# Role of Glycine Metabolism in Cardiovascular Disease

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $787,639

## Abstract

PROJECT SUMMARY
Cardiovascular Disease (CVD) is the number one cause of death for both men and women in the US.
However, the prevalence of CVD in women at advanced ages actually outnumbers men, and women generally
face a worse prognosis following a primary CVD event. Thus, there is a critical need for identifying and
understanding the sex-specific biological mechanisms that underlie the development of CVD in order to reduce
the morbidity and mortality associated with CVD, particularly in women. In this regard, our recent
metabolomics and genetic analyses in a cohort of ~10,000 CVD patients, followed by independent replication
in >53,000 subjects, led to the discovery that one of the major genetic determinants of plasma glycine levels is
strongly associated with 12% reduced risk of CVD in women (p=6.3x10-5) but not men (p=0.95). The lead
variant underlying this striking sex-specific association is located in carbamoyl phosphate synthase 1 (CPS1),
which encodes the rate-limiting enzyme in the urea cycle, and the athero-protective allele is associated with
increased glycine levels and decreased urea cycle metabolites. This novel finding represents one of the first
sexually dimorphic associations reported in the literature for CVD in either men or women, and the magnitude
of its effect is equivalent to the most strongly associated loci identified thus far for CVD. However,
epidemiological or experimental data directly linking glycine levels with CVD are lacking, and additional studies
are needed to prove that glycine metabolism is causally and inversely related to the development of
atherosclerosis. The overall goals of our application are to address these fundamentally important gaps in
knowledge. We hypothesize that glycine metabolism represents a novel sex-specific, protective, and causal
pathway for CVD. To investigate this hypothesis, we propose integrative clinical, genetics, and bioinformatics
approaches in human populations, complemented with studies that leverage targeted genetic perturbation and
dietary manipulation in animal models. In Specific Aim 1, we will determine the clinical association of glycine-
related metabolites with prevalent and incident CVD phenotypes in two independent human cohorts (n>6000),
and test whether these associations are modulated by female sex hormones. In parallel, we will conduct the
largest meta-analyses of genome-wide association study (GWAS) data to date for these metabolites
(n>12,600) and determine whether newly identified loci exhibit sex-specific associations with risk of CVD by
leveraging GWAS results from the CARDIoGRAM Consortium (n~185,000). In Specific Aim 2, we will
characterize the sex-specific metabolomics profile, atherosclerosis susceptibility, and functional/mechanistic
consequences of dietary glycine supplementation or Cps1 deficiency in mice. Taken together, the proposed
studies will leverage novel biomarker measures in independent human cohorts, already existing large-scale
GWAS data, new...

## Key facts

- **NIH application ID:** 9860937
- **Project number:** 5R01HL133169-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Hooman Allayee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $787,639
- **Award type:** 5
- **Project period:** 2017-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9860937

## Citation

> US National Institutes of Health, RePORTER application 9860937, Role of Glycine Metabolism in Cardiovascular Disease (5R01HL133169-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9860937. Licensed CC0.

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