Open Access Open Badges Research article

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Elena López-Isac1, Lara Bossini-Castillo1, Carmen P Simeon2, María Victoria Egurbide3, Juan José Alegre-Sancho4, Jose Luis Callejas5, José Andrés Roman-Ivorra6, Mayka Freire7, Lorenzo Beretta8, Alessandro Santaniello8, Paolo Airó9, Claudio Lunardi10, Nicolas Hunzelmann11, Gabriela Riemekasten12, Torsten Witte13, Alexander Kreuter14, Jörg H W Distler15, Annemie J Schuerwegh16, Madelon C Vonk17, Alexandre E Voskuyl18, Paul G Shiels19, Jacob M van Laar20, Carmen Fonseca21, Christopher Denton21, Ariane Herrick22, Jane Worthington22, Shervin Assassi23, Bobby P Koeleman24, Maureen D Mayes23, Timothy RDJ Radstake25, Javier Martin1* and Spanish Scleroderma Group

Author Affiliations

1 Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n 18016-Armilla, Granada, Spain

2 Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain

3 Department of Internal Medicine, Hospital Universitario Cruces, Barakaldo, Spain

4 Department of Rheumatology, Hospital del Doctor Peset, Valencia, Spain

5 Department of Internal Medicine, Hospital Clínico San Cecilio, Granada, Spain

6 Rheumatology Department, Hospital Universitario La Fe, Valencia, Spain

7 Department of Internal Medicine, Thrombosis and Vasculitis Unit, Complexo Hospitalario Universitario de Vigo, Vigo, Spain

8 Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggioire Policlinico di Milano, Milan, Italy

9 UO Reumatologia ed Immunologia Clinica, Spedali Civili, Brescia, Italy

10 Department of Medicine, Università degli Studi di Verona, Verona, Italy

11 Department of Dermatology, University of Cologne, Cologne, Germany

12 Department of Rheumatology and Clinical Immunology, Charité University Hospital, and German Rheumatism Research Centre, a Leibniz Institute, Berlin, Germany

13 Hannover Medical School, Hannover, Germany

14 Ruhr University of Bochum, Bochum, Germany

15 Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany

16 Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

17 Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

18 Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands

19 Section of Epigenetics, Inst. Cancer Sciences, MVLS, University of Glasgow, Glasgow, UK

20 Institute of Cellular Medicine, Newcastle University, Newcastle, UK

21 Centre for Rheumatology, Royal Free and University College Medical School, London, UK

22 Arthritis Research UK Epidemiology Unit and NIHR Manchester Musculoskeletal Biomedical Research Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

23 The University of Texas Health Science Center–Houston, Houston, TX, USA

24 Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

25 Department of Rheumatology and Clinical Immunology, University Medical Center, Utrecht, The Netherlands

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Arthritis Research & Therapy 2014, 16:R6  doi:10.1186/ar4432

Published: 9 January 2014



A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.


Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays.


We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.


Our results suggest a role of PPARG gene in the development of SSc.