Cardiovascular disease (CVD) is the leading cause of death worldwide and more than 80% of these deaths occur in low- and middle-income countries. The global burden of CVD has accelerated the need to better understand its epidemiology, identification, and treatment, particularly in high-risk and understudied population groups. African ancestry individuals have a higher risk of CVD events and mortality compared to European ancestry individuals and this racial/ethnic difference is not explained by traditional CVD risk factors or access to healthcare alone. Although mechanisms for the race differences in CVD epidemiology are complex and multifactorial, it is clear that molecular and genetic differences in susceptibility play an important role. Emerging evidence, primarily from animal models and in vitro experiments, indicates that the Wingless (Wnt) signaling pathway plays a role in angiogenesis, vascular calcification, and atherosclerosis. However, less is known about the role of the Wnt signaling pathway in CVD in humans. In addition, human studies have focused on only a limited subset of Wnt related proteins and have not assessed other key components of the Wnt signaling pathway in CVD. Our preliminary data in African ancestry men and women with a functional and race specific missense variant (Ala64Thr) in the Wnt co-receptor, Frizzled-1 (FZD1), revealed greater carotid ultrasound intima-media thickness compared to those with the wild-type genotype (Ala64Ala). In order to more comprehensively quantify the association between the Wnt pathway and subclinical CVD in humans, we will utilize data from our large, ongoing cohort study of African ancestry men aged =40 years. We are currently performing abdominal and chest CT scans for a study of ectopic adiposity and diabetes in 1200 African ancestry men. During this study, we are also obtaining and archiving images of carotid artery ultrasound and brachial-ankle pulse-wave velocity. These data will form the basis of the Aims of this proposal, which are to quantify the association between blood levels of Wnt pathway gene and protein expression with measures of subclinical CVD including coronary and aortic artery calcification, common carotid intima-media thickness and adventitial diameter, brachial-ankle pulse-wave velocity and ankle-brachial index in 365 men of African ancestry. We will also perform genotype-directed recruitment of 100 men with a known functional variant in the FZD1 gene and test for a difference in measures of subclinical CVD between variant carriers and non-carrier controls that will be recruited from the general study population. The successful completion of these research aims, along with an intensive training and mentorship plan, will provide the applicant with new skills and hands-on training in five major areas: epidemiologic field research, deeper subclinical CVD phenotyping, and training in cardiovascular physiology, molecular epidemiology laboratory training and grantsmanship. This Career Development Award will provide the applicant with protected time for didactic training and development of new skills that will lay the foundation for an independent research career in the molecular epidemiology of subclinical CVD.