Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Background:

• Interleukin-10 (IL-10) is an immunoregulatory cytokine elevated in systemic lupus erythematosus (SLE) patients, correlating with disease activity.
• Previous studies established an association between IL-10 and autoimmune diseases, prompting further investigation into causal variants and mechanisms.

Purpose of the Study:

• To fine-map causal variants within the IL10 gene cluster associated with SLE.
• To explore the underlying molecular mechanisms by which these variants influence IL-10 expression and SLE risk.

Main Methods:

• Genomic association studies of 19 tag SNPs across the IL10 gene cluster in 15,533 subjects from four ancestries.
• SNP imputation and electrophoretic mobility shift assays (EMSA) to identify causal variants and transcription factor binding.
• Analysis of IL-10 mRNA and protein levels, and phosphorylated Elk-1 (p-Elk-1) in peripheral blood mononuclear cells (PBMCs) from SLE patients.

Main Results:

• The IL10 variant rs3024505 showed the strongest association with SLE in European Americans (EA) (P=2.7×10⁻⁸).
• SNP imputation identified rs3122605 (upstream of IL10) as a likely causal variant, where the risk allele (G) is dose-dependently associated with elevated IL-10 mRNA and protein.
• Electrophoretic mobility shift assays revealed specific binding of transcription factor Elk-1 to the rs3122605-G allele, and increased p-Elk-1 levels correlated with SLE disease activity.

Conclusions:

• The IL10 variant rs3122605, through preferential binding of activated Elk-1, upregulates IL-10 expression.
• This mechanism confers an increased risk for SLE in European Americans, highlighting a specific genetic pathway in disease pathogenesis.