PROJECT SUMMARY/ABSTRACT Background: Both sex and gender have profound effects on cardiovascular disease (CVD) occurrence and associated risk factors. Differences in CVD between men and women are often attributed to biologic sex, such as hormones, but all individuals are also deeply affected by the gender norms and expectations of their society. However, few studies have examined the impact of gender on CVD. The impact of gender can be measured in part through gender-related variables (GRV) classified in the domains of gender roles, gender relations, gender identity, institutionalized gender, discrimination, and behavioral/lifestyle risk factors. Integrating the impact of both biologic sex and sociocultural gender, metabolomic profiles capture the downstream effects of genomic as well as environmental factors. Our research group, and others have characterized metabolomic profiles associated with CVD. However, no studies have examined the impact of gender on the metabolome, which may offer clues about biologic mechanistic pathways related to gender. Goal: We will examine the intersection of sex and gender on CVD and the metabolome through sex-based comparisons of the effects of gender on CVD. We will attempt to separate the impact of sex and gender through sex-stratified evaluation of gender effects on the metabolome and subsequent CVD risk, to better understand the health impacts of gender, particularly in women. Setting: We have assembled an exceptional team with deep expertise in women's health, cardiovascular disease outcomes, metabolomics, and biostatistics/ bioinformatics. Research Plan: Our aims leverage three large, unique cohorts: (1) the UK Biobank (UKB) including 502,386 men and women, 118,014 with metabolomics; (2) the Women's Health Initiative including 93,676 women in the Observational Study (WHI-OS) and 2306 with metabolomics in a CHD case-control study (WHI-CHD) that includes OS and hormone trial (HT) participants; and the (3) Nurses' Health Studies: NHS1 with 121,700 women and 908 with metabolomics (NHS-stroke), and NHS2 with 116,430 women. We will examine the association of GRVs and a composite gender score (GS) with metabolomic profiles and with CVD outcomes. The GS will be derived in the UKB and tested for association with CVD outcomes in UKB by sex and generation, as well as compared to associations with CVD in the WHI-OS, NHS1 and NHS2. Moreover, we will evaluate the relationship between gender score and GRV with metabolomic profiles, and their association with CVD. Relevance to Public Health: This research will improve our understanding of the impact of gender and the intersection of sex and gender, on CVD and the metabolome. Evaluating the impact of gender in women through GRV and relating these with the metabolome and cardiovascular outcomes will advance our understanding of the impact of gender on health and may inform CVD prevention strategies.