# Connecting the gap between GWAS and functional targets for lupus susceptibility

> **NIH NIH R21** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2022 · $262,200

## Abstract

ABSTRACT
Systematic lupus erythematosus (SLE or lupus) is a currently incurable autoimmune disease, characterized by
abnormal immune cell (e.g., B-lymphocytes) response and the production of numerous pathogenic
autoantibodies, culminating in multi-organ damage (e.g., kidneys, skin). While the etiology of SLE is incompletely
understood, a substantial genetic contribution is well established. Several genome-wide association studies
(GWAS) have identified over 100 SLE predisposing loci (p<5x10-8), mostly single nucleotide polymorphisms
(SNPs). Most of these SNPs do not directly alter protein products, and previous work from us and others have
shown that many such SNPs are enriched within cis regulatory elements (cRE) (i.e., enhancers and silencers)
and likely to modulate gene expression. However, pinpointing the causal, predisposing SNPs within cREs and
deciphering their precise mechanisms represent major obstacles to progress in the field. Consequently, this
knowledge gap has severely hindered the translation of GWAS findings into clinical applications. Hence, there
is a profound need for unbiased, comprehensive, and high-throughput approaches to address the mechanistic
link between hundreds of potential regulatory SNPs (rSNPs) and SLE susceptibility. We hypothesize that SLE-
predisposing rSNPs aberrantly induce cRE activities that influence the expression of target genes in unstimulated
and/or stimulated B-cells. To systematically delineate rSNPs and their impact on target genes, we propose to
establish a high-throughput experimental pipeline to determine and validate rSNPs underlying GWAS loci. In
Aim 1, we will apply the high-throughput technique “Self-Transcribing Active Regulatory Region-sequencing”
(STARR-seq) to functionally quantify the regulatory activities of hundreds of SNP-containing regions
simultaneously. Using Raji cells (B-lymphocyte) in both unstimulated and stimulated conditions, we will apply
STARR-seq to evaluate 756 selected rSNPs within 79 distinct GWAS loci for SLE susceptibility. In Aim 2a, we
will apply next-generation (NG)-Capture-C to detect SNP-specific effects on cis interactions with endogenous,
cognate target genes in Raji cells, needing no strong a priori hypothesis of target genes and functional
consequences. We will evaluate the same set of 756 SNPs in Aim 1 and Aim 2a. We anticipate this two-prong
tandem strategy will bridge the gap between GWAS-derived rSNPs and mechanistic links to their target genes.
To validate the effectiveness and accuracy of the proposed methods, Aim 2b will use CRISPR-based
(epi)genetic editing of a selected rSNP to validate the allele-specific functional effects on the endogenous target
gene(s) in isogenic cells. Collectively, the proposed unbiased approaches for discovering and validating SLE
“causal” SNPs is high risk/high reward and may lead to breakthroughs in the understanding of SLE etiology and
intervention strategies. Discovery of rSNPs, cREs, and their target genes will significa...

## Key facts

- **NIH application ID:** 10433444
- **Project number:** 1R21AI168943-01
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Swapan K. Nath
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $262,200
- **Award type:** 1
- **Project period:** 2022-05-05 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433444

## Citation

> US National Institutes of Health, RePORTER application 10433444, Connecting the gap between GWAS and functional targets for lupus susceptibility (1R21AI168943-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10433444. Licensed CC0.

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