Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus.
A combined forward and reverse genetic approach was undertaken to test the candidacy of IRAK1 (interleukin-1 receptor associated kinase-1) as an X chromosome-encoded risk factor for systemic lupus erythematosus (SLE). In studying approximately 5,000 subjects and healthy controls, 5 SNPs spanning the IRAK1 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 IRAK1 was next examined by using congenic mouse models bearing the disease loci: Sle1 or Sle3. IRAK1 deficiency abrogated all lupus-associated phenotypes, including IgM and IgG autoantibodies, lymphocytic activation, and renal disease in both models. In addition, the absence of IRAK1 reversed the dendritic cell "hyperactivity" associated with Sle3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establish IRAK1 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.
Jacob
Chaim O
CO
The Lupus Genetic Group, Department of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA. jacob@usc.edu
Zhu
Jiankun
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Armstrong
Don L
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Yan
Mei
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Han
Jie
J
Zhou
Xin J
XJ
Thomas
James A
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Reiff
Andreas
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Myones
Barry L
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Ojwang
Joshua O
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Kaufman
Kenneth M
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Klein-Gitelman
Marisa
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McCurdy
Deborah
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Wagner-Weiner
Linda
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Silverman
Earl
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Ziegler
Julie
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Kelly
Jennifer A
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Merrill
Joan T
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Harley
John B
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Ramsey-Goldman
Rosalind
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Vila
Luis M
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Bae
Sang-Cheol
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Vyse
Timothy J
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Gilkeson
Gary S
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Gaffney
Patrick M
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Moser
Kathy L
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Langefeld
Carl D
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Zidovetzki
Raphael
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Mohan
Chandra
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