# Deep Phenotyping of Human Knockouts and Population Studies of the APOC3 Pathway

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $678,976

## Abstract

Several recent studies indicate that loss of function (LoF) mutations in the apolipoprotein C-III (APOC3) gene offer
protection from coronary heart disease (CHD) risk, possibly by reducing circulating triglyceride-rich lipoproteins
(TRLs). Inhibition of the apoC-III pathway can provide an attractive therapeutic mechanism to lower CHD risk.
There are however many outstanding uncertainties that exist, including impact of apoC-III deficiency on (i)
lipoprotein kinetics; (ii) high density lipoprotein remodeling and functionality; (iii) non-lipid related pathways; (iv) the
mechanisms by which apoC-III inhibition may reduce CHD risk, (v) the relative contribution of different lipoprotein-
associated apoC-III levels on CHD; (vi) liver function and insulin resistance from a safety perspective.
 In this application, we propose studies to address these gaps by leveraging natural human models of
apoC-III deficiency. We have identified the world’s first humans with homozygous APOC3 genetic deficiency who
are from an isolated Pakistani village with a high prevalence of consanguinity. Recruitment of all inhabitants in this
village (~5000 people) has already been completed; genotyping in a subset has already identified 113 APOC3
knockouts with complete apoC-III deficiency providing opportunities for detailed phenotyping.
 Specifically, in AIM-1, we will conduct deep phenotyping studies in 113 human APOC3 knockouts (n = 113)
and in an equal number of heterozygotes and non-carriers to address the following: (i) role of apoC-III deficiency in
modulating protein and lipid composition of TRLs to impact the activity of extracellular lipases; (ii) effect of apoC-III
deficiency on subclasses of LDL; (iii) role of apoC-III in modulating Lp(a) levels and composition; and (iv)
contribution of apoC-III deficiency to modulation of HDL composition and function. We will also address the
consequences of genetic APOC3 deficiency on (iv) systemic lipid and glucose metabolism and a range of proteins
related to inflammation and other pathways (v) dose-response association with atherosclerosis.
 In AIM-2, we will conduct lipoprotein kinetic studies using isotope tracers on 18 trios of APOC3 null
homozygotes, heterozygotes, and non-carriers to evaluate the impact of apoC-III deficiency on kinetics of apoB-
containing lipoproteins and production and clearance of HDL apoA-I. We will also generate human iPS cells from 5
APOC3 knockouts and 5 matched/related non-carriers and differentiate them into hepatocytes to evaluate (a)
VLDL apoB and TG production (b) TRL and LDL uptake and (c) SRB1 mediated HDL uptake.
 In AIM-3, we will measure total plasma apoC-III and lipoprotein-associated (apoB lipoproteins, HDL, and
Lp[a]) apoC-III in 5,000 participants from the EPIC-Norfolk cohort (2,500 with incident CHD events). These studies
will enable assessment of: (i) disease mediation; (ii) CHD risk progressively adjusted for lipoprotein-associated
apoC-III levels and other factors; (iii) dose-resp...

## Key facts

- **NIH application ID:** 9902507
- **Project number:** 5R01HL133339-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Daniel James Rader
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $678,976
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9902507

## Citation

> US National Institutes of Health, RePORTER application 9902507, Deep Phenotyping of Human Knockouts and Population Studies of the APOC3 Pathway (5R01HL133339-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9902507. Licensed CC0.

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