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Title: 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
Authors: Arismendi, Maria
Giraud, Matthieu
Ruzehaji, Nadira
Dieude, Philippe
Koumakis, Eugenie
Ruiz, Barbara
Airo, Paolo
Cusi, Daniele
Matucci-Cerinic, Marco
Salvi, Erika
Cuomo, Giovanna
Hachulla, Eric
Diot, Elisabeth
Caramaschi, Paola
Riccieri, Valeria
Avouac, Jerome
Kayser, Cristiane [UNIFESP]
Allanore, Yannick
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)
Issue Date: 21-Mar-2015
Publisher: Biomed Central Ltd
Citation: Arthritis Research & Therapy. London: Biomed Central Ltd, v. 17, 11 p., 2015.
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.
ISSN: 1478-6354
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