PROJECT SUMMARY/ABSTRACT Despite major advances over recent decades, cardiovascular disease (CVD) remains a leading cause of death in the USA and globally and risk for factors that predispose to CVD remain incompletely understood. Although symptomatic food allergy is relatively uncommon in adults, nearly 1 in 5 adults make IgE antibodies to food that can be detected in circulation; the majority of those with IgE antibodies are unaware of the IgE, do not have symptoms related to food and routinely consume the foods to which they make IgE. We recently published findings from a study of 4996 adults in the National Health and Examination Survey (NHANES) with replication in 960 adults in the Multi-Ethnic Study of Atherosclerosis (MESA) that showed a significantly increased risk of CVD-related mortality associated with IgE antibodies specific for cow’s milk. Although a novel observation, these findings fit within an increasing body of evidence that inflammation, including Th2-related allergic pathways, contribute to CVD development. The goal of this proposal is to expand our research in order to address several important questions: i) do IgE antibodies specific for other food allergens also confer CVD risk? ii) which specific subtypes or markers of CVD are associated with IgE to foods? iii) does consumption of a food to which an individual is sensitized increase risk of CVD? To address these questions, we will comprehensively assess the relationship between food antibodies and CVD mortality in the discovery sub- cohort of MESA that we have previously studied (Aim 1), validate the findings of our preliminary data and Aim 1 in the entire MESA cohort, examining which CVD phenotypes are associated with food specific IgE and whether consumption of allergen increases risk (Aim 2), and take advantage of an ongoing cohort of those undergoing clinically indicated coronary CT angiography (CAVA-CCTA) to understand the relationship between food specific IgE and atherosclerotic plaque. Together, these aims are designed to provide strong evidence in support of our hypothesis that food sensitization, in a manner dependent on consumption, confers CVD risk. Confirmation of our recently published findings would have high potential for clinical impact because they suggest an opportunity for precision nutritional prevention of CVD, could change food allergy guidelines which currently encourage those who have asymptomatic IgE to foods to consume the food, question whether oral immunotherapy for food allergy could have unintended long-term consequences, and suggest a potential use of anti-IgE therapies for CVD.