Identification ofIRAK1as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus

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Abstract
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 ≈5,000 subjects and healthy controls, 5 SNPs spanning theIRAK1gene showed disease association (Pvalues 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:Sle1orSle3. 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 withSle3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establishIRAK1as 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.