Gorlova, O;
Martin, JE;
Rueda, B;
Koeleman, BP;
Ying, J;
Teruel, M;
Diaz-Gallo, LM;
... Martin, J; + view all
(2011)
Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.
PLoS Genet
, 7
(7)
, Article e1002178. 10.1371/journal.pgen.1002178.
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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.
| Type: | Article |
|---|---|
| Title: | Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1002178 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pgen.1002178 |
| Language: | English |
| Additional information: | © 2011 Gorlova et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the following grants: J Martin was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain, and in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain. TRDJ Radstake was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). J Martin and TRDJ Radstake were sponsored by the Orphan Disease Program grant from the European League Against Rheumatism (EULAR). BPC Koeleman is supported by the Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). BZ Alizadeh is supported by the Netherlands Organization for Health Research and Development (ZonMW grant 016.096.121). Genotyping of the Dutch control samples was sponsored by US National Institutes of Mental Health funding, R01 MH078075 (ROA). The German controls were from the PopGen biobank (to BPC Koeleman). The PopGen project received infrastructure support through the German Research Foundation excellence cluster “Inflammation at Interfaces.” The USA studies were supported by NIH/NIAMS Scleroderma Family Registry and DNA Repository (N01-AR-0-2251), NIH/NIAMS-RO1- AR055258, NIH/NIAMS Center of Research Translation in Scleroderma (1P50AR054144), and the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-07-01-0111). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | Alleles, Autoantibodies, Female, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA Antigens, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Scleroderma, Systemic |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1378214 |
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