UBE2L3 – Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by multi-organ inflammation and autoantibody production. UBE2L3 encodes the E2 ubiquitin-conjugating enzyme UBCH7, which regulates NF-κB activation and immune cell function. Early candidate gene studies and genome-wide association studies (GWAS) have implicated UBE2L3 variants in SLE susceptibility across ethnicities.

The association of UBE2L3 with SLE was first replicated in European cohorts by the GAPAID consortium, where SNP rs5754217 demonstrated a significant risk for skin involvement in 208 patients versus 152 controls (PMID:27021335). Subsequent GWAS meta-analysis in Han Chinese (1,659 cases, 3,398 controls) identified rs2298428 as the top risk allele (P_meta=2.70×10⁻⁹) with consistent replication in 4,935 additional subjects (joint P_all=1.31×10⁻¹¹) (PMID:25880549).

Cross-phenotype analyses integrating IgA nephropathy (1,180 cases, 899 controls) and SLE (1,639 cases, 2,410 controls) highlighted UBE2L3 among shared loci, with eQTL data confirming higher UBE2L3 expression in risk allele carriers (PMID:34076728). A Korean GWAS meta-analysis (400 + 1,196 patients, 445 + 2,085 controls) further validated UBE2L3 as an SLE locus common to Asian and Caucasian populations (PMID:23740238).

Functional exploration of the SLE-associated haplotype revealed that the risk allele (T) of rs2298428 correlates with increased UBE2L3 mRNA and UBCH7 protein levels in immune cells, establishing a cis-eQTL effect consistent with elevated proinflammatory signaling (PMID:22476155).

Epistasis studies demonstrated that UBE2L3 rs131654 interacts synergistically with TNFAIP3 rs2230926 to modulate NF-κB activity and cytokine production in B cells, providing mechanistic evidence of gene-gene interaction in SLE pathogenesis (PMID:32334614).

Recent high-resolution chromatin assays mapped allele-specific effects of the UBE2L3/YDJC risk haplotype, revealing enhanced YY1-mediated promoter looping and loss of CTCF binding that upregulate UBE2L3 transcription in B cells (PMID:34279042).

Collectively, genetic and functional data consistently support UBE2L3 as a strong susceptibility gene for SLE, acting through increased expression and dysregulated NF-κB signaling. UBE2L3 genotype could inform risk stratification and targeted modulation of ubiquitin pathways in SLE management.

References

• Clinical rheumatology • 2016 • Genetic association study of systemic lupus erythematosus and disease subphenotypes in European populations. PMID:27021335
• Arthritis research & therapy • 2015 • Meta-analysis of two Chinese populations identifies an autoimmune disease risk allele in 22q11.21 as associated with systemic lupus erythematosus. PMID:25880549
• Molecular genetics and genomics : MGG • 2021 • Shared genetic study gives insights into the shared and distinct pathogenic immunity components of IgA nephropathy and SLE. PMID:34076728
• Annals of the rheumatic diseases • 2014 • Ethnic specificity of lupus-associated loci identified in a genome-wide association study in Korean women. PMID:23740238
• Genes and immunity • 2012 • A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. PMID:22476155
• Arthritis research & therapy • 2020 • Synergistic activation of NF-κB by TNFAIP3 (A20) reduction and UBE2L3 (UBCH7) augment that synergistically elevate lupus risk. PMID:32334614
• Arthritis & rheumatology • 2022 • Variants on the UBE2L3/YDJC Autoimmune Disease Risk Haplotype Increase UBE2L3 Expression by Modulating CCCTC-Binding Factor and YY1 Binding. PMID:34279042

Evidence Based Scoring (AI generated)