# Lupus Association with Signal Transducer and Activator of Transcription 4 (STAT4)

> **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2020 · —

## Abstract

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<odds ratio (OR)<1.8), the STAT4 allele dependent expression of
STAT4 and STAT1, the demonstration of allele specific binding of STAT1 at ETS1, the relationship of STAT1
to SLE risk loci, and the association of STAT4 with other inflammatory diseases (rheumatoid arthritis (RA),
Sjögren's syndrome (SS), primary biliary cirrhosis (PBC), progressive systemic sclerosis (PSS), and type 1
diabetes (T1D)), we conclude that the STAT1-STAT4 locus has earned our concentrated effort.
 We will experimentally evaluate the relationship between the AICS variants (Aim 1) and STAT4 and STAT1
expression in the context of HMGA1 binding to the A...

## Key facts

- **NIH application ID:** 9898284
- **Project number:** 5I01BX001834-08
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** John Barker Harley
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898284

## Citation

> US National Institutes of Health, RePORTER application 9898284, Lupus Association with Signal Transducer and Activator of Transcription 4 (STAT4) (5I01BX001834-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898284. Licensed CC0.

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