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Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Gorlova, Olga; Martin, Jose-Ezequiel; Rueda, Blanca; Koeleman, Bobby P. C.; Ying, Jun; Teruel, Maria; Diaz-Gallo, Lina-Marcela; Broen, Jasper C.; Vonk, Madelon C. and Simeon, Carmen P., et al. (2011) In PLoS Genetics 7(7).
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 (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... (More)
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. (Less)
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PLoS Genetics
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Public Library of Science
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  • scopus:79960943814
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1553-7404
DOI
10.1371/journal.pgen.1002178
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English
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@article{7ca5bdbe-0211-43b3-b8d5-a84cb21539c0,
  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 (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       = {Gorlova, Olga and Martin, Jose-Ezequiel and Rueda, Blanca and Koeleman, Bobby P. C. and Ying, Jun and Teruel, Maria and Diaz-Gallo, Lina-Marcela and Broen, Jasper C. and Vonk, Madelon C. and Simeon, Carmen P. and Alizadeh, Behrooz Z. and Coenen, Marieke J. H. and Voskuyl, Alexandre E. and Schuerwegh, Annemie J. and van Riel, Piet L. C. M. and Vanthuyne, Marie and van't Slot, Ruben and Italiaander, Annet and Ophoff, Roel A. and Hunzelmann, Nicolas and Fonollosa, Vicente and Ortego-Centeno, Norberto and Gonzalez-Gay, Miguel A. and Garcia-Hernandez, Francisco J. and Gonzalez-Escribano, Maria F. and Airo, Paolo and van Laar, Jacob and Worthington, Jane and Hesselstrand, Roger and Smith, Vanessa and de Keyser, Filip and Houssiau, Fredric and Chee, Meng May and Madhok, Rajan and Shiels, Paul G. and Westhovens, Rene and Kreuter, Alexander and de Baere, Elfride and Witte, Torsten and Padyukov, Leonid and Nordin, Annika and Scorza, Raffaella and Lunardi, Claudio and Lie, Benedicte A. and Hoffmann-Vold, Anna-Maria and Palm, Oyvind and Garcia de la Pena, Paloma and Carreira, Patricia and Varga, John and Hinchcliff, Monique and Lee, Annette T. and Gourh, Pravitt and Amos, Christopher I. and Wigley, Frederick M. and Hummers, Laura K. and Hummers, J. and Nelson, J. Lee and Riemekasten, Gabriella and Herrick, Ariane and Beretta, Lorenzo and Fonseca, Carmen and Denton, Christopher P. and Gregersen, Peter K. and Agarwal, Sandeep and Assassi, Shervin and Tan, Filemon K. and Arnett, Frank C. and Radstake, Timothy R. D. J. and Mayes, Maureen D. and Martin, Javier},
  issn         = {1553-7404},
  language     = {eng},
  number       = {7},
  publisher    = {Public Library of Science},
  series       = {PLoS Genetics},
  title        = {Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1002178},
  volume       = {7},
  year         = {2011},
}