CARDIAC MOLECULAR EPIDEMIOLOGY

Abstract

Biomarkers are used in clinical and research settings to enable prevention, subtype disease, quantify severity, guide treatment, and prioritize therapeutic targets. Large scale high throughput platforms have allowed for measurement of high quantities of proteins in large epidemiologic samples. By combining proteomic assays with results from genomic platforms, biological insights can be gleaned to facilitate clinical relevance of emerging markers. In Study 1, we used the Prospective Urban Rural Epidemiology (PURE) study analyzed in a case-cohort fashion to evaluate the importance of angiotensin-converting enzyme 2 (ACE2) as a cardiometabolic risk marker. Using long-run prospective data, we showed ACE2 predicted incident diabetes, cardiovascular disease, and death beyond traditional cardiac risk factors. In Study 2, we evaluate M-CSF as a causal driver of vascular disease using a similar case-cohort design. We find M-CSF is a strong predictor of stroke, myocardial infarction, heart failure, and death. Using Mendelian randomization, an approach that leverages genetic variants as instrumental variables, we find M-CSF is not only associated with cardiovascular disease and death, but is also a causal driver of the development of vascular disease. In a subsequent Mendelian randomization analysis, we find that body-mass index correlates with increased plasma M-CSF, indicating that M-CSF may play a mediating role between BMI and cardiovascular disease. Finally, in Study 3, we use polygenic risk scores to agnostically prioritize among a set of 539 plasma proteins which ones are dysregulated early in the heart failure disease course. We identify 7 proteins representing a diverse set of pathways including IL6 (Interleukin 6), HGF (Hepatocyte growth factor), and CPM (Carboxypeptidase M) as markers associated with both incident heart failure as well as genetic predisposition to heart failure. Of the 7 identified proteins, 3 maintained prognostic significance for death and hospitalization in those with heart failure (IL6, KIM1, HGF).