Duties & Responsibilities:
An outstanding candidate is sought to work on an original research project to pursue novel epidemiologic analyses related to TMAO and incident subclinical CVD, clinical CVD, and mortality in two U.S. cohorts. Trimethylamine-N-oxide (TMAO) is a novel plasma metabolite of L-carnitine (present in red meat, chicken, fish) and phosphatidylcholine (lecithin) (present in eggs, milk, meats, fish). In vitro and in animal models, plasma TMAO directly accelerates atherosclerosis, altering cholesterol and sterol metabolism independent of known cardiovascular disease (CVD) risk factors. Plasma TMAO is also highly modifiable by both short-term changes in diet as well as habitual diet. These findings suggest that TMAO could be a major novel, modifiable promoter of atherosclerosis that elucidates new pathways of influence of diet beyond traditional risk factors. Yet, while these animal and mechanistic experiments are exciting and promising, evidence on long-term effects of plasma TMAO on clinical events is conflicting. Such data are crucial, as a complement to pathway and experimental research, to understand whether and how plasma TMAO should be further targeted in mechanistic studies and long-term interventional trials in humans. Indeed, limited trial evidence suggests TMAO could be beneficial: in meta-analysis of small, heterogeneous controlled trials in patients with acute MI, L-carnitine supplementation, a precursor of TMAO, was associated with clinical benefits. In contrast, evidence for harm is suggested from samples of patients with pre-existing heart or renal disease from a tertiary medical center (Cleveland Clinic), in whom plasma TMAO was associated with higher CVD events. While provocative, these results are limited by lack of adjustment for major dietary, socioeconomic, and lifestyle confounders; as well as by potential selection bias and reverse causation among patients with known prevalent disease referred to a tertiary medical center. In addition, generalizability of these prior observations are unclear, especially to primary prevention populations.
Thus, longitudinal evidence on long-term relationships of TMAO with CVD is urgently needed. This project will provide crucial evidence on how TMAO, measured serially over time, relates to subclinical CVD, clinical CVD, and mortality in two independent, large, well-established, prospective community-based US cohorts: the Multi-Ethnic Study of Atherosclerosis (MESA), comprising 6,800 middle-aged white, Black, Hispanic, and Chinese adults; and the Cardiovascular Health Study (CHS), comprising 5,148 older white and Black adults. Use of these two cohorts allows prospective investigation of onset of subclinical atherosclerosis, clinical CVD events, and total mortality across a wide age range and different races. These endpoints provide robust, complementary evidence to assess how TMAO may influence atherosclerotic risk. The diversity and inclusion of two community-based cohorts are also key strengths for generalizability. The large number of well-measured health behaviors, risk factors, and disease phenotypes in these cohorts will also facilitate multivariable adjustment to minimize confounding. The results will have tremendous impact for understanding whether and how plasma TMAO influences CVD, informing the need for and design of focused studies on mechanistic pathways between TMAO, its determinants, and CVD; and of large intervention studies testing new lifestyle, drug, and molecular interventions targeting TMAO.
This postdoctoral fellow will work with the principal investigator (PI), other project faculty, and the rest of the research team to help achieve the project aims. She or he will focus on leading of analyses, abstract preparation, and manuscript drafting, with a focus on peer-reviewed scientific abstracts and manuscripts that will investigate the independent relationships of serial measures of plasma TMAO with longitudinal onset and progression of subclinical CVD, with incident CVD events, and with total mortality. The overall work and findings will be critical to inform whether and how plasma TMAO influences CVD. The publication of research results in high-quality journals and national and international conferences is expected.
The mentoring and training will be under the direction of PI Dr. Dariush Mozaffarian, Dean of the Friedman School of Nutrition Science & Policy at Tufts University (http://nutrition.tufts.edu/profile/faculty/dariush-mozaffarian). The post-doctoral fellow will also work with a multi-disciplinary team including nutritionists, public health experts, medical doctors, epidemiologists and biostatisticians/modelers, and will also have the opportunity to interface with international experts and stakeholders. Major emphasis will be placed on leading original analyses and manuscripts, career development, and transition toward an independent research career. A competitive salary, benefits, and travel/educational opportunities in the interdisciplinary environment at the Friedman School of Nutrition Science and Policy are offered.
This position is anticipated to be for 2-2.5 years. The initial appointment is for 1 year with annual renewal conditional on performance. The ability to work in the US is required in order to apply for this position.