Identification of NF-kappa B and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis

Identification of NF-kappa B and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis

Author Arismendi, Maria Google Scholar
Giraud, Matthieu Google Scholar
Ruzehaji, Nadira Google Scholar
Dieude, Philippe Google Scholar
Koumakis, Eugenie Google Scholar
Ruiz, Barbara Google Scholar
Airo, Paolo Google Scholar
Cusi, Daniele Google Scholar
Matucci-Cerinic, Marco Google Scholar
Salvi, Erika Google Scholar
Cuomo, Giovanna Google Scholar
Hachulla, Eric Google Scholar
Diot, Elisabeth Google Scholar
Caramaschi, Paola Google Scholar
Riccieri, Valeria Google Scholar
Avouac, Jerome Google Scholar
Kayser, Cristiane Autor UNIFESP Google Scholar
Allanore, Yannick Google Scholar
Institution Paris Descartes Univ
Minist Educ Brazil
Paris Diderot Univ
Spedali Civil Brescia
Univ Milan
Fdn Filarete
Univ Florence
Univ Naples 2
Univ Lille 2
CHU Bretonneau
Azienda Osped Univ Integrata Verona
Univ Roma La Sapienza
Universidade Federal de São Paulo (UNIFESP)
Abstract Introduction: Systemic sclerosis (SSc) and primary biliary cirrhosis (PBC) are rare polygenic autoimmune diseases (AIDs) characterized by fibroblast dysfunction. 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.Methods: 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).Results: We observed an association between PLCL2 rs1372072 (odds ratio (OR) = 1.22, 95% confidence interval (CI) 1.12 to 1.33, P-adj = 7.22 x 10(-5)), nuclear factor-kappa-B (NF-kappa B) rs7665090 (OR = 1.15, 95% CI 1.06 to 1.25, P-adj = 0.01), and IRF8 rs11117432 (OR = 0.75, 95% CI 0.67 to 0.86, P-adj = 2.49 x 10(-4)) with SSc susceptibility. Furthermore, phenotype stratification showed an association between rs1372072 and rs11117432 with the limited cutaneous subgroup (lcSSc) (P-adj = 4.45 x 10(-4) and P-adj = 0.001), whereas rs7665090 was associated with the diffuse cutaneous subtype (dcSSc) (P-adj = 0.003). Genotype-mRNA expression correlation analysis revealed that the IRF8 protective allele was associated with increased interferon-gamma (IFN-gamma) expression (P = 0.03) in patients with SSc but decreased type I IFN (IFIT1) expression in patients and controls (P = 0.02). in addition, we found an epistatic interaction between NF-kappa B and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P= 4 x 10(-4)) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-kappa B susceptibility allele.Conclusions: An analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-kappa B and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-kappa B gene variants that might play a role in SSc susceptibility.
Language English
Sponsor Association des Sclerodermies de France
Date 2015-03-21
Published in Arthritis Research & Therapy. London: Biomed Central Ltd, v. 17, 11 p., 2015.
ISSN 1478-6354 (Sherpa/Romeo, impact factor)
Publisher Biomed Central Ltd
Extent 11
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000354065900001

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