Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression

Abstract

Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.

Association ofinterleukin-10gene single nucleotide polymorphisms with rheumatoid arthritis in a Chinese population

“…One previous study showed that serum IL-10 levels were positively correlated with the presence in serum of RF and anti-CCP antibodies in RA patients 24. Similar studies have also been conducted in other autoimmune diseases such as systemic lupus erythematosus (SLE),28 29 and showed that serum IL-10 levels in SLE patients were positively related to increased disease activity 30. Interindividual variability in IL-10 expression is affected by genetic variance, and so IL-10 gene polymorphisms might affect its expression and activity, and thereby influence RA pathogenesis.…”

Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

“…SNP genotypes that met the quality control criteria8 were included for association tests. Subjects with missing genotype rates >10% shared identity by descent >0.4, gender mismatch or genetic outliers (estimated using principal components analysis and ADMIXMAP9 10) were removed, resulting in 15 292 unrelated subjects with clean data.…”

Advances in lupus genetics and epigenetics

“…Our group has identified an IL10 upstream SNP that tags a risk haplotype associated with SLE in European population [36 ▪▪ ]. The SLE-risk allele is associated with increased IL10 expression by preferentially binds to the phosphorylated transcription factor Elk-1.…”