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

yannick Allanore 1, 2, 3, * Mohamad Saad 4 Philippe Dieudé 5, 6 Jérôme Avouac 1, 2, 3 Jorg H. W. Distler 7 Philippe Amouyel 8 Marco Matucci-Cerinic 9 Gabriella Riemekasten 10 Paolo Airo 11 Inga Melchers 12 Eric Hachulla 13 Daniele Cusi 14, 15 H-Erich Wichmann 16, 17 Julien Wipff 1, 2, 3 Jean-Charles Lambert 8 Nicolas Hunzelmann 18 Kiet Tiev 19 Paola Caramaschi 20 Elisabeth Diot 21 Otylia Kowal-Bielecka 22 Gabriele Valentini 23 Luc Mouthon 24 László Czirják 25 Nemanja Damjanov 26 Erika Salvi 14, 15 Costanza Conti 27 Martina Müller 16, 28 Ulf Müller-Ladner 29 Valeria Riccieri 30 Barbara Ruiz 2 Jean-Luc Cracowski 31 Luc Letenneur 32 Anne-Marie Dupuy 33 Oliver Meyer 5, 6 André Kahan 1, 2 Arnold Munnich 3 Catherine Boileau 3, 34 Maria Martinez 4 
* Corresponding author
Abstract : 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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Submitted on : Tuesday, July 3, 2012 - 4:07:42 PM
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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, Public Library of Science, 2011, 7 (7), pp.e1002091. ⟨10.1371/journal.pgen.1002091⟩. ⟨inserm-00714204⟩



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