TNFAIP3 – Systemic Lupus Erythematosus

TNFAIP3 encodes the ubiquitin-editing enzyme A20, a critical negative regulator of NF-κB signaling. Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by multisystem inflammation and autoantibody production, with both common variant and rare monogenic contributions. TNFAIP3 loss‐of‐function and regulatory variants have been repeatedly implicated in SLE susceptibility, consistent with its central role in restraining inflammatory pathways.

Genetic evidence includes a de novo frameshift in a patient with neuropsychiatric SLE (PMID:31625129) and strong genome‐wide association signals near TNFAIP3 in multiple cohorts (rs5029939, meta-analysis P = 2.89 × 10⁻¹²; PMID:19165918; confirmed in Chinese Han, P < 5.17 × 10⁻⁴²; PMID:19838193). These findings have been replicated across ancestries and large case‐control studies, establishing a robust association.

The variant spectrum spans rare protein‐truncating alleles (e.g., c.1809del (p.Thr604fs)), coding polymorphisms (c.2117G>A (p.Arg706Gln)) and noncoding TT>A enhancer variants that modulate TNFAIP3 expression (PMID:20483768; PMID:30529365). Recurrent regulatory alleles in high linkage disequilibrium define haplotypes conferring both risk and protection across populations.

Functional assays demonstrate that A20 deficiency in patient‐derived cells and genome‐edited models results in enhanced NF-κB and MAPK pathway activation, elevated pro‐inflammatory cytokines, and impaired downregulation of immune signaling (PMID:31625129). TALEN‐mediated knockout of the TNFAIP3 enhancer recapitulates reduced TNFAIP3 expression and sustained NF-κB signaling, directly linking candidate causal variants to gene dysregulation (PMID:26821284).

The pathogenic mechanism is haploinsufficiency: heterozygous loss or insufficient expression of A20 fails to terminate NF-κB–driven inflammation and promotes inflammasome hyperactivation. In a systematic review of 191 HA20 patients, 16 (8.4 %) met SLE criteria with early onset, multiorgan involvement, and heightened inflammatory markers (PMID:39672252).

Integration of genetic and experimental data supports a Strong clinical validity of the TNFAIP3–SLE association with Moderate genetic and functional evidence. TNFAIP3 genotyping may inform diagnosis of monogenic SLE, risk stratification, and targeted anti-inflammatory therapies. Key Take-home: TNFAIP3 haploinsufficiency and common regulatory variants converge on NF-κB dysregulation to drive SLE pathogenesis, providing a clinically actionable genetic marker.

References

• Journal of clinical immunology • 2019 • A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus Erythematosus PMID:31625129
• Nature genetics • 2008 • Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus PMID:19165918
• Nature genetics • 2009 • Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus PMID:19838193
• Journal of immunology (Baltimore, Md. : 1950) • 2010 • African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity PMID:20483768
• Human immunology • 2019 • Functional variants of TNFAIP3 are associated with systemic lupus erythematosus in a cohort of Chinese Han population PMID:30529365
• Genes and immunity • 2016 • TALEN-mediated enhancer knockout influences TNFAIP3 gene expression and mimics a molecular phenotype associated with systemic lupus erythematosus PMID:26821284
• Autoimmunity reviews • 2025 • A20 haploinsufficiency diagnosis beyond systemic lupus erythematosus: A systematic review of the literature PMID:39672252

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