IRF5 – Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by elevated type I interferon (IFN) production and multi-organ involvement. Interferon regulatory factor 5 (IRF5) encodes a transcription factor that drives type I IFN and pro-inflammatory cytokine expression; genetic variants in IRF5 have been robustly associated with SLE across diverse populations and ethnicities. Early candidate-gene studies in Scandinavian cohorts (679 cases, 438 controls) identified IRF5 SNPs with joint linkage and association signals (unadjusted P<10⁻⁷) implicating IRF5 as an SLE susceptibility gene (PMID:15657875).

Subsequent case-control analyses in 1,829 African-American and 3,041 Caucasian subjects replicated associations for rs2004640 and rs3807306, with conditional analyses pinpointing rs3807306 as the primary driver in African Americans (PMID:18288123). A comprehensive evaluation in 485 Swedish cases and 563 controls uncovered 16 associated SNPs and two length polymorphisms, including a CGGGG indel and rs10488631 (P1.4), defining independent risk haplotypes (PMID:18063667).

Large-scale genome-wide association studies (GWAS) further confirmed IRF5 among seven established loci in Chinese Han (1,047 cases, 1,205 controls; P_combined6,400 cases; n>7,400 controls) demonstrated a pooled OR of 1.41 (95% CI 1.34–1.49) for rs2004640 and OR 1.23 (95% CI 1.08–1.39) for rs10954213 in Europeans (PMID:21834935).

Functional assays have provided concordant evidence: SLE risk haplotypes correlate with enhanced IRF5 mRNA and protein expression in patient blood cells, driven by rs2004640-mediated promoter usage, CGGGG indel effects on SP1 binding, and rs10954213-dependent polyadenylation (PMID:20112383). Electrophoretic mobility shift assays and luciferase reporter studies confirmed allele-specific transcription factor binding at exon 1 and exon 6 regulatory regions (PMID:17393452).

Murine models furnish experimental concordance with human data: IRF5 knockout in FcgammaRIIB⁻/⁻Yaa and MRL/lpr lupus models completely abrogates autoantibody production and tissue pathology, demonstrating an obligate requirement for IRF5 in SLE pathogenesis (PMID:20007534). Dominant-negative IRF5 variants impair MyD88-mediated transactivation and downstream cytokine induction, underscoring the functional importance of IRF5 integrity (PMID:19430534).

The convergence of extensive genetic association, replicated across ancestries, robust functional validation in patient cells, and definitive animal model data meets ClinGen criteria for a Definitive gene–disease relationship. IRF5 variant analysis enhances diagnostic risk stratification and highlights the type I IFN pathway as a therapeutic axis in SLE.

References

• American Journal of Human Genetics • 2005 • Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. PMID:15657875
• Genes and Immunity • 2008 • Interferon regulatory factor-5 is genetically associated with systemic lupus erythematosus in African Americans. PMID:18288123
• Human Molecular Genetics • 2008 • Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus. PMID:18063667
• Nature Genetics • 2009 • Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. PMID:19838193
• International Journal of Immunogenetics • 2011 • A meta-analysis of the association of IRF5 polymorphism with systemic lupus erythematosus. PMID:21834935
• Arthritis and Rheumatism • 2010 • Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus. PMID:20112383
• Journal of Immunology • 2010 • IFN regulatory factor 5 is required for disease development in the FcgammaRIIB-/-Yaa and FcgammaRIIB-/- mouse models of systemic lupus erythematosus. PMID:20007534
• PLoS One • 2009 • Functional analysis of a dominant negative mutation of interferon regulatory factor 5. PMID:19430534

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