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Cutting Edge: Autoimmune Disease Risk Variant of STAT4 Confers Increased Sensitivity to IFN- in Lupus Patients In Vivo¹

Silvia N. Kariuki^*, Kyriakos A. Kirou, Emma J. MacDermott, Lilliana Barillas-Arias, Mary K. Crow and Timothy B. Niewold^2,*

^* Section of Rheumatology, University of Chicago, Chicago, IL 60637; and Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, NY 10021

Increased IFN- signaling is a primary pathogenic factor in systemic lupus erythematosus (SLE). STAT4 is a transcription factor that is activated by IFN- signaling, and genetic variation of STAT4 has been associated with risk of SLE and rheumatoid arthritis. We measured serum IFN- activity and simultaneous IFN--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- activity and greater IFN--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- signaling. The IFN regulatory factor 5 SLE risk genotype was associated with higher serum IFN- activity; however, STAT4 showed dominant influence on the sensitivity of PBMC to serum IFN-. These data provide biologic relevance for the risk variant of STAT4 in the IFN- pathway in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI059893, Alliance for Lupus Research, Mary Kirkland Center for Lupus Research, and Lupus Research Institute (all to M.K.C.) and by National Institutes of Health Clinical and Translational Science Awards K12 Scholar Award RR025000-02, National Institute of Allergy and Infectious Diseases Clinical Research Loan Repayment Grant AI071651, Arthritis Foundation Post-Doctoral Fellowship Award, and Arthritis National Research Foundation Scholar Award (all to T.B.N.).

² Address correspondence and reprint requests to Dr. Timothy B. Niewold, University of Chicago, Section of Rheumatology, 5841 South Maryland Avenue, MC 0930, Chicago, IL 60637. E-mail address: tniewold{at}medicine.bsd.uchicago.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; IFIT, IFN-induced protein with tetratricopeptide; IRF, IFN regulatory factor; MX, myxovirus resistance; PKR, dsRNA-activated protein kinase; RBP, RNA-binding protein; SNP, single nucleotide polymorphism.

⁴ The online version of this article contains supplemental material.

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