Identification of novel genetic markers associated with the clinical phenotypes of systemic sclerosis through a genome wide association strategy
Year: 2010
Type: article
Study design: Observational Study
Abstract: 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 , 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 , OR = 0.75) and a suggestive but consistent association among populations of GRB10 rs12540874 polymorphism (P = 1.27x10 , OR = 1.15) with the lcSSc subtype of the disease. Furthermore, significant association of SOX5 rs11047102 polymorphism (P = 1.39x10 , 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 ), and in the HLA-DPA1/B1 loci allelic combination with ATA ( P = 4.57x10 ). 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: O Gorlova, J M Martin, B Rueda, BPC Koeleman, J Ying, M Teruel, L M Diaz-Gallo, J C Broen, M C Vonk, C P Simeon, B Z Alizadeh, MJH Coenen, A E Voskuyl, A J Schuerwegh, PLCM van Riel, M Vanthuyne, R van ‘t Slot, A Italiaander, R A Ophoff, N Hunzelmann, V Fonollosa, N Ortego-Centeno, M A González-Gay, F J García-Hernández, M F González-Escribano, P Airo, J van Laar, J Worthington, R Hesselstrand, V Smith, F De Keyser, F Houssiau, M M Chee, R Madhok, P Shiels, R Westhovens, A Kreuter, E de Baere, T Witte, L Padyukov, A Nordin, R Scorza, C Lunardi, B A Lie, A M Hoffmann-Vold, P García de la Peña, P Carreira, J Varga, M Hinchcliff, A T Lee, P Gourh, C I Amos, G Riemekasten, A Herrick, L Beretta, C Fonseca, C P Denton, P K Gregersen, S Agarwal, S Assassi, F K Tan, F C Arnett, TRDJ Radstake, M D Mayes, J Martin
Institutions: The University of Texas MD Anderson Cancer Center, Consejo Superior de Investigaciones Científicas, Instituto de Parasitología y Biomedicina "López - Neyra", University Medical Center Utrecht, Radboud University Nijmegen, Radboud University Medical Center, Vall d'Hebron Hospital Universitari, University Medical Center Groningen, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Leiden University, Cliniques Universitaires Saint-Luc, UCLouvain, University of Cologne, Complejo Hospitalario Universitario de Granada, Marqués de Valdecilla University Hospital, Hospital Universitario Virgen del Rocío, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, University of Brescia, Newcastle University, Manchester Academic Health Science Centre, University of Manchester, Lund University, Ghent University, Glasgow Royal Infirmary, KU Leuven, St. Josef-Hospital, Ruhr University Bochum, Ghent University Hospital, Medizinische Hochschule Hannover, Karolinska Institutet, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Verona, Oslo University Hospital, Hospital Universitario Ramón y Cajal, Hospital Universitario 12 De Octubre, Northwestern University, Feinstein Institute for Medical Research, The University of Texas Health Science Center at Houston, Charité - Universitätsmedizin Berlin, The Royal Free Hospital, University College London
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,890
OpenAlex ID: W2119081136