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

Olga Gorlova, Jose-Ezequiel Martin, Blanca Rueda, Bobby PC Koeleman, Jun Ying, Maria Teruel, Lina-Marcela Diaz-Gallo, Jasper C Broen, Madelon C Vonk and Carmen P Simeon, et al. (2011) 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 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
PULMONARY-FIBROSIS, JAPANESE POPULATION, FUNCTIONAL POLYMORPHISM, IRF5, SIGNALING PATHWAYS, ALOPECIA-AREATA, RISK-FACTOR, SUSCEPTIBILITY, SCLERODERMA, STAT4
journal title
PLOS GENETICS
PLoS Genet.
volume
7
issue
7
article_number
e1002178
pages
11 pages
Web of Science type
Article
Web of Science id
000293338600027
JCR category
GENETICS & HEREDITY
JCR impact factor
8.694 (2011)
JCR rank
11/155 (2011)
JCR quartile
1 (2011)
ISSN
1553-7390
DOI
10.1371/journal.pgen.1002178
language
English
UGent publication?
yes
classification
A1
copyright statement
I have retained and own the full copyright for this publication
id
2053950
handle
http://hdl.handle.net/1854/LU-2053950
date created
2012-03-01 09:43:35
date last changed
2012-03-01 16:48:25
@article{2053950,
  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.},
  articleno    = {e1002178},
  author       = {Gorlova, Olga and Martin, Jose-Ezequiel and Rueda, Blanca and Koeleman, Bobby PC 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 JH and Voskuyl, Alexandre E and Schuerwegh, Annemie J and van Riel, Piet LCM 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 Gonz{\'a}lez-Gay, Miguel A and Garc{\'i}a-Hern{\'a}ndez, Francisco J and Gonz{\'a}lez-Escribano, Mar{\'i}a 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, {\O}yvind and Garc{\'i}a de la Pe{\~n}a, 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 RDJ and Mayes, Maureen D and Martin, Javier},
  issn         = {1553-7390},
  journal      = {PLOS GENETICS},
  keyword      = {PULMONARY-FIBROSIS,JAPANESE POPULATION,FUNCTIONAL POLYMORPHISM,IRF5,SIGNALING PATHWAYS,ALOPECIA-AREATA,RISK-FACTOR,SUSCEPTIBILITY,SCLERODERMA,STAT4},
  language     = {eng},
  number       = {7},
  pages        = {11},
  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},
}

Chicago
Gorlova, Olga, Jose-Ezequiel Martin, Blanca Rueda, Bobby PC Koeleman, Jun Ying, Maria Teruel, Lina-Marcela Diaz-Gallo, 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).
APA
Gorlova, O., Martin, J.-E., Rueda, B., Koeleman, B. P., Ying, J., Teruel, M., Diaz-Gallo, L.-M., 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).
Vancouver
1.
Gorlova O, Martin J-E, Rueda B, Koeleman BP, Ying J, Teruel M, et al. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLOS GENETICS. 2011;7(7).
MLA
Gorlova, Olga, Jose-Ezequiel Martin, Blanca Rueda, et al. “Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis Through a Genome-wide Association Strategy.” PLOS GENETICS 7.7 (2011): n. pag. Print.