Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus

Chaim O. Jacob, Jiankun Zhu, Don L. Armstrong, Mei Yan, Jie Han, Xin J. Zhou, James A. Thomas, Andreas Reiff, Barry L. Myones, Joshua O. Ojwang, Kenneth M. Kaufman, Marisa Klein-Gitelman, Deborah McCurdy, Linda Wagner-Weiner, Earl Silverman, Julie Ziegler, Jennifer A. Kelly, Joan T. Merrill, John B. Harley, Rosalind Ramsey-GoldmanLuis M. Vila, Sang Cheol Bae, Timothy J. Vyse, Gary S. Gilkeson, Patrick M. Gaffney, Kathy L. Moser, Carl D. Langefeld, Raphael Zidovetzki, Chandra Mohan

Research output: Contribution to journalArticle

174 Scopus citations

Abstract

A combined forward and reverse genetic approach was undertaken to test the candidacy of IRAKI (interleukin-1 receptor associated kinase-1) as an X chromosome-encoded risk factor for systemic lupus erythematosus (SLE). In studying ≈5,000 subjects and healthy controls, 5 SNPs spanning the IRAKI gene showed disease association (P values reaching 10 -10, odds ratio >1.5) in both adult- and childhood-onset SLE, in 4 different ethnic groups, with a 4 SNP haplotype (GGGG) being strongly associated with the disease. The functional role of IRAKI was next examined by using congenic mouse models bearing the disease loci: Sle1 or Sle3. IRAKI deficiency abrogated all lupus-associated phenotypes, including IgM and IgG autoantibodies, lymphocytic activation, and renal disease in both models. In addition, the absence of IRAKI reversed the dendritic cell "hyperactivity" associated with Sle3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establish IRAK 1 as a disease gene in lupus, capable of modulating at least 2 key checkpoints in disease development. This demonstration of an X chromosome gene as a disease susceptibility factor in human SLE raises the possibility that the gender difference in SLE may in part be attributed to sex chromosome genes.

Original languageEnglish (US)
Pages (from-to)6256-6261
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number15
DOIs
StatePublished - Apr 14 2009

Keywords

  • Autoimmune disease
  • Genetic association
  • Inflammation
  • Interferon
  • SNP

ASJC Scopus subject areas

  • General

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    Jacob, C. O., Zhu, J., Armstrong, D. L., Yan, M., Han, J., Zhou, X. J., Thomas, J. A., Reiff, A., Myones, B. L., Ojwang, J. O., Kaufman, K. M., Klein-Gitelman, M., McCurdy, D., Wagner-Weiner, L., Silverman, E., Ziegler, J., Kelly, J. A., Merrill, J. T., Harley, J. B., ... Mohan, C. (2009). Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proceedings of the National Academy of Sciences of the United States of America, 106(15), 6256-6261. https://doi.org/10.1073/pnas.0901181106