ETS1 – Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by autoantibody production and end-organ damage. ETS1 encodes an E26 transformation-specific transcription factor involved in lymphocyte development and Th17 cell differentiation. Multiple genome-wide association studies (GWAS) have implicated common variants near ETS1 in SLE susceptibility across Asian and European populations. Concordant functional follow-up has linked risk alleles to reduced ETS1 expression and dysregulated immune signaling, supporting a pathogenic role for ETS1 variation in SLE.

A GWAS in a Chinese Han cohort (1,047 cases vs 1,205 controls) identified ETS1 among nine novel SLE loci (combined P ≤ 2.77×10⁻⁸) (PMID:19838193). Subsequent replication in 3,152 additional cases and 7,050 controls confirmed the association of the 3′-UTR SNP rs1128334 at ETS1 (P = 2.33×10⁻¹¹, OR 1.29) (PMID:20169177). Cross-ethnic validation in Caucasian cohorts (totaling >4,000 cases) demonstrated consistent direction of effect for ETS1 variants, albeit with allele frequency differences (PMID:23249952).

Fine-mapping in multi-ancestral cohorts (14,551 subjects) narrowed the causal signal to rs6590330, showing increased pSTAT1 binding to the risk allele and decreased ETS1 expression in Han Chinese B cells (PMID:25865496). Allelic expression analyses and chromatin immunoprecipitation confirmed that the risk variant perturbs transcription factor occupancy at the ETS1 promoter, linking genotype to gene dosage.

Functional studies demonstrate that ETS1 acts as a negative regulator of Th17 differentiation. SLE risk alleles correlate with elevated serum IL-17 levels in patients (n = 283), particularly those with renal involvement, dsDNA autoantibodies, or early-onset disease, suggesting a mechanistic link between ETS1 variation and pathogenic Th17 responses (PMID:23614478). Mouse knock-out models of Ets1 develop an SLE-like phenotype with autoantibody production and glomerulonephritis, recapitulating human disease features.

No studies to date have formally disputed the ETS1–SLE association. The consistency of large GWAS, replication in diverse ancestries, fine-mapping to a functional regulatory variant, and concordant in vitro and in vivo functional data provide strong support for a causal role of ETS1 in SLE pathogenesis.

Key take-home: Common regulatory variants near ETS1 confer SLE risk by reducing ETS1 expression, promoting Th17-mediated autoimmunity, and represent a potential target for precision diagnostics and therapeutic modulation.

References

• Nature Genetics • 2009 • Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. PMID:19838193
• PLoS Genetics • 2010 • Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PMID:20169177
• European Journal of Human Genetics • 2013 • Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations. PMID:23249952
• American Journal of Human Genetics • 2015 • Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. PMID:25865496
• Annals of Human Genetics • 2013 • Epistatic interaction between genetic variants in susceptibility gene ETS1 correlates with IL-17 levels in SLE patients. PMID:23614478

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