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.

ABIN1 Dysfunction as a Genetic Basis for Lupus Nephritis

“…Both of these variants are in noncoding regions of TNIP1. 31,32 No SNPs reached the Bonferroni-corrected significant threshold in other populations, which concurs with published data using lupus as the phenotype. 30 …”

“…rs4958881 was previously reported to be associated with systemic sclerosis, but not SLE. 32 Additionally, ABIN1 expression was decreased in systemic sclerosis skin lesions and in dermal fibroblasts from patients with systemic sclerosis compared with controls, and transgenic expression of ABIN1 abrogated matrix protein expression induced by inflammatory cytokines in fibroblast from patients with systemic sclerosis. 32 This suggests that the rs4958881 variant could result in lower renal expression of ABIN1 in LN, leading to increased mesangial cell matrix production typically seen in class III and IV LN in humans 49 and found in the ABIN1[D485N] knockin mice.…”

“…32 Additionally, ABIN1 expression was decreased in systemic sclerosis skin lesions and in dermal fibroblasts from patients with systemic sclerosis compared with controls, and transgenic expression of ABIN1 abrogated matrix protein expression induced by inflammatory cytokines in fibroblast from patients with systemic sclerosis. 32 This suggests that the rs4958881 variant could result in lower renal expression of ABIN1 in LN, leading to increased mesangial cell matrix production typically seen in class III and IV LN in humans 49 and found in the ABIN1[D485N] knockin mice.In summary, our data suggest that mutations in ABIN1 represent a new genetic basis for LN through the novel pathophysiologic mechanism of aberrant regulation of NFkB and MAPK activity ( Figure 5). This is supported by knockin mice expressing a mutation of ABIN1 with loss of NF-kB and MAPK inhibitory function and a strong association of a novel TNIP1 polymorphism and LN in an SLE patient population with a higher incidence of LN.…”

Multifaceted contribution of the TLR4-activated IRF5 transcription factor in systemic sclerosis

“…Although how the TLR4 signaling pathway contributes to SSc pathogenesis remains enigmatic, it is interesting that several independent case-control and genome-wide association studies identify IFN regulatory factor 5 (IRF5), a member of the IFN regulatory factor (IRF) family, as an SSc susceptibility gene (10)(11)(12)(13)(14)(15). IRFs were identified primarily in the research of the type I IFN system and have been shown to have functionally diverse roles in the regulation of the innate and adaptive immune responses (16).…”

ABIN1 in the pathogenesis of Glomerulonephritis and the novel polocyte-neutrophil proinflammatory axis.

“…The mega kit was sufficient for purification from up to 100 mL LB broth at high turbidity. rs3792783, rs2233287) [71], SLE (rs7708392) [67], psoriasis (rs3762999, rs999556, rs17728338) [72,73], and psoriatic arthritis (rs17728338, one of psoriasis SNPs) [74]. In addition, 347 ancestral-informative markers (AIMs) spanning the genome were genotyped.…”