# Research Project 1 - Hepatocellular Genetic Epidemiology of Fatty Liver Disease in Hispanics

> **NIH NIH U54** · UNIVERSITY OF TEXAS RIO GRANDE VALLEY · 2024 · $658,576

## Abstract

PROJECT SUMMARY
Fatty liver disease (FLD) is a major public health issue that affects millions of people worldwide. The two major
subtypes of FLD include alcoholic FLD (AFLD) and nonalcoholic FLD (NAFLD) although the threshold of alcohol
intake for subdivision is controversial. FLD is defined by excess fat in the liver and can lead to a more profound
disease state of steatohepatitis (SH) in which there is liver inflammation/damage that may be reflected in hepatic
fibrosis. SH can lead to liver failure or hepatocellular carcinoma. Major risk factors predisposing individuals to
the development of FLD include biological factors (obesity, insulin resistance, type 2 diabetes) demographic
characteristics (e.g., sex, age and ethnicity), behavioral and lifestyle-related variables (e.g., alcohol intake,
dietary behavior and physical activity), and other environmental factors (e.g., infectious agents such as hepatitis
viruses, microbiome variability, exposure to pollutants/contaminants/toxins). Hispanics are disparately impacted
by NAFLD with the highest observed prevalence of NAFLD in the world.
Risk for NAFLD is due to a complex mixture of genetic and environmental factors and their interactions that are
still largely unidentified. Quantitative endophenotypes (i.e., biomarkers that are genetically correlated with
disease risk) have important properties that can speed the discovery of disease-related genetic causal factors
and aid in individual-level risk estimation. Here we propose a novel deep cellular phenotyping assessment of
induced pluripotent stem cell (iPSC)-derived hepatocyte response to experimental lipid overload challenge,
which mimics dietary lipid overfeeding. This experimental epidemiological study will allow us to rigorously test
for genotype-by-environment interactions (GEI) to better understand the etiology/mechanisms of NAFLD risk
and to enhance early detection and halt progression. Specifically, we will identify novel iPSC-derived
hepatocellular endophenotypes involved in NAFLD risk in Mexican Americans, a health disparity population,
using a high-throughput multiomic approach. The study will use existing data and cellular biosamples from 900
participants in our longitudinal Mexican American Family Study (MAFS), who have been extensively phenotyped
(including liver MRI) and genetically characterized. Our specific aims include: 1) discovery of novel hepatocellular
cellular endophenotypes for NAFLD risk by quantitative genome-wide RNA sequencing and functional evaluation
of hepatocytes derived from existing iPSCs in 400 subjects; (2) discovery of multivariate hepatocellular
transcriptional coherence endophenotypes using single-cell sequencing; and (3) confirmation of the highest
ranking NAFLD endophenotypes using MRI-derived liver fat measures from an additional 500 MAFS subjects
from the same families.
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease and it
disparately affects minority p...

## Key facts

- **NIH application ID:** 10930969
- **Project number:** 5U54HG013247-02
- **Recipient organization:** UNIVERSITY OF TEXAS RIO GRANDE VALLEY
- **Principal Investigator:** JOANNE E. CURRAN
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $658,576
- **Award type:** 5
- **Project period:** 2023-09-18 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930969

## Citation

> US National Institutes of Health, RePORTER application 10930969, Research Project 1 - Hepatocellular Genetic Epidemiology of Fatty Liver Disease in Hispanics (5U54HG013247-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10930969. Licensed CC0.

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