title: Effects of IRF5 lupus risk haplotype on pathways predicted to influence B cell functions.
abstract: Both genetic and environmental interactions affect systemic lupus erythematosus (SLE) development and pathogenesis. One known genetic factor associated with lupus is a haplotype of the interferon regulatory factor 5 (IRF5) gene. Analysis of global gene expression microarray data using gene set enrichment analysis identified multiple interferon- and inflammation-related gene sets significantly overrepresented in cells with the risk haplotype. Pathway analysis using expressed genes from the significant gene sets impacted by the IRF5 risk haplotype confirmed significant correlation with the interferon pathway, Toll-like receptor pathway, and the B-cell receptor pathway. SLE patients with the IRF5 risk haplotype have a heightened interferon signature, even in an unstimulated state (P = 0.011), while patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of controls. These results identify multiple genes in functionally significant pathways which are affected by IRF5 genotype. They also establish the IRF5 risk haplotype as a key determinant of not only the interferon response, but also other B-cell pathways involved in SLE.
authors.affiliation: Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Clark
authors.forename: Amanda
authors.initials: A
authors.lastname: Templeton
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dominguez
authors.forename: Rufei
authors.initials: R
authors.lastname: Lu
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Vidal
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Kelly
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kauffman
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: Judith A
authors.initials: JA
authors.lastname: James
authors.forename: Brian D
authors.initials: BD
authors.lastname: Poole
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D030541:Databases, Genetic; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D007372:Interferons / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D015398:Signal Transduction
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D007372:Interferons