Of the many genes recently discovered to be associated with Systemic Lupus Erythematosus the haplotype in STAT4 is among the most powerful outside the HLA region. STAT4 is an important inflammatory transcription factor with the level in the cell determining the magnitude of the response to the genes that STAT4 controls. This association is curious because it is localized in the fourth intron and the biological relevance of the relationship of this piece of DN to the function or activity of STAT4 is poorly understood. Our preliminary together with recent literature show that the risk allele expresses a higher level of STAT4 mRNA and protein and leads to increased sensitivity to Interferon-? (IFN-?). The variant causing the association with lupus in STAT4 is located in a 55.5kb haplotype. DNA sequencing has defined many differences between the risk and non-risk haplotype. We will incorporate new genotyping and DNA sequencing data available and now being generated into a complete map, defining the genomic boundaries containing the causal variant(s) and identifying all of the possible variants that could contribute to disease risk and reducing the interval (Aim 1). Next, since disease risk appears to be related to expression, we will explore sequence specific epigenetic alterations in histone marks and DNA methylation to identify the regions of the risk haplotype that are poised for increased STAT4 mRNA production (Aim 2). This will be a novel application of epigenetics for allele specific gene mapping and candidate causal variant identification that if successful will have general application for identifying gene variants that change disease risk by changing expression level. We will evaluate the hypothesis that the differential binding of transcription factors are responsible for the difference in STAT4 gene expression with informatic approaches to identify potential risk haplotype differences controlling gene expression and by applying in vitro methods to establish which of the identified variants is actually responsible for the change in gene expression (Aim 3). We anticipate identifying the causal variant in STAT4 and explaining some of the important details of the mechanism that generates risk for lupus. Finally, throughout the proposed program of research on STAT4 we will explore progressively more sophisticated strategies for decreasing the increased STAT4 activity in the risk haplotype (Aim 4). Initially, we will explore the potential impact on STAT4 activity with the known inhibitors (lisopfylline, curcumin, and statins). Later in the program and after we identify candidate causal transcription factors, we will deliver specific shRNA with lentivirus vectors to inhibit the actionof the candidate causal transcription factor(s), which may have the potential to reduce the increased STAT4 expression of the risk allele, returning the level of expression of the risk haplotype close to the STAT4 expression of the non-risk allele and, thereby, reducing the risk of lupus. STAT4 also is associated with rheumatoid arthritis, Crohn's disease, and type 1 diabetes, giving broad importance to any effort to understand STAT4 mechanism in autoimmunity, especially if this knowledge were to bring us closer to more effective and specific therapies for the immune dysfunction of these diseases.

Public Health Relevance

There are more than a 1000 cases of systemic lupus erythematosus in the Active Duty Military, with about half of these occurring in African-American, Hispanic, and other minority populations. Most of these cases are boarded out of the military upon diagnosis. There are many more cases in the DVA and lupus can be a serious, life plan altering, deadly disease that remains poorly understood. We propose to understand lupus at the level of its genetics at gene called STAT4, which is a protein that unleashes aspects of the inflammatory response when provided with specific stimuli. Elucidating the STAT4-related mechanism of disease and the exploration of the STAT4-related therapeutic strategies, would provide opportunities to improve management of lupus and other STAT4 associated disorders including Crohn's disease, rheumatoid arthritis, and type 1 diabetes, progress against which is clearly relevant to the VA mission.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX001834-01
Application #
8327991
Study Section
Immunology A (IMMA)
Project Start
2012-10-01
Project End
2016-09-30
Budget Start
2012-10-01
Budget End
2013-09-30
Support Year
1
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Cincinnati VA Medical Center Research
Department
Type
DUNS #
827658092
City
Cincinnati
State
OH
Country
United States
Zip Code
45220
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
Aberle, Teresa; Bourn, Rebecka L; Chen, Hua et al. (2017) Use of SLICC criteria in a large, diverse lupus registry enables SLE classification of a subset of ACR-designated subjects with incomplete lupus. Lupus Sci Med 4:e000176
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
Zhao, Jian; Giles, Brendan M; Taylor, Rhonda L et al. (2016) Preferential association of a functional variant in complement receptor 2 with antibodies to double-stranded DNA. Ann Rheum Dis 75:242-52
Kariuki, S N; Ghodke-Puranik, Y; Dorschner, J M et al. (2015) Genetic analysis of the pathogenic molecular sub-phenotype interferon-alpha identifies multiple novel loci involved in systemic lupus erythematosus. Genes Immun 16:15-23
Kottyan, Leah C; Zoller, Erin E; Bene, Jessica et al. (2015) The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Hum Mol Genet 24:582-96
Alexander, Eileen S; Martin, Lisa J; Collins, Margaret H et al. (2014) Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis. J Allergy Clin Immunol 134:1084-1092.e1
Morris, D L; Fernando, M M A; Taylor, K E et al. (2014) MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun 15:210-7

Showing the most recent 10 out of 28 publications