Trimethylamine-N-oxide (TMAO), a pro-atherogenic metabolite, has recently emerged as a promising novel risk factor for cardiovascular disease (CVD). Animal studies demonstrate that TMAO levels are regulated by both genetic and environmental factors. In humans, while habitual and acute dietary exposures have been shown to contribute to TMAO homeostasis, no studies have examined the role of genetic and epigenetic variation in the TMAO-CVD pathophysiologic pathway. Additionally, the associations of TMAO itself with intermediate CVD phenotypes such as plasma lipids have not been investigated. Using existing rich phenotype, genotype, and DNA methylation data on 1049 participants of the Genetics of Lipid Lowering and Diet Network (GOLDN) study, we propose an integrated approach to investigating the biological mechanisms underlying plasma TMAO and the risk of CVD. Specifically, we will: (1) measure plasma TMAO in GOLDN and test for its associations with the available set of cardiovascular phenotypes, including plasma lipids and serum inflammatory cytokines; (2) conduct a genome- and epigenome-wide study to identify and replicate DNA sequence and methylation variants associated with plasma TMAO; (3) perform methylation quantitative trait analysis to link genetic and epigenetic determinants of this novel risk marker. If successful, our study will lay the groundwork for personalized nutritional approaches to CVD risk reduction. Our findings could enable future researchers and clinicians to identify individuals harboring genetic and/or epigenetic variants associated with increased plasma TMAO and guide them to limit their consumption of dietary TMAO precursors, such as red meat, fish, and eggs, ultimately leading to improved cardiovascular health.
|Program type||Mentored Clinical & Population Research Program|
|Effective start/end date||01/01/2014 → 12/31/2015|