Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles PLoS Genetics Year : 2011

Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.

1 Service de rhumatologie [CHU Cochin]
2 IC UM3 (UMR 8104 / U1016) - Institut Cochin
3 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
4 CPTP - Centre de Physiopathologie Toulouse Purpan
5 Service de Rhumatologie
6 Immunopathologie rénale, récepteurs et inflammation
7 Department of Internal Medicine 3
8 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
9 Departments of Medicine, Biomedicine & Rheumatology
10 Department of Rheumatology and Clinical Immunology
11 Rheumatology and Clinical Immunology
12 Clinical Research Unit for Rheumatology
13 Service de médecine interne [Lille]
14 Department of Medicine, Surgery, and Dentistry
15 Genomics and Bioinformatics Platform
16 Institute of Medical Informatics, Biometry, and Epidemiology
17 Institute of Epidemiology I
18 Department of Dermatology
19 CHU Saint-Antoine [AP-HP]
20 Rheumatology Unit
21 Pathologies Respiratoires : Protéolyse et Aérosolthérapie
22 Department of Rheumatology and Internal Medicine
23 Department of Clinical and Experimental Medicine
24 Service de médecine interne et centre de référence des maladies rares [CHU Cochin]
25 Department of Immunology and Rheumatology
26 Institute of Rheumatology
27 Kos Genetic SRL
28 Institute of Genetic Epidemiology
29 Department of Rheumatology and Clinical Immunology
30 Division of Rheumatology
31 CIC Grenoble - Centre d'Investigation Clinique [Grenoble]
32 Epidémiologie et Biostatistique [Bordeaux]
33 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
34 Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré]
Costanza Conti
  • Function : Author
Barbara Ruiz
  • Function : Author


Systemic sclerosis (SSc) is an orphan, complex, inflammatory disease affecting the immune system and connective tissue. SSc stands out as a severely incapacitating and life-threatening inflammatory rheumatic disease, with a largely unknown pathogenesis. We have designed a two-stage genome-wide association study of SSc using case-control samples from France, Italy, Germany, and Northern Europe. The initial genome-wide scan was conducted in a French post quality-control sample of 564 cases and 1,776 controls, using almost 500 K SNPs. Two SNPs from the MHC region, together with the 6 loci outside MHC having at least one SNP with a P<10(-5) were selected for follow-up analysis. These markers were genotyped in a post-QC replication sample of 1,682 SSc cases and 3,926 controls. The three top SNPs are in strong linkage disequilibrium and located on 6p21, in the HLA-DQB1 gene: rs9275224, P = 9.18×10(-8), OR = 0.69, 95% CI [0.60-0.79]; rs6457617, P = 1.14×10(-7) and rs9275245, P = 1.39×10(-7). Within the MHC region, the next most associated SNP (rs3130573, P = 1.86×10(-5), OR = 1.36 [1.18-1.56]) is located in the PSORS1C1 gene. Outside the MHC region, our GWAS analysis revealed 7 top SNPs (P<10(-5)) that spanned 6 independent genomic regions. Follow-up of the 17 top SNPs in an independent sample of 1,682 SSc and 3,926 controls showed associations at PSORS1C1 (overall P = 5.70×10(-10), OR:1.25), TNIP1 (P = 4.68×10(-9), OR:1.31), and RHOB loci (P = 3.17×10(-6), OR:1.21). Because of its biological relevance, and previous reports of genetic association at this locus with connective tissue disorders, we investigated TNIP1 expression. A markedly reduced expression of the TNIP1 gene and also its protein product were observed both in lesional skin tissue and in cultured dermal fibroblasts from SSc patients. Furthermore, TNIP1 showed in vitro inhibitory effects on inflammatory cytokine-induced collagen production. The genetic signal of association with TNIP1 variants, together with tissular and cellular investigations, suggests that this pathway has a critical role in regulating autoimmunity and SSc pathogenesis.


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inserm-00714204 , version 1 (03-07-2012)



Yannick Allanore, Mohamad Saad, Philippe Dieudé, Jérôme Avouac, Jorg H. W. Distler, et al.. Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.. PLoS Genetics, 2011, 7 (7), pp.e1002091. ⟨10.1371/journal.pgen.1002091⟩. ⟨inserm-00714204⟩
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