THU0026 Genetic Variation Near IRF8 is Associated with Serologic and Cytokine Profiles in Systemic Lupus Erythematosus and Multiple Sclerosis

Abstract

Background Alleles of IRF8 have been associated with susceptibility to both systemic lupus erythematosus (SLE) and multiple sclerosis (MS). While type I interferon (IFN) is thought to be causal in SLE, type I IFN is used as a therapy in MS. Objectives We investigated whether the IRF8 alleles were associated with differences in serum IFN in SLE or MS. Methods Single nucleotide polymorphisms (SNPs) in IRF8 (associated with SLE and MS respectively) were genotyped in 627 SLE patients of African-American, European-American, and Cretan origin, 73 MS patients, and matched controls. Serum type I IFN was measured using a functional reporter cell assay. Results The MS-associated rs17445836 G allele was associated with the presence of anti-dsDNA autoantibodies in SLE patients across all ancestral backgrounds (meta-analysis OR=1.92). The same allele was associated with decreased serum IFN activity in SLE patients with anti-dsDNA antibodies, and the subgroup of MS patients with secondary progressive MS. The rs17445836 G allele was associated with decreased type I IFN-induced gene expression in PBMC from SLE patients who lacked anti-dsDNA antibodies. No associations were observed with the rs12444486 allele. Conclusions The rs17445836 G allele was associated with decreased type I IFN responses in both SLE and MS patients. The association of this allele with low IFN SLE and with MS, a condition characterized by low circulating type I IFN levels, suggests that this allele is associated with autoimmunity in the setting of low type I IFN levels. These data also suggest a role for this allele in humoral autoimmune responses. Disclosure of Interest None Declared