title: Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis.
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.
authors.affiliation: Université Paris Descartes, Rhumatologie A, INSERM, U1016, Hôpital Cochin, APHP, Paris, France. yannick.allanore@cch.aphp.fr
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.forename: Mohamad
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authors.lastname: Saad
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.forename: Jérôme
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authors.lastname: Avouac
authors.forename: Jorg H W
authors.initials: JH
authors.lastname: Distler
authors.forename: Philippe
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authors.forename: Marco
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authors.lastname: Matucci-Cerinic
authors.forename: Gabriella
authors.initials: G
authors.lastname: Riemekasten
authors.forename: Paolo
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authors.lastname: Airo
authors.forename: Inga
authors.initials: I
authors.lastname: Melchers
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Julien
authors.initials: J
authors.lastname: Wipff
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Lambert
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hunzelmann
authors.forename: Kiet
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authors.lastname: Tiev
authors.forename: Paola
authors.initials: P
authors.lastname: Caramaschi
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Diot
authors.forename: Otylia
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authors.lastname: Kowal-Bielecka
authors.forename: Gabriele
authors.initials: G
authors.lastname: Valentini
authors.forename: Luc
authors.initials: L
authors.lastname: Mouthon
authors.forename: László
authors.initials: L
authors.lastname: Czirják
authors.forename: Nemanja
authors.initials: N
authors.lastname: Damjanov
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.forename: Costanza
authors.initials: C
authors.lastname: Conti
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Ulf
authors.initials: U
authors.lastname: Müller-Ladner
authors.forename: Valeria
authors.initials: V
authors.lastname: Riccieri
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruiz
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Cracowski
authors.forename: Luc
authors.initials: L
authors.lastname: Letenneur
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Dupuy
authors.forename: Oliver
authors.initials: O
authors.lastname: Meyer
authors.forename: André
authors.initials: A
authors.lastname: Kahan
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D005060:Europe; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005858:Germany; D059866:HLA-DQ beta-Chains / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007558:Italy; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics* / Q000276:immunology; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology; D020743:rhoB GTP-Binding Protein / Q000235:genetics* / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; C484393:PSORS1C1 protein, human; D011506:Proteins; C117046:TNIP1 protein, human; D020743:rhoB GTP-Binding Protein