title: Identification of NF-κB and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis.
abstract: BACKGROUND
  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 × 10(-5)), nuclear factor-kappa-B (NF-κB) 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 × 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 × 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-γ) 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-κB and IRF8 (OR = 0.56, 95% CI 0.00 to 0.74, P = 4 × 10(-4)) which in turn revealed that the IRF8 protective effect is dependent on the presence of the NF-κB susceptibility allele.
  
  
  CONCLUSIONS
  An analysis of pleiotropic genes identified two new susceptibility genes for SSc (NF-κB and PLCL2) and confirmed the IRF8 locus. Furthermore, the IRF8 variant influenced the IFN signature, and we found an interaction between IRF8 and NF-κB gene variants that might play a role in SSc susceptibility.
authors.affiliation: Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France. arismendi.ma@gmail.com.|CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, 70040-020, Brazil. arismendi.ma@gmail.com.
authors.forename: Maria
authors.initials: M
authors.lastname: Arismendi
authors.affiliation: Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France. matthieu.giraud@inserm.fr.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Giraud
authors.affiliation: Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France. nadira.ruzehaji@inserm.fr.
authors.forename: Nadira
authors.initials: N
authors.lastname: Ruzehaji
authors.affiliation: Paris Diderot University, Rheumatology Department, Hôpital Bichat Claude Bernard, APHP, Paris, France. philippe.dieude@bch.aphp.fr.|Paris Diderot University, INSERM U699, Hôpital Bichat Claude Bernard, Paris, France. philippe.dieude@bch.aphp.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Dieudé
authors.affiliation: Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France. koumakis@hotmail.com.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Koumakis
authors.affiliation: Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France. barbara.ruiz@inserm.fr.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruiz
authors.affiliation: Rheumatology and Clinical Immunology, Spedali Civili, Brescia, Italy. airo@bresciareumatologia.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Airo
authors.affiliation: University of Milano, Department of Medicine, Surgery and Dentistry San Paolo & Genomics and Bioinformatics Platform, Fondazione Filarete, Milan, Italy. daniele.cusi@unimi.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cusi
authors.affiliation: Department of Biomedicine & Division of Rheumatology AOUC, Department of Rheumatology AVC, Department of Medicine & Denothe Centre, University of Florence, Florence, Italy. marco.matuccicerinic@unifi.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Matucci-Cerinic
authors.affiliation: University of Milano, Department of Medicine, Surgery and Dentistry San Paolo & Genomics and Bioinformatics Platform, Fondazione Filarete, Milan, Italy. salvi.erika@gmail.com.
authors.forename: Erika
authors.initials: E
authors.lastname: Salvi
authors.affiliation: Department of Clinical and Experimental Medicine, Rheumatology Unit, Second University of Naples, Naples, Italy. giovanna.cuomo@unina2.it.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cuomo
authors.affiliation: Université Lille II, Médecine Interne, Lille, France. eric.hachulla@chru-lille.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Hachulla
authors.affiliation: INSERM U618, IFR 135, CHU Bretonneau, Tours, France. ediot@med.univ-tours.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Diot
authors.affiliation: Rheumatology Unit, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy. paola.caramaschi@ospedaleuniverona.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Caramaschi
authors.affiliation: Division of Rheumatology, Department of Medical Clinic and Therapy, University "Sapienza" of Rome, Rome, Italy. valeria.riccieri@uniroma1.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Riccieri
authors.affiliation: Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France. jerome.avouac@cch.aphp.fr.|Paris Descartes University, Rheumatology A Department, Cochin Hospital, APHP, Paris, France. jerome.avouac@cch.aphp.fr.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Avouac
authors.affiliation: Department of Rheumatology, Federal University of São Paulo, São Paulo, Brazil. criskayser@terra.com.br.
authors.forename: Cristiane
authors.initials: C
authors.lastname: Kayser
authors.affiliation: Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France. yannick.allanore@cch.aphp.fr.|Paris Descartes University, Rheumatology A Department, Cochin Hospital, APHP, Paris, France. yannick.allanore@cch.aphp.fr.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000235:genetics*; D007371:Interferon-gamma / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000473:pathology; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D000099185:Interferon Regulatory Factor-8; C530632:PLCL2 protein, human