# Ikaros family genes and lupus susceptibility across ethnically diverse populations

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2021 · $781,667

## Abstract

Project Summary
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a substantial genetic component.
Recent genome-wide association studies (GWAS) have identified SLE associated loci, including IKZF1 and
IKZF2, encoded for ikaros and helios proteins, respectively. These proteins play important roles in regulation of
differentiation of immune cells important in SLE development and drugs which regulate these protein levels are
used to treat refractory cutaneous lupus and nephritis making a strong case for the importance of these genes
in SLE. Our recent ImmunoChip-based association study in Asians firmly established IKZF1-SLE association
and detected additional independent variants (10-24<p<10-8). While IKZF1 results are also well-supported in
non-Asian populations, due to poor SNP coverage, European-GWAS identified IKZF2 (1.2x10-13) could not be
thoroughly assessed in our study. However, our bioinformatics data predicted several IKZF1-2 variants as
eQTLs, again indicating their regulatory roles in expression. Despite solid evidence of association, a gap exists
in defining mechanisms with IKZF1-2 variants, hence, the functional effects of IKZF1-2 risk alleles in SLE
remains largely unaddressed. Since SLE is 3-5 times more prevalent in individuals of non-European ancestry,
a comprehensive, sequence-based trans-ethnic mapping (TEM) approach will be informative to both identify
additional causal variants, and understand SLE clinical heterogeneity across ethnicities. We have successfully
applied TEM in SLE, and our research team has the expertise, resources and infrastructure necessary to move
beyond GWAS and accelerate discovery and analysis of functional variants. We successfully identified causal
variants and their functional consequences in ITGAM, BLK, IFIH1 and NCF2. We will apply our expertise in
new variant discovery, localizing functional variants, and correlation of functional risk variants in IKZF1-2 on
cellular and molecular surrogates associated with SLE. In Aim 1, we will localize additional SLE-predisposing
variants from IKZF1-2 by performing comprehensive trans-ethnic mapping across four ethnically diverse
populations (N>20,000 from Asian, African-American, European-American, and Hispanic descent). Promising
variants, especially imputed and low frequency variants, will be validated by confirmatory genotyping. We will
also correlate genetic and clinical heterogeneity using clinical sub-phenotypes and autoantibody profiles. In
Aim 2, we will use cutting-edge approaches to directly identify functional variants in the enhancers of IKZF1-2
important for regulating expression using a novel allele-specific reporter system which works in the native
chromatin context and in relevant cell types. This enables direct experimental validation of the most important
variants in a human model cell system. Data generated will provide answers about SLE disease mechanisms
influenced by IKZF1-2 variants, and the understanding of function ...

## Key facts

- **NIH application ID:** 10238826
- **Project number:** 5R01AI132532-04
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Joel Marvin Guthridge
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $781,667
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10238826

## Citation

> US National Institutes of Health, RePORTER application 10238826, Ikaros family genes and lupus susceptibility across ethnically diverse populations (5R01AI132532-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10238826. Licensed CC0.

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