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


The aim of this study was to determine the genetic components contributing to the different systemic sclerosis (SSc) clinical sub-phenotypes of limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and with the most common SSc-specific autoantibodies, anti-centromere (ACA) and anti-topoisomerase I (ATA) through a genome-wide association study (GWAS) and a large replication study stratified for these disease features.


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 1x10-5, 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 = 2.32x10-12, OR = 0.75) and a suggestive but consistent association among populations of GRB10 rs12540874 polymorphism (P = 1.27x10-6, OR = 1.15) with the lcSSc subtype of the disease. Furthermore, significant association of SOX5 rs11047102 polymorphism (P = 1.39x10-7, 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 = 1.79x10-61), and in the HLA-DPA1/B1 loci allelic combination with ATA (P = 4.57x10-76).


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.

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O Gorlova, J M Martin, B Rueda, BPC Koeleman, F C Arnett, TRDJ Radstake, M D Mayes and J Martin contributed equally to this work.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Gorlova, O., Martin, J.M., Rueda, B. et al. Identification of novel genetic markers associated with the clinical phenotypes of systemic sclerosis through a genome wide association strategy. J Transl Med 8 (Suppl 1), O1 (2010).

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