Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus

Radstake, Timothy R. D. J.; Gorlova, Olga Y.; Rueda, Blanca; Martin, Jose-Ezequiel; Alizadeh, Behrooz Z.; Palomino-Morales, Rogelio; Coenen, Marieke J.H.; Vonk, Madelon C.; Voskuyl, Alexandre E.; Schuerwegh, Annemie J.; Broen, Jasper; Riel, P.L.C.M. van; Slot, Ruben van ‘t; Italiaander, Annet; Ophoff, Roel A.; Riemekasten, Gabriela; Hunzelmann, N.; Simeón, Carmen P.; Ortego-Centeno, Norbérto; González-Gay, Miguel Á.; González‐Escribano, María Francisca; Airò, Paolo; Laar, Jaap van; Herrick, Ariane L.; Worthington, Jane; Hesselstrand, Roger; Smith, Vanessa; Keyser, Filip De; Houssiau, F.; Chee, Meng May; Madhok, Rajan; Shiels, Paul G.; Westhovens, René; Kreuter, Alexander; Kiener, Hans P.; Baere, Elfride De; Witte, Torsten; Padykov, Leonid; Klareskog, Lars; Beretta, Lorenzo; Scorza, R; Lie, Benedicte A.; Hoffmann‐Vold, Anna‐Maria; Carreira, Patrícia; Varga, John; Hinchcliff, Monique; Gregersen, Peter K.; Lee, Annette T.; Jin, Ying; Han, Younghun; Weng, Shih‐Feng; Amos, Christopher I.; Wigley, Fredrick M.; Hummers, Laura K.; Nelson, J. Lee; Agarwal, Sandeep K.; Assassi, Shervin; Gourh, Pravitt; Tan, Filemon K.; Koeleman, Bobby P. C.; Arnett, Frank C.; Martı́n, Javier; Mayes, Maureen D.

doi:10.1038/ng.565

Cited by 365 publications

(308 citation statements)

References 23 publications

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“…This is consistent with the findings of a GWAS, which failed to identify an association between PTPN22 C1858T and SSc. 119 MS is a common autoimmune disease that targets the central nervous system. A study of family-based samples showed no association between PTPN22 C1858T and MS. 11 This lack of association was confirmed by a GWAS.…”

Section: Diseases Showing No or Weak Association With Ptpn22mentioning

confidence: 99%

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

et al. 2012

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Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a strong susceptibility gene shared by many autoimmune diseases. The aim of this study was to explore the mechanisms underlying this relationship. We performed a comprehensive analysis of the association between PTPN22 polymorphism C1858T and autoimmune diseases. The results showed a remarkable pattern; PTPN22 C1858T was strongly associated with type I diabetes, rheumatoid arthritis, immune thrombocytopenia, generalized vitiligo with concomitant autoimmune diseases, idiopathic inflammatory myopathies, Graves' disease, juvenile idiopathic arthritis, myasthenia gravis, systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitis and Addison's disease. By contrast, PTPN22 C1858T showed a negligible association with systemic sclerosis, celiac disease, multiple sclerosis, psoriasis, ankylosing spondylitis, pemphigus vulgaris, ulcerative colitis, primary sclerosing cholangitis, primary biliary cirrhosis, Crohn's disease and acute anterior uveitis. Further analysis revealed a clear distinction between the two groups of diseases with regard to their targeted tissues: most autoimmune diseases showing an insignificant association with PTPN22 C1858T manifest in skin, the gastrointestinal tract or in immune privileged sites. These results showed that the association of PTPN22 polymorphism with autoimmune diseases depends on the localization of the affected tissue, suggesting a role of targeted organ variation in the disease manifestations.

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Section: Diseases Showing No or Weak Association With Ptpn22mentioning

confidence: 99%

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

et al. 2012

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“…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).…”

mentioning

confidence: 99%

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

Saigusa

Asano

Taniguchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Systemic sclerosis (SSc) is a multisystem autoimmune disorder with clinical manifestations resulting from tissue fibrosis and extensive vasculopathy. A potential disease susceptibility gene for SSc is IFN regulatory factor 5 (IRF5), whose SNP is associated with milder clinical manifestations; however, the underlying mechanisms of this association remain elusive. In this study we examined IRF5-deficient (Irf5−/−) mice in the bleomycin-treated SSc murine model. We show that dermal and pulmonary fibrosis induced by bleomycin is attenuated in Irf5−/− mice. Interestingly, we find that multiple SSc-associated events, such as fibroblast activation, inflammatory cell infiltration, endothelial-to-mesenchymal transition, vascular destabilization, Th2/Th17 skewed immune polarization, and B-cell activation, are suppressed in these mice. We further provide evidence that IRF5, activated by Toll-like receptor 4 (TLR4), binds to the promoters of various key genes involved in SSc disease pathology. These observations are congruent with the high level of expression of IRF5, TLR4, and potential endogenous TLR4 ligands in SSc skin lesions. Our study sheds light on the TLR4-IRF5 pathway in the pathology of SSc with clinical implications of targeting the IRF5 pathways in the suppression of disease development.

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“…The same region had been previously associated with several autoimmune diseases [20][21][22][23][24][25][26][27] . Another MHC locus has been found in the region that includes the HLA-DPA1, BPB1 and DPB2 genes.…”

Section: Antigen Elaboration and Presentationmentioning

confidence: 99%

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

Salvadori

Rosso

2015

WJN

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Immunoglobulin A (IgA) nephropathy is one of the most common glomerulonephritis and its frequency is probably underestimated because in most patients the disease has an indolent course and the kidney biopsy is essential for the diagnosis. In the last years its pathogenesis has been better identified even if still now several questions remain to be answered. The genetic wide association studies have allowed to identifying the relevance of genetics and several putative genes have been identified. The genetics has also allowed explaining why some ancestral groups are affected with higher frequency. To date is clear that IgA nephropathy is related to auto antibodies against immunoglobulin A1 (IgA1) with poor O-glycosylation. The role of mucosal infections is confirmed, but which are the pathogens involved and which is the role of Toll-like receptor polymorphism is less clear. Similarly to date whether the disease is due to the circulating immunocomplexes deposition on the mesangium or whether the antigen is already present on the mesangial cell as a "lanthanic" deposition remains to be clarified. Finally also the link between the mesangial and the podocyte injury and the tubulointerstitial scarring, as well as the mechanisms involved need to be better clarified.

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Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus

Cited by 365 publications

References 23 publications

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

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

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

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