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Human Molecular Genetics Advance Access published online on March 13, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp119
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype

B. Rueda1, J. Broen2, C. Simeon3, R. Hesselstrand4, B. Diaz5, H. Sanchez5, N. Ortego-Centeno6, G. Riemekasten7, V. Fonollosa3, M.C. Vonk2, F.H.J. van den Hoogen8, J. Sanchez-Román9, M.A. Aguirre-Zamorano10, R. García-Portales11, A. Pros12, M.T. Camps13, M.A. Gonzalez-Gay14, M.J.H. Coenen15, P. Airo16, L. Beretta17, R. Scorza17, J. van Laar18, M.F. Gonzalez-Escribano19, J.L. Nelson20, T.R.D.J. Radstake2 and J. Martin1,*

1 Instituto de Parasitologia y Biomedicina "Lopez-Neyra" (CSIC), Granada, Spain 2 Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 3 Servicio de Medinina Interna, Hospital Valle de Hebron, Barcelona, Spain 4 Department of Rheumatology, Lund University Hospital, S-221 85 Lund, Sweden 5 Servicio de Medicina Interna, Hospital Universitario Central de Asturias, Oviedo, Spain 6 Servicio de Medicina Interna, Hospital Clínico Universitario, Granada, Spain 7 Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany 8 Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands 9 Servicio de Medicina Interna. Hospital Virgen del Rocio, Sevilla, Spain 10 Servicio de Reumatología. Hospital Reina Sofía, Córdoba, Spain 11 Servicio Medicina Interna. Hospital Virgen de la Victoria, Málaga, Spain 12 Servicio de Reumatología, Hospital del Mar, Barcelona, Spain 13 Servicio de Medicina Interna, Hospital Carlos Haya, Malaga, Spain 14 Servicio de Reumatología, Hospital Xeral-Calde, Lugo, Spain 15 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 16 Servizio di Reumatologia ed Immunologia Clinica Spedali Civili, Brescia, Italy 17 Referral Center for Systemic Autoimmune Diseases, University of Milan, Milan, Italy 18 Department of Rheumatology, Newcastle, United Kingdom 19 Servicio de Inmunología, Hospital Virgen del Rocio, Sevilla 20 Department of Medicine, University of Washington, Seattle, Washington, United States of America

* Correspondence to: Javier Martin MD, PhD., Instituto de Parasitologia y Biomedicina "López-Neyra". Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud. Avenida del Conocimiento s/n 18100-Armilla (Granada), Spain. Tel.: +34-958-181669 Fax: +34-958-181632. E-mail: martin{at}ipb.csic.es

Received December 3, 2008; Revised February 25, 2009; Accepted March 9, 2009

The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients (896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc) and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population (P=1.9 x 10-5 OR 1.61 95 % CI 1.29-1.99), but not with dcSSc (P=0.41 OR 0.84 95 % CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P=1.02 x 10–7 95 % CI 2.11-5.31). The association of the rs7574865 T alle with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15-1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.


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