Genetic variation near IRF8 is associated with serologic and cytokine profiles in systemic lupus erythematosus and multiple sclerosis

• Published in: Genes and immunity Vol. 14; no. 8; pp. 471 - 478
• Main Authors: Chrabot, B S, Kariuki, S N, Zervou, M I, Feng, X, Arrington, J, Jolly, M, Boumpas, D T, Reder, A T, Goulielmos, G N, Niewold, T B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2013; Nature Publishing Group
• Subjects: 631/208/205; 631/208/726/649; 631/250/249/1313/1613; 631/250/249/1313/1666; Alleles; Anti-DNA antibodies; Autoantibodies; Autoantibodies - immunology; Autoimmune diseases; Biomedical and Life Sciences; Biomedicine; Cancer Research; Case-Control Studies; Cytokines; DNA - immunology; Gene Expression; Genes; Genetic aspects; Genetic diversity; Genetic variation; Human Genetics; Humans; Identification and classification; Immunological tolerance; Immunology; Interferon; Interferon Regulatory Factors - genetics; Interferon Type I - blood; Lupus; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lymphocytes B; Multiple sclerosis; Multiple Sclerosis - blood; Multiple Sclerosis - genetics; Multiple Sclerosis - immunology; original-article; Peripheral blood; Polymorphism, Single Nucleotide; Regression analysis; Rheumatology; Systemic lupus erythematosus; Transcription factors; United States > US; Crete; Chicago Illinois; type I interferon; interferon regulatory factors; systemic lupus erythematosus; autoantibodies
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2013.42

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.