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Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by loss of self-tolerance and production of pathogenic autoantibodies. Interleukin-10 (IL-10) is a key immunoregulatory cytokine with pleiotropic effects on B cell survival, antibody production, and T cell differentiation. Dysregulated IL-10 expression contributes to the aberrant immune activation observed in SLE, making IL10 a compelling candidate risk locus. Genetic and functional data have implicated regulatory variants in the IL10 promoter and 5′ region as modifiers of SLE susceptibility.
Early case–control studies in Italian cohorts identified a microsatellite allele (IL10.G-140bp) at position ‑1100 significantly enriched in 205 SLE patients versus 631 controls (PMID:12486603) and suggested a direct role of the repeat number in disease risk. A large GWAS replication in 1 963 European cases and 4 329 controls confirmed IL10 as a genome-wide significant locus (OR 1.19, P < 5 × 10⁻⁸) alongside TNIP1, PRDM1, JAZF1 and UHRF1BP1 (PMID:19838195). Additional case–control analyses in 848 Chinese patients versus 461 controls demonstrated that the rs3024498-C allele confers a five-fold increased risk of SLE (OR 5.118, P = 0.002) and correlates with arthritis, malar rash and proteinuria (PMID:29199038). A multilocus study in 239 Italian SLE patients and 278 controls further supported association of IL10 rs3024505 with SLE susceptibility (OR 1.52, P = 0.02) (PMID:25369137).
Collectively, these independent studies across diverse populations provide replicated association of IL10 regulatory variants with SLE susceptibility. Although one Korean cohort (n = 680) found no case–control differences in IL10 promoter haplotypes, they reported IL10-592C and +955G genotypes associated with higher damage index among SLE patients (PMID:16287924). The convergence of genome-wide significance, strong effect sizes in east Asian cohorts, and phenotype-specific associations support a moderate level of genetic evidence under ClinGen criteria.
Functional characterization of the IL10 promoter variant at ‑1082 (c.-1082A>G) demonstrated allele-specific transcription factor binding and promoter activity. The -1082A allele enhances binding of ETS-like factors and Sp1, yielding a two-fold increase in reporter activity in B cells and monocytes (PMID:11964134; PMID:18843277). Furthermore, in SLE patient monocytes, up-regulation of miR-199-3p suppresses PARP-1 and activates ERK1/2, leading to increased IL-10 production (PMID:30991045). These concordant mechanistic studies substantiate the impact of non-coding IL10 variants on cytokine expression in immune cells.
No major conflicting evidence has overturned the IL10–SLE association; rather, functional assays and differential phenotype correlations have enriched our understanding of how IL10 dysregulation contributes to lupus pathogenesis. While further family-based segregation data are lacking given the polygenic nature of SLE, the cumulative data justify a moderate ClinGen classification.
In summary, IL10 promoter variants, particularly c.-1082A>G, are reproducibly associated with SLE risk and affect IL-10 expression via transcription factor binding and miRNA-mediated pathways. These insights support IL10 genotype as a potential biomarker for risk stratification and a target for precision immunomodulatory therapies.
Gene–Disease AssociationModerateMultiple well-powered case–control and GWAS studies across European and Asian cohorts demonstrating significant association of IL10 regulatory variants with SLE risk Genetic EvidenceModerateReplication in >3 000 cases, genome-wide significance in large cohorts, consistent effect of promoter and 5' variants Functional EvidenceModerateAllele-specific transcription factor binding at c.-1082A>G and miRNA-PARP1-ERK1/2 mediated regulation concordantly modulate IL-10 expression |