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Lookup NU author(s): Professor Jaap Van Laar
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 (IcSSc) 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 = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-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 = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and autoantibody 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.
Author(s): Gorlova O, Martin JE, Rueda B, Koeleman BPC, Ying J, Teruel M, Diaz-Gallo LM, Broen JC, Vonk MC, Simeon CP, Alizadeh BZ, Coenen MJH, Voskuyl AE, Schuerwegh AJ, van Riel PLCM, Vanthuyne M, van't Slot R, Italiaander A, Ophoff RA, Hunzelmann N, Fonollosa V, Ortego-Centeno N, Gonzalez-Gay MA, Garcia-Hernandez FJ, Gonzalez-Escribano MF, Airo P, van Laar J, Worthington J, Hesselstrand R, Smith V, de Keyser F, Houssiau F, Chee MM, Madhok R, Shiels PG, Westhovens R, Kreuter A, de Baere E, Witte T, Padyukov L, Nordin A, Scorza R, Lunardi C, Lie BA, Hoffmann-Vold AM, Palm O, de la Pena PG, Carreira P, Varga J, Hinchcliff M, Lee AT, Gourh P, Amos CI, Wigley FM, Hummers LK, Hummers J, Nelson JL, Riemekasten G, Herrick A, Beretta L, Fonseca C, Denton CP, Gregersen PK, Agarwal S, Assassi S, Tan FK, Arnett FC, Radstake TRDJ, Mayes MD, Martin J, Spanish Scleroderma Grp
Publication type: Article
Publication status: Published
Journal: PLoS Genetics
Year: 2011
Volume: 7
Issue: 7
Print publication date: 14/07/2011
Date deposited: 27/02/2012
ISSN (electronic): 1553-7390
Publisher: Public Library of Science
URL: http://dx.doi.org/10.1371/journal.pgen.1002178
DOI: 10.1371/journal.pgen.1002178
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