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=9.1810 8 , OR=0.69, 95% CI [0.600.79]; rs6457617, P=1.1410 7 and rs9275245, P=1.3910 7 . Within the MHC region, the next most associated SNP (rs3130573, P=1.8610 5 , OR=1.36 [1.181.56]) 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=5.7010 10 , OR:1.25), TNIP1 (P=4.6810 9 , OR:1.31), and RHOB loci (P=3.1710 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.

... Arthritis Scleroderma Systemic Lupus Erythematosus Genome-Wide Scan Identifies TNIP1 , PSORS1C1 , and RHOB as Novel Risk Loci for Systemic Sclerosis Genome-Wide Scan in Systemic Sclerosis Allanore Yannick 1 2 * Saad Mohamad 3 Dieud Philippe 4 Avouac Jrme 1 2 Distler Jorg H. W. 5 Amouyel Philippe 6 Matucci-Cerinic Marco 7 Riemekasten Gabriella 8 Airo Paolo 9 Melchers Inga 10 Hachulla Eric 11 Cusi Daniele 12 13 Wichmann H.-Erich 14 15 Wipff Julien 1 2 Lambert Jean

... 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=9.1810 8 , OR=0.69, 95% CI [0.600.79]; rs6457617, P=1.1410 7 and rs9275245, P=1.3910 7 . Within the MHC region, the next most associated SNP (rs3130573, P=1.8610 5 , OR=1.36 [1.181.56]) 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=5.7010 10 , OR:1.25), TNIP1 (P=4.6810 9 , OR:1.31), and RHOB loci (P=3.1710 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

... association at the known HLA-DQB1 region and revealed associations at PSORS1C1 , TNIP1 , and RHOB loci, in agreement with a strong immune genetic component. Because of its biological relevance, and previous reports of genetic association at this locus with other connective tissue disorders, we investigated TNIP1 expression. We observed a markedly reduced expression of the gene and its protein product in SSc, as well as its potential implication in control of extra-cellular matrix synthesis, providing a

... been reported but rs6457617 was also identified as the most associated SNP in the previous US/European GWAS study [18] . Of note, the three SNPs in HLA-DQB1 are in strong LD (r 2 >0.97). Within the MHC region, the next most associated SNP (rs3130573, P=1.8610 5 , OR=1.36[1.181.56]) is located in the psoriasis susceptibility 1 candidate 1 ( PSORS1C1 ) gene ( Table 2 ), a candidate gene for psoriasis [23] . Conditional analyses of susceptibility variants within MHC showed that there were two independent association signals at rs6457617 ( HLA-DQB1 ) and at rs3130573 ( PSORS1C1 ). Indeed, the association at PSORS1C1 remained significant (P<2.110 5 ) after controlling for the association at HLA-DQB1 and the association at HLA-DQB1 remained also significant (P<1.510 7 ) after controlling for the association at PSORS1C1 ( Table S2 ). 10.1371/journal.pgen.1002091.g001 Figure 1 Genome-wide association results from the discovery phase. (A) Quantile-quantile plot for test statistics (logistic

... cutaneous systemic sclerosis; TOPO: anti topoisomerase I antibodies; ACA: anti-centromere antibodies. 10.1371/journal.pgen.1002091.t002 Table 2 Genome-wide association and replication for systemic sclerosis risk variants. Discovery (564 cases/ 1,776 controls) Replication (1,682 cases/ 3,926 controls) Combined (2,246 cases/ 4,684 controls) Chr. (closest gene) Pos. (bp) SNP Minor/ Major MAF Cases/ Controls P OR 95%CI MAF Cases/ Controls $P OR 95%CI **P $P OR 95%CI MHC loci 6p21(PSORS1C1) 31 214 247

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Gene: PSORS1C1 - psoriasis susceptibility 1 candidate 1 - (NCBI)

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