IRAK1 – Systemic Lupus Erythematosus

Interleukin-1 receptor-associated kinase 1 (IRAK1) is a key signaling molecule downstream of Toll-like receptors (TLRs) and the interleukin-1 receptor, implicated in innate immune activation in systemic lupus erythematosus (SLE). Genetic association studies across diverse populations have repeatedly identified IRAK1 variants as risk factors for SLE, consistent with the female predominance of this X-linked locus.

In a Chinese Han case–control cohort of 667 SLE patients and 667 matched healthy controls, the IRAK1 single-nucleotide polymorphisms rs3027898 (C allele vs A: OR = 1.438, 95% CI = 1.180–1.750, p < 0.001) and rs1059702 (A allele vs G: OR = 1.383, 95% CI = 1.143–1.674, p = 0.001) were significantly associated with increased SLE risk, and rs3027898 C correlated with reduced oral ulcer prevalence ([PMID:23435933]).

Fine-mapping of the Xq28 locus in 15 783 SLE cases and controls from four ancestral groups identified six SNPs in the TMEM187-IRAK1-MECP2 region with genome-wide significance (p < 5×10⁻⁸). Conditional analyses pinpointed rs1059702 as the most likely causal variant (p_meta = 1.3×10⁻²⁷, OR = 1.43), encoding p.Ser196Phe in IRAK1 and enhancing NF-κB activation in vitro, while also modulating MECP2 expression ([PMID:22904263]).

A combined human and mouse genetic study confirmed IRAK1 as an SLE risk gene: five SNPs across IRAK1 showed association (P ≤ 10⁻¹⁰, OR > 1.5) in adult and childhood-onset SLE across four ethnicities; congenic mice bearing Sle1 or Sle3 loci lacking IRAK1 exhibited abrogation of autoantibody production, lymphocyte activation, and renal pathology, and reversed dendritic cell hyperactivity ([PMID:19329491]).

No formal segregation analyses in families have been reported for IRAK1 variants in SLE; however, the reproducibility across independent cohorts and ethnicities, combined with functional knockout data, provide robust evidence for a causal role of IRAK1 in SLE susceptibility.

Mechanistically, the p.Ser196Phe variant increases IRAK1 kinase-mediated NF-κB signaling, and genetic ablation of IRAK1 in lupus-prone mice reverses hallmark disease features, supporting a gain-of-function pathogenic mechanism. IRAK1 thus represents both a genetic biomarker and a putative drug target in SLE.

Key Take-home: X-linked IRAK1 variants, notably p.Ser196Phe, are strongly and reproducibly associated with SLE risk across ancestries, and functional studies confirm IRAK1 as a critical mediator of lupus pathogenesis, highlighting its utility for diagnosis and therapeutic targeting.

References

• Inflammation Research • 2013 • Association of interleukin-1 receptor-associated kinase (IRAK1) gene polymorphisms (rs3027898, rs1059702) with systemic lupus erythematosus in a Chinese Han population PMID:23435933
• Annals of the Rheumatic Diseases • 2013 • Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups PMID:22904263
• Proceedings of the National Academy of Sciences of the United States of America • 2009 • Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus PMID:19329491

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