# Epigenetic fine-mapping of cardiometabolic disease loci in the human liver

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $736,385

## Abstract

Epigenetic fine-mapping of cardiometabolic disease loci in the human liver
Summary
Cardiovascular disease (CVD) is the leading cause of mortality in the world: an estimated 17; 500; 000
people worldwide died from CVD-related illness in 2012. While disease altering therapies such as statins
have had a tremendous health impact, many individuals are unresponsive to treatment or go undiagnosed
until a fatal event occurs. Moreover, while clinical risk factors and family history are significantly predictive
of CVD risk, risk prediction and early clinical intervention must be improved to diminish the lethality of
the disease. Scientific studies have uncovered common genetic variation at more than 182 separate genetic
loci that contribute to variability in CVD, coronary artery disease (CAD), myocardial infarction (MI) risk,
and associated metabolites including blood lipids. However, several critical limitations have restricted the
translational impact of these study findings on clinical medicine. Importantly, while we know that temporal,
genomic, and cellular context varies dramatically across individuals, current GWAS studies assume a static
context across all samples. Indeed, it is precisely this dynamic context that will shed light on how a specific
genetic variant impacts molecular traits, which, in turn, modulate disease risk. Furthermore, a primary tissue
involved in CVD is the human liver, which has been difficult to deeply phenotype because of the difficulty
of acquiring liver samples.
 In this proposal, the PIs will address these critical limitations by creating a deep molecular phenotype
map of 200 human liver biopsy samples, by developing essential statistical tools to predict the genomic
regulatory signals in these rich liver data, and by using these predictions to drive experimental validation
of regulatory signals through reporter assays and genome editing in order to study the mechanisms of the
genetic regulation of CVD risk. In Aim 1, in collaboration with two transplant surgeons at Penn, the PIs pro-
pose to build a comprehensive map of the genetic and epigenetic traits of 200 human liver biopsy samples.
In Aim 2, the PIs propose to develop statistical methods to identify regulatory genetic variants using paired
sample design to share strength across the multiple epigenetic traits. While study data of this type is cur-
rently rare, we anticipate substantial growth in studies of this type and broad use of our analytic approaches.
In Aim 3, the PIs propose to develop experimental methods to validate the mechanisms by which functional
SNPs impact CVD risk. In particular, we will develop massively parallel CRE reporter assays and genome
engineering in iPSC derived hepatocytes to characterize the precise mechanism of multiple CVD risk vari-
ants. Throughout this proposal, the PIs will develop, evaluate, and make public new analytic tools that take
advantage of many-core computing environments, and will make publicly available all of the genetic and
...

## Key facts

- **NIH application ID:** 9874000
- **Project number:** 5R01HL133218-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Christopher David Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $736,385
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9874000

## Citation

> US National Institutes of Health, RePORTER application 9874000, Epigenetic fine-mapping of cardiometabolic disease loci in the human liver (5R01HL133218-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9874000. Licensed CC0.

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