title: Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo.
abstract: Increased IFN-alpha signaling is a primary pathogenic factor in systemic lupus erythematosus (SLE). STAT4 is a transcription factor that is activated by IFN-alpha signaling, and genetic variation of STAT4 has been associated with risk of SLE and rheumatoid arthritis. We measured serum IFN-alpha activity and simultaneous IFN-alpha-induced gene expression in PBMC in a large SLE cohort. The risk variant of STAT4 (T allele; rs7574865) was simultaneously associated with both lower serum IFN-alpha activity and greater IFN-alpha-induced gene expression in PBMC in SLE patients in vivo. Regression analyses confirmed that the risk allele of STAT4 was associated with increased sensitivity to IFN-alpha signaling. The IFN regulatory factor 5 SLE risk genotype was associated with higher serum IFN-alpha activity; however, STAT4 showed dominant influence on the sensitivity of PBMC to serum IFN-alpha. These data provide biologic relevance for the risk variant of STAT4 in the IFN-alpha pathway in vivo.
authors.affiliation: Section of Rheumatology, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Silvia N
authors.initials: SN
authors.lastname: Kariuki
authors.forename: Kyriakos A
authors.initials: KA
authors.lastname: Kirou
authors.forename: Emma J
authors.initials: EJ
authors.lastname: MacDermott
authors.forename: Lilliana
authors.initials: L
authors.lastname: Barillas-Arias
authors.forename: Mary K
authors.initials: MK
authors.lastname: Crow
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Niewold
mesh_terms: D000483:Alleles; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000097:blood* / Q000235:genetics / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D012307:Risk Factors; D050797:STAT4 Transcription Factor / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human