The genetics of life threatening diseases offer the possibility of fundamental insights into pathophysiology that can transform diagnosis and management. Genome wide genetic association studies (GWASs) of the past decade have identified DNA sequence genotypic relationships to disease phenotypes, usually without any accompanying insight into the incredibly complex biology that operates between genotype and disease risk. Our DVA Merit Award work has focused on the genetics of Systemic Lupus Erythematosus (SLE). There are now >50 established and published genetic associations and our recent results will raise this to >100 SLE risk loci. Associations without mechanisms are of very limited practical utility. Our present focus has become elucidating these mechanisms and we have made much progress at the IRF5 and ETS1 lupus risk loci. Using frequentist and Bayesian statistics along with the differences and similarities of the associated variants in the major human ancestries we generate Ancestry Informed Credible Sets (AICSs) of plausibly causal variants. The subsequent search for allele specific functional consequences for these variants is enormously aided by all of the work now underway characterizing the protein and RNA species that interact with chromatin. Using the dataset infrastructure now available and methods that identify DNA ligands, we have identified ZBTB3 and STAT1 as relatively specific AICS risk allele transcription factors for IRF5 and ETS1, respectively. We propose to focus on the important association in the STAT4 gene with SLE where STAT1, this time through its expression, again appears to be important. We have reduced the plausibly causal variants from 56 to only 4 variants in the 2nd and 4th introns of STAT4. We have results suggesting the astonishing possibility that HMGA1 binds with varying allele specificity to 3 of the 4 variants in the AICS for the STAT4 locus. HMGA1 acts as a chromatin scaffold influencing DNA looping and chromatin conformation. We (and others) have shown that STAT4 expression is altered by the risk haplotype. We have recent data showing that STAT1 expression is also associated with STAT4 alleles. In addition, we show association of the DNA binding sites of STAT1 with the 53 published SLE risk loci (p?10-10). With the strong association at STAT4 with SLE across all human ancestries (1.2

Public Health Relevance

We propose to elucidate the mechanism that is responsible for disease risk of systemic lupus erythematosus (SLE) at a genetic locus called STAT4. There are many thousands of veteran patients with this condition. Understanding the mechanism would help in the development of new therapies, help us better understand therapies that are available both for SLE and other conditions. Our orientation is that we may find opportunities for treating SLE among existing therapeutics. The genetic properties at STAT4 in SLE suggest that if mechanism at this locus were explained and could be manipulated, then we would not only understand a fundamental property of human immune regulation, we would also be in a position to use this capacity to help patients with a variety of problematic inflammatory conditions mediated through a STAT4 locus.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
7I01BX001834-06
Application #
9440274
Study Section
Special Panel for Genomics (SPLC)
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cincinnati VA Medical Center Research
Department
Type
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45220
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
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
Patel, Zubin H; Kottyan, Leah C; Lazaro, Sara et al. (2014) The struggle to find reliable results in exome sequencing data: filtering out Mendelian errors. Front Genet 5:16
Chung, Sharon A; Brown, Elizabeth E; Williams, Adrienne H et al. (2014) Lupus nephritis susceptibility loci in women with systemic lupus erythematosus. J Am Soc Nephrol 25:2859-70
Namjou, Bahram; Marsolo, Keith; Caroll, Robert J et al. (2014) Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis. Front Genet 5:401
Kottyan, Leah C; Davis, Benjamin P; Sherrill, Joseph D et al. (2014) Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease. Nat Genet 46:895-900

Showing the most recent 10 out of 24 publications