IRF5 variants associated with systemic lupus erythematosus

摘要

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type IIFN pathway. Notably, type IIFN production is regulated by a class of IFN regulatory factors (IRFs)-especially IRF5-that regulate the production of the proinflammatory cytokines following Toll-like receptor (TLR) signaling. Now, investigators demonstrate an association of a single nucleotide polymorphism (SNP) in IRF5 (rs2004640 T allele) with SLE in 4 independent case-control cohorts and by family-based transmission disequilibrium test analysis. Functionally, the rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5isoforms. In addition, the authors identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon IB splice site. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.