Genetic variants and disease‐associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus

Abstract

Objective Genetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF‐5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF‐5 expression and the IRF5 risk haplotype in SLE patients. Methods IRF‐5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real‐time polymerase chain reaction, minigene assay, and flow cytometry. Single‐nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype. Results IRF‐5 expression and alternative splicing were significantly up‐regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression. Conclusion This study provides the first formal proof that IRF‐5 expression and alternative splicing are significantly up‐regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF‐5 transcript and protein expression in patients with SLE.