# APOL1 variants: Understanding the basis of disparities in rates of kidney disease

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $432,500

## Abstract

SUMMARY
Although APOL1 risk alleles are among the most powerful common genetic disease variants identified to date
in terms of frequency and effect size, the presence of two risk alleles (a high-risk genotype) does not lead to
kidney disease in all or even most individuals. We have been seeking factors that lead from APOL1 risk
genotype to overt kidney disease. We have identified candidate genetic factors that modify the risk of disease.
We have begun to dissect the upstream and downstream biochemical modifiers of APOL1-associated disease
and believe that we have made significant progress towards these goals. Our genetic and biochemical studies
have shown that pro-inflammatory stimuli such as interferons can regulate APOL1 expression leading to overt
disease in individuals with a high-risk APOL1 genotype, and that disease is reversible when the stimuli are
removed. We have begun investigating post-transcriptional modifications of APOL1 mRNA and the effect of
microRNA on APOL1 levels. In this application, we outline studies to continue pursuing what we believe to be
the most fruitful of these directions. We aim to do the following: Aim 1. Define the genetics and biology of
loci modifying the APOL1-associated FSGS phenotype. We will replicate the admixture associations in
individuals with FSGS that we have identified on Chr18q22-23 and Chr6p21-22 loci and determine if there is
evidence of admixture association at other genomic regions as well. We will perform fine-mapping to identify
the variants driving the admixture signal. We will perform functional tests of genes and their haplotype-defining
variants. Aim 2: Define how inflammatory factors and pathways upregulate APOL1 expression in vitro and
in vivo. We will elucidate how TLR4 activation (by LPS and lipids) drives APOL1 expression as we did
previously for TLR3 activation (by double-stranded RNA). We will validate these pathways for APOL1 induction
in vivo and observe how various inflammatory stimuli drive APOL1 expression in different kidney cell types. We
will then ask how induction of wild-type and risk-variant APOL1 via these stimuli impacts kidneys in vivo and
whether we can reverse APOL1 toxicity by blocking inflammation-driven APOL1 expression. Aim 3. Determine
how the APOL1 3'UTR and microRNA regulate APOL1 function. We will identify the tissues and cells
where APOL1 3'-UTR cleavage occurs. We will determine how APOL1 mRNA cleavage alters mRNA half-life
and regulation by miRNA. We will explore how 3'-UTR cleavage alters APOL1 translation and trafficking.
Lastly, we will pair a genome-wide miRNA screen with profiling of human glomerular miRNA expression to
identify miRNA that regulate APOL1 in health and disease.

## Key facts

- **NIH application ID:** 9857494
- **Project number:** 5R01MD007092-09
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** David J Friedman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,500
- **Award type:** 5
- **Project period:** 2012-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857494

## Citation

> US National Institutes of Health, RePORTER application 9857494, APOL1 variants: Understanding the basis of disparities in rates of kidney disease (5R01MD007092-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9857494. Licensed CC0.

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