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

Yannick Allanore, Mohamad Saad, Philippe Dieudé, Jérôme Avouac, Jorg H.W. Distler, Philippe Amouyel, Marco Matucci-Cerinic, Gabriella Riemekasten, Paolo Airo, Inga Melchers, Eric Hachulla, Daniele Cusi, H. Erich Wichmann, Julien Wipff, Jean Charles Lambert, Nicolas Hunzelmann, Kiet Tiev, Paola Caramaschi, Elisabeth Diot, Otylia Kowal-Bielecka & 18 others Gabriele Valentini, Luc Mouthon, László Czirják, Nemanja Damjanov, Erika Salvi, Costanza Conti, Martina Müller, Ulf Müller-Ladner, Valeria Riccieri, Barbara Ruiz, Jean Luc Cracowski, Luc Letenneur, Anne Marie Dupuy, Oliver Meyer, André Kahan, Arnold Munnich, Catherine Boileau, Maria Martinez

Research output: Contribution to journalArticle

145 Citations (Scopus)

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.

Original languageEnglish
Article numbere1002091
JournalPLoS Genetics
Volume7
Issue number7
DOIs
Publication statusPublished - 1 Jul 2011
Externally publishedYes

Fingerprint

Systemic Scleroderma
sclerosis
Single Nucleotide Polymorphism
genome
Genome
loci
gene
Genome-Wide Association Study
orphan
collagen
connective tissues
Connective Tissue
immune system
disequilibrium
quality control
pathogenesis
skin
genomics
sampling
Skin

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Allanore, Y., Saad, M., Dieudé, P., Avouac, J., Distler, J. H. W., Amouyel, P., ... Martinez, M. (2011). Genome-Wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genetics, 7(7), [e1002091]. https://doi.org/10.1371/journal.pgen.1002091

Genome-Wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. / Allanore, Yannick; Saad, Mohamad; Dieudé, Philippe; Avouac, Jérôme; Distler, Jorg H.W.; Amouyel, Philippe; Matucci-Cerinic, Marco; Riemekasten, Gabriella; Airo, Paolo; Melchers, Inga; Hachulla, Eric; Cusi, Daniele; Wichmann, H. Erich; Wipff, Julien; Lambert, Jean Charles; Hunzelmann, Nicolas; Tiev, Kiet; Caramaschi, Paola; Diot, Elisabeth; Kowal-Bielecka, Otylia; Valentini, Gabriele; Mouthon, Luc; Czirják, László; Damjanov, Nemanja; Salvi, Erika; Conti, Costanza; Müller, Martina; Müller-Ladner, Ulf; Riccieri, Valeria; Ruiz, Barbara; Cracowski, Jean Luc; Letenneur, Luc; Dupuy, Anne Marie; Meyer, Oliver; Kahan, André; Munnich, Arnold; Boileau, Catherine; Martinez, Maria.

In: PLoS Genetics, Vol. 7, No. 7, e1002091, 01.07.2011.

Research output: Contribution to journalArticle

Allanore, Y, Saad, M, Dieudé, P, Avouac, J, Distler, JHW, Amouyel, P, Matucci-Cerinic, M, Riemekasten, G, Airo, P, Melchers, I, Hachulla, E, Cusi, D, Wichmann, HE, Wipff, J, Lambert, JC, Hunzelmann, N, Tiev, K, Caramaschi, P, Diot, E, Kowal-Bielecka, O, Valentini, G, Mouthon, L, Czirják, L, Damjanov, N, Salvi, E, Conti, C, Müller, M, Müller-Ladner, U, Riccieri, V, Ruiz, B, Cracowski, JL, Letenneur, L, Dupuy, AM, Meyer, O, Kahan, A, Munnich, A, Boileau, C & Martinez, M 2011, 'Genome-Wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis', PLoS Genetics, vol. 7, no. 7, e1002091. https://doi.org/10.1371/journal.pgen.1002091
Allanore, Yannick ; Saad, Mohamad ; Dieudé, Philippe ; Avouac, Jérôme ; Distler, Jorg H.W. ; Amouyel, Philippe ; Matucci-Cerinic, Marco ; Riemekasten, Gabriella ; Airo, Paolo ; Melchers, Inga ; Hachulla, Eric ; Cusi, Daniele ; Wichmann, H. Erich ; Wipff, Julien ; Lambert, Jean Charles ; Hunzelmann, Nicolas ; Tiev, Kiet ; Caramaschi, Paola ; Diot, Elisabeth ; Kowal-Bielecka, Otylia ; Valentini, Gabriele ; Mouthon, Luc ; Czirják, László ; Damjanov, Nemanja ; Salvi, Erika ; Conti, Costanza ; Müller, Martina ; Müller-Ladner, Ulf ; Riccieri, Valeria ; Ruiz, Barbara ; Cracowski, Jean Luc ; Letenneur, Luc ; Dupuy, Anne Marie ; Meyer, Oliver ; Kahan, André ; Munnich, Arnold ; Boileau, Catherine ; Martinez, Maria. / Genome-Wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. In: PLoS Genetics. 2011 ; Vol. 7, No. 7.
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T1 - Genome-Wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis

AU - Allanore, Yannick

AU - Saad, Mohamad

AU - Dieudé, Philippe

AU - Avouac, Jérôme

AU - Distler, Jorg H.W.

AU - Amouyel, Philippe

AU - Matucci-Cerinic, Marco

AU - Riemekasten, Gabriella

AU - Airo, Paolo

AU - Melchers, Inga

AU - Hachulla, Eric

AU - Cusi, Daniele

AU - Wichmann, H. Erich

AU - Wipff, Julien

AU - Lambert, Jean Charles

AU - Hunzelmann, Nicolas

AU - Tiev, Kiet

AU - Caramaschi, Paola

AU - Diot, Elisabeth

AU - Kowal-Bielecka, Otylia

AU - Valentini, Gabriele

AU - Mouthon, Luc

AU - Czirják, László

AU - Damjanov, Nemanja

AU - Salvi, Erika

AU - Conti, Costanza

AU - Müller, Martina

AU - Müller-Ladner, Ulf

AU - Riccieri, Valeria

AU - Ruiz, Barbara

AU - Cracowski, Jean Luc

AU - Letenneur, Luc

AU - Dupuy, Anne Marie

AU - Meyer, Oliver

AU - Kahan, André

AU - Munnich, Arnold

AU - Boileau, Catherine

AU - Martinez, Maria

PY - 2011/7/1

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N2 - 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.

AB - 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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