title: Genetic variation near IRF8 is associated with serologic and cytokine profiles in systemic lupus erythematosus and multiple sclerosis.
abstract: Alleles of interferon (IFN) regulatory factor 8 (IRF8) are associated with susceptibility to both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Although high-type I IFN is thought to be causal in SLE, type I IFN is used as a therapy in MS. We investigated whether IRF8 alleles were associated with type I IFN levels or serologic profiles in SLE and MS. Alleles that have been previously associated with SLE or MS were genotyped in SLE and MS patients. The MS-associated rs17445836G allele was associated with anti-double-stranded DNA (dsDNA) autoantibodies in SLE patients (meta-analysis odds ratio=1.92). The same allele was associated with decreased serum IFN activity in SLE patients with anti-dsDNA antibodies, and with decreased type I IFN-induced gene expression in peripheral blood mononuclear cell from anti-dsDNA-negative SLE patients. In secondary progressive MS patients, rs17445836G was associated with decreased serum type I IFN. Rs17445836G was associated with increased IRF8 expression in SLE patient B cells. In summary, IRF8 rs17445836G is associated with human autoimmune disease characterized by low-type I IFN levels, and this may have pharmacogenetic relevance as type I IFN is modulated in SLE and MS. The association with autoantibodies and increased IRF8 expression in B cells supports a role for rs17445836G in humoral tolerance.
authors: Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA.
authors: B S
authors: BS
authors: Chrabot
authors: S N
authors: SN
authors: Kariuki
authors: M I
authors: MI
authors: Zervou
authors: X
authors: X
authors: Feng
authors: J
authors: J
authors: Arrington
authors: M
authors: M
authors: Jolly
authors: D T
authors: DT
authors: Boumpas
authors: A T
authors: AT
authors: Reder
authors: G N
authors: GN
authors: Goulielmos
authors: T B
authors: TB
authors: Niewold
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D016022:Case-Control Studies; D004247:DNA / Q000276:immunology; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D007370:Interferon Type I / Q000097:blood*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics* / Q000276:immunology; D009103:Multiple Sclerosis / Q000097:blood / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D000099185:Interferon Regulatory Factor-8
chemical_list: D001323:Autoantibodies; D004247:DNA; D050835:Interferon Regulatory Factors; D007370:Interferon Type I; D000099185:Interferon Regulatory Factor-8
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