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

McCarthy, M.I. et al. (2011) Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genetics, 7(7), e1002178. (doi: 10.1371/journal.pgen.1002178)



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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.

Item Type:Articles
Additional Information: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.
Glasgow Author(s) Enlighten ID:Broen, Mr Jasper and Shiels, Professor Paul
Authors: McCarthy, M.I., Gorlova, O., Martin, J.-E., Rueda, B., Koeleman, B.P.C., Ying, J., Teruel, M., Diaz-Gallo, L., Broen, J.C., Vonk, M.C., Simeon, C.P., Alizadeh, B.Z., Coenen, M.J.H., Voskuyl, A.E., Schuerwegh, A.J., van Riel, P., Vanthuyne, M., van 't Slot, R., Italiaander, A., Ophoff, R.A., Hunzelmann, N., Fonollosa, V., Ortego-Centeno, N., González-Gay, M.A., García-Hernández, F.J., González-Escribano, M.F., Airo, P., van Laar, J., Worthington, J., Hesselstrand, R., Smith, V., de Keyser, F., Houssiau, F., Chee, M.M., Madhok, R., Shiels, P., Westhovens, R., Kreuter, A., de Baere, E., Witte, T., Padyukov, L., Nordin, A., Scorza, R., Lunardi, C., Lie, B.A., Hoffmann-Vold, A.-M., Palm, Ø., García de la Peña, P., Carreira, P., Varga, J., Hinchcliff, M., Lee, A.T., Gourh, P., Amos, C.I., Wigley, F.M., Hummers, L.K., Nelson, J.L., Riemekasten, G., Herrick, A., Beretta, L., Fonseca, C., Denton, C.P., Gregersen, P.K., Agarwal, S., Assassi, S., Tan, F., Arnett, F.C., Radstake, T., Mayes, M.D., and Martin, J.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN (Online):1553-7404
Copyright Holders:Copyright © 2011 Gorlova et al.
First Published:First published in PLoS Genetics 2011 7(7): e1002178
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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