4.6 Article

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

Journal

PLOS GENETICS
Volume 9, Issue 10, Pages -

Publisher

PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003870

Keywords

-

Funding

  1. US National Institutes of Health [R01AR043814, P30AR48311, R01CA141700, RC1AR058621, P01AI083194, P01AR049084, R01AR33062, K24AR002138, P602AR30692, UL1RR025741, R01AR43727, P01AR052915, U01AI090909]
  2. Lupus Research Institute
  3. Alliance for Lupus Research grants
  4. U.S. Department of Defense [PR094002]
  5. US Department of Veterans Affairs
  6. Arthritis National Research Foundation
  7. Charles Barkley Research Award
  8. Ministry for Health and Welfare, Republic of Korea [A120404]
  9. Swedish Research Council of Medicine
  10. Arthritis Research UK
  11. Arthritis Foundation
  12. National Center for Advancing Translational Sciences (NCATS) [UL1RR025014-02, UL1TR000165, UL1RR025005]
  13. National Center for Research Resources (NCRR) component of the National Institutes of Health (NIH)
  14. Kirkland Scholar Award
  15. Federico Wilhelm Agricola Foundation
  16. Wake Forest University Health Sciences Center for Public Health Genomics
  17. MKE/KEIT [10035615]
  18. UCLA Clinical and Translational Science Institute (CTSI) [UL1RR033176, UL1TR000124]
  19. US NIH [R01AR057172, R01AI063274, RC2AR058959, R01AR043274, P30AR053483, P30GM103510, U19AI082714, U01AI101934, P60AR049459, UL1RR029882, K08AI083790, L30AI071651, UL1RR024999, P60AR053308, UL1TR000004, R01AR051545-01A2, R21AI070304, 1R01AR054459]
  20. Korea Evaluation Institute of Industrial Technology (KEIT) [10035615] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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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 = 2.7x10(-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.

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