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.
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Acknowledgements
SN Kariuki—HHMI Gilliam Fellowship for Advanced Study; AT Reder—National MS Society RG#4509A/2; TB Niewold—Research grants from the NIH (R01 AR060861, K08 AI083790, P30 DK42086, Clinical Research Loan Repayment AI071651, CTSA Pilot Grant from UL1 RR024999), Lupus Research Institute Novel Research Grant and Alliance for Lupus Research Target Identification in Lupus Grant.
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Chrabot, B., Kariuki, S., Zervou, M. et al. Genetic variation near IRF8 is associated with serologic and cytokine profiles in systemic lupus erythematosus and multiple sclerosis. Genes Immun 14, 471–478 (2013). https://doi.org/10.1038/gene.2013.42
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DOI: https://doi.org/10.1038/gene.2013.42
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