TY - JOUR
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
Y1 - 2011/7
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.
UR - https://www.scopus.com/pages/publications/79960934301
U2 - 10.1371/journal.pgen.1002091
DO - 10.1371/journal.pgen.1002091
M3 - Article
C2 - 21750679
AN - SCOPUS:79960934301
SN - 1553-7390
VL - 7
JO - PLoS Genetics
JF - PLoS Genetics
IS - 7
M1 - e1002091
ER -