
  • P Airo16,
  • J van Laar17,
  • J Worthington18,
  • R Hesselstrand19,
  • V Smith20,
  • F De Keyser20,
  • F Houssiau10,
  • M M Chee21,
  • R Madhok21,
  • P Shiels21,
  • R Westhovens22,
  • A Kreuter23,
  • E de Baere24,
  • T Witte25,
  • L Padyukov26,
  • A Nordin26,
  • R Scorza27,
  • C Lunardi28,
  • B A Lie29,
  • A M Hoffmann-Vold30,
  • P García de la Peña31,
  • P Carreira13, 32,
  • J Varga33,
  • M Hinchcliff33,
  • A T Lee34,
  • P Gourh35,
  • C I Amos1,
  • G Riemekasten36,
  • A Herrick18,
  • L Beretta27,
  • C Fonseca37,
  • C P Denton37,
  • P K Gregersen34,
  • S Agarwal35,
  • S Assassi35,
  • F K Tan35,
  • F C Arnett35,
  • TRDJ Radstake4,
  • M D Mayes35 and
  • J Martin2
Contributed equally
Journal of Translational Medicine20108(Suppl 1):O1

Published: 25 November 2010


Systemic SclerosisRs11047102 PolymorphismAssociation StrategyDiscovery PhaseAllelic Combination


The aim of this study was to determine the genetic components contributing to the different systemic sclerosis (SSc) clinical sub-phenotypes of limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and with the most common SSc-specific autoantibodies, anti-centromere (ACA) and anti-topoisomerase I (ATA) through a genome-wide association study (GWAS) and a large replication study stratified for these disease features.


In the discovery phase 2,296 SSc patients and 5,171 healthy controls were analyzed for genetic associations in lcSSc, dcSSc, ACA positive and ATA positive subgroups. The non-HLA SNPs associated with each subphenotype with a genomic control corrected P value lower than 1x10-5, not previously associated with SSc, were selected for replication in 9 independent cohorts from the US and Europe comprising an additional 3,175 SSc patients and 4,971 controls. In addition, meta-analyses including all patients and healthy controls were conducted for each subphenotype.


Three out of the 18 non-HLA SNPs selected for replication showed evidence of association. Meta-analysis including GWAS and replication cohorts showed a strong association of IRF8 rs11642873 polymorphism (P = 2.32x10-12, OR = 0.75) and a suggestive but consistent association among populations of GRB10 rs12540874 polymorphism (P = 1.27x10-6, OR = 1.15) with the lcSSc subtype of the disease. Furthermore, significant association of SOX5 rs11047102 polymorphism (P = 1.39x10-7, OR = 1.36) with the ACA positive patients was detected. In the HLA region, specific patterns of SNPs associated with the ACA and ATA subgroups were observed, reflected by highly associated haplotype in the HLA-DQB1 locus with ACA (P = 1.79x10-61), and in the HLA-DPA1/B1 loci allelic combination with ATA (P = 4.57x10-76).


We have identified three new genes (IRF8, GRB10, and SOX5) associated with clinical manifestations of SSc, emphasizing the differential genetic component of each subphenotype of this disease. Within the HLA region, we have observed that HLA-DQB1 and HLA-DPA1/B1 associations with SSc are likely confined to specific auto-antibody positive patients.


Authors’ Affiliations

Dept. of Epidemiology, M.D. Anderson Cancer Center, Houston, USA
Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain
Dept. of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
Dept. of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain
Dept. of Epidemiology, University Medical Centre Groningen, Groningen, The Netherlands
Dept. of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Dept. of Rheumatology, Vrije Universiteit (VU) Medical Centre, Amsterdam, The Netherlands
Dept. of Rheumatology, University of Leiden, Nijmegen, The Netherlands
Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
Dept. of Dermatology, University of Cologne, Cologne, Germany
Servicio de Medicina Interna, Hospital Clínico Universitario, Granada, Spain
Servicio de Reumatología, Hospital Marqués de Valdecilla, Santander, Spain
Servicio de Medicina Interna, Hospital Virgen del Rocio, Sevilla, Spain
Servicio de Inmunología, Hospital Virgen del Rocío, Sevilla, Spain
Rheumatology Unit and Chair, Spedali Civili, Università degli Studi, Brescia, Italy
Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK
Dept. of Rheumatology and Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
Dept. of Clinical Sciences, Division of Rheumatology, Lund University, Lund, Sweden
Ghent University, Ghent, Belgium
Centre for Rheumatic Diseases, Glasgow Royal Infirmary Glasgow, UK
Katholieke Universiteit Leuven, Leuven, Belgium
Dept. of Dermatology, Josefs-Hospital, Ruhr University Bochum, Germany
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
Hannover Medical School, Hannover, Germany
Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy
Dept. of Clinical and Experimental Medicine, University Hospital, University of Verona, Italy
Institute of Immunology, Oslo University Hospital Rikshospitalet, Oslo, Norway
Dept. of Rheumatology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
Servicio de Reumatología, Hospital Ramón y Cajal, Madrid, Spain
Hospital 12 de Octubre, Madrid, Spain
Northwestern University Feinberg School of Medicine, Chicago, USA
Feinstein Institute of Medical Research, Manhasset, USA
The University of Texas Health Science Center–Houston, Houston, USA
Dept. of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany
Centre for Rheumatology, Royal Free and University College School, London, UK


© Martin et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.