Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Olga Y. Gorlova(The University of Texas MD Anderson Cancer Center), Jose‐Ezequiel Martín(Consejo Superior de Investigaciones Científicas), Jose‐Ezequiel Martín(Consejo Superior de Investigaciones Científicas), Blanca Rueda‐Medina(Consejo Superior de Investigaciones Científicas), Bobby P. C. Koeleman(The University of Texas MD Anderson Cancer Center), Binwu Ying(The University of Texas MD Anderson Cancer Center), María Teruel(Consejo Superior de Investigaciones Científicas), Lina-Marcela Díaz-Gallo(Consejo Superior de Investigaciones Científicas), Jasper Broen(Radboud University Nijmegen), Madelon C. Vonk(Radboud University Nijmegen), Carmen Pilar Simeón‐Aznar(University Medical Center Groningen), Behrooz Z. Alizadeh(University Medical Center Groningen), Marieke J. H. Coenen(Radboud University Nijmegen), Alexandre E. Voskuyl(Leiden University), Annemie J. Schuerwegh(Leiden University), Piet L. C. M. van Riel(Cliniques Universitaires Saint-Luc), Marie Vanthuyne(Cliniques Universitaires Saint-Luc), Ruben van ‘t Slot(University Medical Center Utrecht), Annet Italiaander(University Medical Center Utrecht), Roel A. Ophoff(University of Cologne), Nicolas Hunzelmann(University of Cologne), V Fonollosa(Hospital Virgen del Valle), Norberto Ortego‐Centeno(Marqués de Valdecilla University Hospital), Miguel Á. González‐Gay(Marqués de Valdecilla University Hospital), Francisco José García Hernández(Hospital Universitario Virgen del Rocío), María Francisca González‐Escribano(Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia), Paolo Airó(Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia), Jacob M. van Laar(Manchester Academic Health Science Centre), Jane Worthington(Lund University), Roger Hesselstrand(Lund University), Vanessa Smith(Ghent University Hospital), Filip De Keyser(Cliniques Universitaires Saint-Luc), F. Houssiau(Cliniques Universitaires Saint-Luc), Meng May Chee(Glasgow Royal Infirmary), Rajan Madhok(Glasgow Royal Infirmary), Paul G. Shiels(Western Infirmary), René Westhovens(St. Josef-Hospital), Alexander Kreuter(Ghent University Hospital), Elfride de Baere(Ghent University Hospital), Torsten Witte(Karolinska Institutet), Leonid Padyukov(Karolinska Institutet), Annica Nordin(University of Milan), R Scorza(University of Verona), Claudio Lunardi(University of Verona), Benedicte A. Lie(Oslo University Hospital), Anna‐Maria Hoffmann‐Vold(Oslo University Hospital), Øyvind Palm(Oslo University Hospital), Paloma García de la Peña(Research Institute Hospital 12 de Octubre), Patrícia Carreira(Northwestern University), Spanish Scleroderma Group(Northwestern University), John Varga(Northwestern University), Monique Hinchcliff(Northwestern University), Annette T. Lee(Feinstein Institute for Medical Research), Pravitt Gourh(Johns Hopkins University), Christopher I. Amos(The University of Texas MD Anderson Cancer Center), Frederick M. Wigley(Johns Hopkins University), Laura K. Hummers(Fred Hutch Cancer Center), J. Hummers(Johns Hopkins University), J. Lee Nelson(Manchester Academic Health Science Centre), Gabriella Riemekasten(University of Milan), Ariane L. Herrick(Manchester Academic Health Science Centre), Lorenzo Beretta(University of Milan), Carmen Fonseca(Feinstein Institute for Medical Research), Christopher P. Denton(The Royal Free Hospital), Peter K. Gregersen(Feinstein Institute for Medical Research), Sandeep K. Agarwal(The University of Texas Health Science Center at Houston), Shervin Assassi(The University of Texas Health Science Center at Houston), Filemon K. Tan(Radboud University Nijmegen), Frank C. Arnett(The University of Texas Health Science Center at Houston), Timothy R. D. J. Radstake(Consejo Superior de Investigaciones Científicas), Maureen D. Mayes(The University of Texas Health Science Center at Houston), Javier Martin(Consejo Superior de Investigaciones Científicas), Javier Martin(Consejo Superior de Investigaciones Científicas)
PLoS Genetics
July 14, 2011
10.1371/journal.pgen.1002178
Cited by 233Open Access
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Abstract

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.

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