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Identification of new SLE-associated genes with a two-step Bayesian study design
Armstrong, D L,Reiff, A,Myones, B L,Quismorio Jr, F P,Klein-Gitelman, M,McCurdy, D,Wagner-Weiner, L,Silverman, E,Ojwang, J O,Kaufman, K M,Kelly, J A,Merrill, J T,Harley, J B,Bae, S-C,Vyse, T J,Gilkeso Macmillan Publishers Limited 2009 GENES AND IMMUNITY Vol.10 No.5
In our earlier study, we utilized a Bayesian design to probe the association of ∼1000 genes (∼10 000 single-nucleotide polymorphisms (SNPs)) with systemic lupus erythematosus (SLE) on a moderate number of trios of parents and children with SLE. Two genes associated with SLE, with a multitest-corrected false discovery rate (FDR) of <0.05, were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In this report, using a large population of controls and adult- or childhood-onset SLE cases, we have extended the earlier investigation to explore the SLE association of 10 of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit a significant (FDR<0.05) association with SLE, both confirming some genes that have earlier been found to be associated with SLE (PTPN22 and IRF5) and presenting novel findings of genes (KLRG1, interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR)8 and CASP10), which have not been reported earlier. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.Genes and Immunity (2009) 10, 446–456; doi:10.1038/gene.2009.38; published online 14 May 2009
Jacob, Chaim O,Zhu, Jiankun,Armstrong, Don L,Yan, Mei,Han, Jie,Zhou, Xin J,Thomas, James A,Reiff, Andreas,Myones, Barry L,Ojwang, Joshua O,Kaufman, Kenneth M,Klein-Gitelman, Marisa,McCurdy, Deborah,Wa National Academy of Sciences 2009 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.106 No.15
<P>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.</P>