Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA.
Genes Immun. 2013 Dec;14(8):471-8. doi: 10.1038/gene.2013.42. Epub 2013 Aug 22.
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.
干扰素（IFN）调节因子 8（IRF8）的等位基因与系统性红斑狼疮（SLE）和多发性硬化症（MS）的易感性有关。虽然认为高类型 I IFN 是 SLE 的病因，但在 MS 中使用 I 型 IFN 作为治疗方法。我们研究了 IRF8 等位基因是否与 SLE 和 MS 中的 I 型 IFN 水平或血清学特征相关。在 SLE 和 MS 患者中对先前与 SLE 或 MS 相关的等位基因进行了基因分型。与 MS 相关的 rs17445836G 等位基因与 SLE 患者的抗双链 DNA（dsDNA）自身抗体相关（荟萃分析优势比=1.92）。相同的等位基因与抗 dsDNA 抗体的 SLE 患者血清 IFN 活性降低以及抗 dsDNA 阴性 SLE 患者外周血单个核细胞中 I 型 IFN 诱导基因表达降低有关。在继发性进展性 MS 患者中，rs17445836G 与血清 I 型 IFN 降低有关。rs17445836G 与 SLE 患者 B 细胞中 IRF8 表达增加有关。总之，IRF8 rs17445836G 与以低 I 型 IFN 水平为特征的人类自身免疫性疾病相关，这可能具有药物遗传学相关性，因为 SLE 和 MS 中调节了 I 型 IFN。与自身抗体和 B 细胞中 IRF8 表达增加的关联支持 rs17445836G 在体液免疫耐受中的作用。
