Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo.
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.
Kariuki
Silvia N
SN
Section of Rheumatology, University of Chicago, Chicago, IL 60637, USA.
Kirou
Kyriakos A
KA
MacDermott
Emma J
EJ
Barillas-Arias
Lilliana
L
Crow
Mary K
MK
Niewold
Timothy B
TB
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
C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human