Abstract Circulating proteomic profiles are strongly influenced by diet and may act as important molecular transducers of the diet’s effects on coronary heart disease (CHD). Dietary quality and circadian/temporal eating habits have been consistently related to CHD. However, how these factors may affect CHD progression mechanistically remains poorly defined. Recent studies indicate that diet is among the leading factors determining personalized and diet-specific differences in the proteome and proteotypes defined by specific combinations of proteomic profiles. The overarching goal of this proposal is to perform proteome-wide study of the dynamic interrelationships between diet (quality and circadian/temporal eating patterns), circulating proteomic profiles, and CHD risk. Using an exceptionally cost-efficient design that leverages existing resources from six large prospective cohorts: the Nurses’ Health Study (NHS), NHS2, the POUNDS LOST trial, Jackson Heart Study (JHS), Coronary Artery Risk Development in Young Adults (CARDIA) Study, and UK Biobank, we propose to identify the proteotypes for the dietary quality and circadian/temporal eating patterns measured by ‘gold standard’ and objective nutrition assessment methods (Aim 1). We will examine the associations of circulating proteomic profiles (dietary factors and circadian/temporal eating patterns-related proteotypes, and proteome-wide profiles) and their dynamic changes over 10 years with incidence of CHD (Aim 2). We will also assess whether non-protein vascular risk factors for CHD mediate the proteome-CHD relation (Aim 3). In addition, we will perform multi-omics analysis on the proteome-metabolome associations with CHD (Aim 4). This renewal application is built upon an exceptional resource for understanding CHD risk factors in women and has been continuously funded for 38 years (resulting in >410 publications and contributing to the training of >200 early-career investigators). The findings of our proposed project are expected to lead to identification of new determinants of CHD at the molecular level, offer novel insight into the mechanistic pathways, and advance the development of new preventive and therapeutic strategies.