As a follow up to our previous genetic studies both in childhood-onset and adult-onset SLE, our goal is to identify major genetic risk factors in novel genes and characterize the causal mutations and the mechanisms of disease involvement of these new genes. For the purpose of these studies we have assembled an unparalleled study population of 6,500 adult-onsets and 1,100 childhood-onset cases of SLE and a large multidisciplinary collaborative team of investigators. Based on Bayesian methodology, we developed a gene selection tool to increase the power of genetic association studies, and we devised a novel microarray platform to discover susceptibility genes contributing to SLE. We tested our model in a cohort of childhood-onset SLE families and replicated the results in a second much larger childhood-onset SLE cohort and a very large cohort of adult onset SLE. We propose to identify the causal variants in the following new genes:
F AIM, IRAK1, KLRG1, TNFSF4, TLR8 and SELP by fine mapping, re-sequencing and re-evaluation of the new SNPs identified through sequencing in case-control association studies in four different ethnicities in both childhood-onset and adult-onset cohorts. Based on the variants and causal haplotype blocks found, we will conduct hypothesis-based analyses in clinical sub-phenotypes of SLE. Finally we will conduct functional studies toward understanding the mechanisms through which the genetic variants discovered and characterized in sub-phenotypes of SLE may be involved in the causation or perpetuation of SLE. We anticipate that these studies will identify novel gene variants, especially those that are common to several ethnic groups and to both childhood- and adult-onset SLE. Results of these association studies will lead to the molecular characterization of their effects on the gene products and an understanding of the role of these genes in the pathogenesis of SLE. Knowledge gained from these studies will reveal new paradigms and open promising new directions in the understanding and ultimately the treatment of this devastating disorder.

Public Health Relevance

SLE or lupus is a devastating human disease affecting mainly females and is responsible for significant morbidity and suffering to hundreds of thousands of patients within USA. The disease is caused by interacting genetic and environmental factors. The discovery and characterization of the genetic factors which are the goals of this study are crucial for the understanding of the pathology of the disease and will result in novel targets and therapies for this devastating condition.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Wang, Yan Z
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University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Armstrong, D L; Zidovetzki, R; Alarcón-Riquelme, M E et al. (2014) GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region. Genes Immun 15:347-54
Manku, Harinder; Langefeld, Carl D; Guerra, Sandra G et al. (2013) Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4. PLoS Genet 9:e1003554
Namjou, Bahram; Kim-Howard, Xana; Sun, Celi et al. (2013) PTPN22 association in systemic lupus erythematosus (SLE) with respect to individual ancestry and clinical sub-phenotypes. PLoS One 8:e69404
Deng, Yun; Zhao, Jian; Sakurai, Daisuke et al. (2013) MicroRNA-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus. PLoS Genet 9:e1003336
Kaufman, Kenneth M; Zhao, Jian; Kelly, Jennifer A et al. (2013) Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups. Ann Rheum Dis 72:437-44
Sakurai, Daisuke; Zhao, Jian; Deng, Yun et al. (2013) Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression. PLoS Genet 9:e1003870