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, newly developed mouse models, and ex vivo functional studies to reveal the sexually dimorphic genetic architecture of glycine metabolism and determine its biologically causal relationship with CVD.

Public Health Relevance

Even though cardiovascular disease (CVD) is the number one cause of death in both sexes, it has mostly been viewed as a disease of men. However, new evidence suggests that there are distinct differences in the risk factors, development, and outcomes between men and women. We have recently discovered that glycine metabolism represents one such novel mechanism for CVD in women but not men. This project will use integrative genetics approaches and bioinformatics analyses in human populations, complemented with biological experiments in mouse models to determine the sex-specific role of glycine metabolism in CVD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL133169-02
Application #
9413460
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Hasan, Ahmed a K
Project Start
2017-02-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90033
Zewinger, Stephen; Kleber, Marcus E; Tragante, Vinicius et al. (2017) Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study. Lancet Diabetes Endocrinol 5:534-543
Patterson, Michaela; Barske, Lindsey; Van Handel, Ben et al. (2017) Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nat Genet 49:1346-1353
Saleheen, Danish; Zhao, Wei; Young, Robin et al. (2017) Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions. Circulation 135:2336-2353
Hartiala, Jaana; Schwartzman, William S; Gabbay, Julian et al. (2017) The Genetic Architecture of Coronary Artery Disease: Current Knowledge and Future Opportunities. Curr Atheroscler Rep 19:6
Ramos-Lopez, Omar; Milagro, Fermín I; Allayee, Hooman et al. (2017) Guide for Current Nutrigenetic, Nutrigenomic, and Nutriepigenetic Approaches for Precision Nutrition Involving the Prevention and Management of Chronic Diseases Associated with Obesity. J Nutrigenet Nutrigenomics 10:43-62