In 27 years, ?Genetic Linkage with Lupus? (AI024717) has contributed >300 publications to genetics and other phenomena of Systemic Lupus Erythematosus (SLE) and related disorders. There are 53 published SLE risk loci being intensively studied by a small community of dedicated scholars and another ~70 SLE risk loci to be published soon. SLE cannot be fully understood or therapies and preventions designed using these insights until the mechanisms are known explaining why these genetic associations exist. Since regulatory regions dominate as SLE risk loci, we reasoned that there could be shared relationships among SLE risk loci with individual gene regulatory proteins (GRPs) encoded not only by the human host but also by Epstein-Barr virus, the best candidate for SLE etiology. If so, then mechanistic studies would be compellingly important. We found a shared set of about 23 mostly known inflammatory process gene regulatory proteins (GRPs) binding to DNA sequences in transformed B cell lines at as many as half (26 of 53) of the SLE risk loci with effect magnitudes substantially larger than any individual genetic association (4p>10-42). Many of the shared set of GRPs are also associated with Epstein-Barr virus (EBV) infection and transformation of human B cells, including an EBV encoded gene product. Our preliminary data suggest that there are shared SLE generating mechanisms operating across multiple loci, providing fundamental and novel molecular interactions for etiologic understanding and therapeutic intervention. The newly discovered relationships are with loci and not alleles. Genetic associations are with alleles. If the shared set is directly relevant to disease risk, then allelic differences must be present.
In Aim 1 we propose to concentrate AI24717- 28 to -32A1 on characterizing models of the shared set of GRPs by systems biology approaches and new technology applications including, the generation of credible sets at select SLE risk loci, the measurement of the ratio of allele specific DNA sequences bound by selected GRPs, GRP DNA binding motifs, addition of other regulatory molecules such as microRNAs and long-noncoding RNAs, and incorporation of newly discovered SLE risk loci in an effort to improve on the present model of GRP association with SLE loci.
In Aim 2 we will experimentally establish the structure of the regulatory complex and relate this to allelic differences in SLE risk gene expression at specific loci. We will apply standard methods of electrophoretic mobility shift assays (EMSAs), DNA affinity precipitation assays (DAPAs), Western blot, chromatin immunoprecipitation (ChIP-Seq & ChIP-qPCR), and mass spectrometry. We will generate chromatin manipulated cell lines to establish structure and allelic differences and the role of EBV. We will identify the molecular interactions required to form the postulated shared regulatory complex, thereby providing inviting targets for therapeutic innovation. If successful, this project will define a regulatory complex shared among multiple SLE risk loci and provide the molecular details and insights needed to alter this structure and its activity with therapeutic intervention.

Public Health Relevance

There are more than 50 genes that convincingly contribute to the risk of systemic lupus erythematosus (SLE), most of which are located in regions of the human genome that control gene expression. We have found a set of inflammatory gene regulatory proteins that bind about half of the published SLE risk genes. This project will characterize the relationships between SLE disease risk genes and the binding of gene regulatory proteins; we will evaluate how the gene regulatory proteins interact with the specific DNA differences important in SLE to change gene expression in ways that alter disease risk for SLE.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Johnson, David R
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Cincinnati Children's Hospital Medical Center
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Harley, John B; Chen, Xiaoting; Pujato, Mario et al. (2018) Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity. Nat Genet 50:699-707
Patel, Zubin; Lu, Xiaoming; Miller, Daniel et al. (2018) A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum Mol Genet :
Kheir, Joseph M; Guthridge, Carla J; Johnston, Jonathon R et al. (2018) Unique clinical characteristics, autoantibodies and medication use in Native American patients with systemic lupus erythematosus. Lupus Sci Med 5:e000247
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Aberle, Teresa; Bourn, Rebecka L; Munroe, Melissa E et al. (2017) Clinical and Serologic Features in Patients With Incomplete Lupus Classification Versus Systemic Lupus Erythematosus Patients and Controls. Arthritis Care Res (Hoboken) 69:1780-1788

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