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Furthermore, both diseases share some genetic bases with other AIDs, as evidenced by autoimmune gene pleiotropism. The present study was undertaken to investigate whether single-nucleotide polymorphisms (SNPs) identified by a large genome-wide association study (GWAS) in PBC might contribute to SSc susceptibility.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>Sixteen PBC susceptibility SNPs were genotyped in a total of 1,616 patients with SSc and 3,621 healthy controls from two European populations (France and Italy).<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>We observed an association between <jats:italic>PLCL2<\/jats:italic> rs1372072 (odds ratio (OR)\u2009=\u20091.22, 95% confidence interval (CI) 1.12 to 1.33, <jats:italic>P<\/jats:italic><jats:sub>adj<\/jats:sub>\u2009=\u20097.22\u2009\u00d7\u200910<jats:sup>\u22125<\/jats:sup>), nuclear factor-kappa-B (<jats:italic>NF-\u03baB<\/jats:italic>) rs7665090 (OR\u2009=\u20091.15, 95% CI 1.06 to 1.25, <jats:italic>P<\/jats:italic><jats:sub>adj<\/jats:sub>\u2009=\u20090.01), and <jats:italic>IRF8<\/jats:italic> rs11117432 (OR\u2009=\u20090.75, 95% CI 0.67 to 0.86, <jats:italic>P<\/jats:italic><jats:sub>adj<\/jats:sub>\u2009=\u20092.49\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (<jats:italic>P<\/jats:italic><jats:sub>adj<\/jats:sub>\u2009=\u20094.45\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup> and <jats:italic>P<\/jats:italic><jats:sub>adj<\/jats:sub>\u2009=\u20090.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (<jats:italic>P<\/jats:italic><jats:sub>adj<\/jats:sub>\u2009=\u20090.003).  Genotype-mRNA expression correlation analysis revealed that the <jats:italic>IRF8<\/jats:italic> protective allele was associated with increased interferon-gamma (IFN-\u03b3) expression (<jats:italic>P<\/jats:italic>\u2009=\u20090.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (<jats:italic>P<\/jats:italic>\u2009=\u20090.02). In addition, we found an epistatic interaction between <jats:italic>NF-\u03baB<\/jats:italic> and <jats:italic>IRF8<\/jats:italic> (OR\u2009=\u20090.56, 95% CI 0.00 to 0.74, <jats:italic>P<\/jats:italic>\u2009=\u20094\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>) which in turn revealed that the <jats:italic>IRF8<\/jats:italic> protective effect is dependent on the presence of the <jats:italic>NF-\u03baB<\/jats:italic> susceptibility allele.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>An analysis of pleiotropic genes identified two new susceptibility genes for SSc (<jats:italic>NF-\u03baB<\/jats:italic> and <jats:italic>PLCL2<\/jats:italic>) and confirmed the <jats:italic>IRF8<\/jats:italic> locus. Furthermore, the <jats:italic>IRF8<\/jats:italic> variant influenced the IFN signature, and we found an interaction between <jats:italic>IRF8<\/jats:italic> and <jats:italic>NF-\u03baB<\/jats:italic> gene variants that might play a role in SSc susceptibility.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/s13075-015-0572-y","type":"journal-article","created":{"date-parts":[[2015,3,16]],"date-time":"2015-03-16T17:57:07Z","timestamp":1426528627000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Identification of NF-\u03baB and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis"],"prefix":"10.1186","volume":"17","author":[{"given":"Maria","family":"Arismendi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Giraud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadira","family":"Ruzehaji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Dieud\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenie","family":"Koumakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Airo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Cusi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Matucci-Cerinic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Salvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Cuomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Hachulla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Diot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Caramaschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Riccieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00e9r\u00f4me","family":"Avouac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiane","family":"Kayser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Allanore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,3,21]]},"reference":[{"key":"572_CR1","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1093\/rheumatology\/ker269","volume":"51","author":"M Elhai","year":"2012","unstructured":"Elhai M, Meune C, Avouac J, Kahan A, Allanore Y. 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