TNIP1 – Systemic Lupus Erythematosus

Multiple genome-wide association studies have established TNIP1 as a susceptibility locus for systemic lupus erythematosus (SLE). A Chinese Han GWAS in 1,047 cases and 1,205 controls with replication in 3,152 cases and 7,050 controls identified TNIP1 among nine novel loci (P_combined ≤2.77×10⁻⁸) (PMID:19838193). An independent replication in 1,963 cases and 4,329 controls confirmed TNIP1 with an odds ratio of 1.27 (PMID:19838195).

Subsequent multi-ethnic fine-mapping in 8,372 SLE cases and 7,492 controls across European, African American, Hispanic, East Asian and Gullah populations identified two independent TNIP1 risk haplotypes associated with reduced TNIP1 mRNA and ABIN-1 protein levels, supporting a hypomorphic mechanism (PMID:22833143). In Caucasian cohorts, the association of TNIP1 was particularly pronounced in SLE patients with renal and immunological involvement, consistent with earlier Asian findings (PMID:23249952).

Functional characterization of the SLE-associated H1 risk haplotype demonstrated that 11 noncoding variants cumulatively suppress enhancer activity and nuclear protein binding in EBV-transformed B cells, Jurkat and THP-1 cells. Two variants (rs10057690, rs13180950) exhibited allele-specific loss of enhancer function (P3) (PMID:31804013).

In keratinocyte models, siRNA-mediated TNIP1 knockdown combined with TLR3 stimulation (poly(I:C)) led to hyperinduction of inflammasome components (ASC, procaspase-1) and wound-healing markers (S100A8, TGFβ, CCN2), yet paradoxically impaired reepithelialization and viability due to reduced phospho-A20—highlighting a regulatory role of TNIP1 in NF-κB and inflammasome pathways (PMID:32377162).

No monogenic segregation data are available for TNIP1 in SLE, reflecting a complex multifactorial inheritance. Nonetheless, the consistent replication in >12,000 cases and functional concordance of regulatory risk variants support a Moderate gene–disease validity under ClinGen criteria.

Key Take-Home: TNIP1 risk haplotypes confer moderate susceptibility to SLE via hypomorphic ABIN-1 expression driven by enhancer variants, providing potential targets for personalized risk stratification 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
• Nature Genetics • 2009 • A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. PMID:19838195
• European Journal of Human Genetics • 2013 • Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations. PMID:23249952
• Arthritis and Rheumatism • 2012 • Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus. PMID:22833143
• Arthritis & Rheumatology • 2020 • Role of Systemic Lupus Erythematosus Risk Variants With Opposing Functional Effects as a Driver of Hypomorphic Expression of TNIP1 and Other Genes Within a Three-Dimensional Chromatin Network. PMID:31804013
• Mediators of Inflammation • 2020 • Enhanced Wound Healing- and Inflammasome-Associated Gene Expression in TNFAIP3-Interacting Protein 1- (TNIP1-) Deficient HaCaT Keratinocytes Parallels Reduced Reepithelialization. PMID:32377162

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