# GSTM1, APOL1, and their joint contribution to severity of hypertension and chronic kidney disease

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $235,887

## Abstract

Chronic kidney disease (CKD) and its end stage renal disease (ESRD) consequences are a significant public
health burden in the U.S. We recently made the exciting discovery that the highly prevalent GSTM1 total gene
deletion polymorphism (GSTM1 null allele: 0) was associated with more rapid CKD progression in the African
American Study of Kidney Disease (AASK) trial participants, such that patients with one null (0/1) or two null
(0/0) GSTM1 alleles respectively had a 1.7- or 2-fold increased risk for the composite outcome of decline in
estimated glomerular filtration rate (eGFR), OR dialysis OR death, compared to those with two full-gene
sequence active alleles, GSTM1(1/1). Furthermore, there was a genetic interaction between GSTM1(0) alleles
and the African ancestry-specific apolipoprotein L1 gene (APOL1) G1 and G2 risk coding variants to mediate
overall risk in AASK, and the active GSTM1(1/1) genotype offset the risk of CKD in those with APOL1 high risk
alleles. This association was very recently replicated in the Atherosclerosis Risk in Communities (ARIC) study
in African Americans (AA) and European Americans (EA). Using an induced hypertension (angiotensin-II) or
CKD (remnant kidney) model in Gstm1 knockout mice, we show that Gstm1 deficiency results in increased
levels of renal oxidative stress, ER stress, inflammation, activation of fibrotic pathway, apoptosis, and kidney
injury. Furthermore, mice lacking Gstm1 and expressing the human APOL1 G2 transgene in podocytes had
worst hypertension in the CKD model, suggesting worse kidney disease. This evidence is consistent with the
prevailing 'two-hit' hypothesis that a second environmental or genetic (eg GSTM1) factor is needed to express
the APOL1 high risk genotype susceptibility as a penetrant loss of kidney function resulting from cellular injury.
We hypothesize that GSTM1, through its role in regulating oxidative stress and inflammation, interacts
with APOL1 to influence susceptibility to hypertension and kidney injury. By integrating mouse models
to inform mechanistic hypotheses with human cohort genetic analyses of the Chronic Renal Insufficiency
Cohort (CRIC); Systolic Blood Pressure Intervention Trial (SPRINT) cohort; and 3 cohorts in the NHLBI Trans-
Omics for Precision Medicine (TOPMed) program: Multi-Ethnic Study of Atherosclerosis (MESA), Jackson
Heart Study (JHS), Women's Health Initiative (WHI) – we will: Aim 1: Test the hypothesis that combined
GSTM1 deficiency and transgenic expression of APOL1 G2 variant augments renal injury in hypertension and
CKD; and determine the contribution of hematopoietic versus parenchymal GSTM1 deletion in kidney injury.
Aim 2: Test the hypothesis that the GSTM1(0) allele interacts with high risk APOL1 genotypes to modulate risk
of proteinuria and/or loss of renal function through effects on blood pressure in 9717 AA in CRIC, SPRINT,
JHS, MESA, WHI; and in 2682 Hispanic American (HA) in CRIC, SPRINT, MESA, WHI. Aim 3: Test whether
the GSTM1(0) and AP...

## Key facts

- **NIH application ID:** 10176256
- **Project number:** 5R01DK094907-07
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Thu H. Le
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $235,887
- **Award type:** 5
- **Project period:** 2012-04-27 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10176256

## Citation

> US National Institutes of Health, RePORTER application 10176256, GSTM1, APOL1, and their joint contribution to severity of hypertension and chronic kidney disease (5R01DK094907-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10176256. Licensed CC0.

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