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

Olga Gorlova*, Jose Ezequiel Martin, Blanca Rueda, Bobby P.C. Koeleman, Jun Ying, Maria Teruel, Lina Marcela Diaz-Gallo, Jasper C. Broen, Madelon C. Vonk, Carmen P. Simeon, Behrooz Z. Alizadeh, Marieke J.H. Coenen, Alexandre E. Voskuyl, Annemie J. Schuerwegh, Piet L.C.M. van Riel, Marie Vanthuyne, Ruben van't Slot, Annet Italiaander, Roel A. Ophoff, Nicolas HunzelmannVicente Fonollosa, Norberto Ortego-Centeno, Miguel A. González-Gay, Francisco J. García-Hernández, María F. González-EscribanoMarí, Paolo Airo, Jacob van Laar, Jane Worthington, Roger Hesselstrand, Vanessa Smith, Filip de Keyser, Fredric Houssiau, Meng May Chee, Rajan Madhok, Paul G. Shiels, Rene Westhovens, Alexander Kreuter, Elfride de Baere, Torsten Witte, Leonid Padyukov, Annika Nordin, Raffaella Scorza, Claudio Lunardi, Benedicte A. Lie, Anna Maria Hoffmann-Vold, Øyvind Palm, García P. de la Peña Paloma, Patricia Carreira, John Varga, Monique Hinchcliff, Annette T. Lee, Pravitt Gourh, Christopher I. Amos, Frederick M. Wigley, Laura K. Hummers, J. Hummers, J. Lee Nelson, Gabriella Riemekasten, Ariane Herrick, Lorenzo Beretta, Carmen Fonseca, Christopher P. Denton, Peter K. Gregersen, Sandeep Agarwal, Shervin Assassi, Filemon K. Tan, Frank C. Arnett, Timothy R.D.J. Radstake, Maureen D. Mayes, Javier Martin

*Corresponding author for this work
159 Citations (Scopus)


The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10 -12, OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10 -6, OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10 -7, OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10 -61, OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10 -76, OR = 8.84), and in NOTCH4 with ACA P = 8.84×10 -21, OR = 0.55) and ATA (P = 1.14×10 -8, OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.

Original languageEnglish
Article numbere1002178
JournalPLoS Genetics
Issue number7
Publication statusPublished - 07.2011

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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