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.

Public Health Relevance

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. Molecular differences in susceptibility play an important role in CVD etiology and the Wnt pathway, while understudied in humans, is hypothesized to play a role in CVD. The overall objective of this Career Development Award is to quantify and describe the association of Wnt pathway expression with subclinical CVD in an attempt to gain novel insight into the etiology of CVD, which may translate into improved risk-prediction, prevention and personalized care.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HL125658-04
Application #
9483769
Study Section
NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
Program Officer
Papanicolaou, George
Project Start
2015-07-15
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kuipers, Allison L; Miljkovic, Iva; Barinas-Mitchell, Emma et al. (2018) Arterial stiffness and hypertension status in Afro-Caribbean men. J Hypertens :
Kuipers, Allison L; Zmuda, Joseph M; Carr, J Jeffrey et al. (2017) Association of ectopic fat with abdominal aorto-illiac and coronary artery calcification in african ancestry men. Atherosclerosis 263:198-204
Kuipers, A L; Miljkovic, I; Evans, R et al. (2016) Optimal serum cholesterol concentrations are associated with accelerated bone loss in African ancestry men. Osteoporos Int 27:1577-1584
Miljkovic, Iva; Kuipers, Allison L; Cvejkus, Ryan et al. (2016) Myosteatosis increases with aging and is associated with incident diabetes in African ancestry men. Obesity (Silver Spring) 24:476-82
Tilves, Curtis M; Zmuda, Joseph M; Kuipers, Allison L et al. (2016) Association of Lipopolysaccharide-Binding Protein With Aging-Related Adiposity Change and Prediabetes Among African Ancestry Men. Diabetes Care 39:385-91
Zhao, Qian; Zmuda, Joseph M; Kuipers, Allison L et al. (2016) Greater skeletal muscle fat infiltration is associated with higher all-cause mortality among men of African ancestry. Age Ageing 45:529-34
Kuipers, Allison L; Kammerer, Candace M; Pratt, J Howard et al. (2016) Association of Circulating Renin and Aldosterone With Osteocalcin and Bone Mineral Density in African Ancestry Families. Hypertension 67:977-82
Kuipers, Allison L; Egwuogu, Heartley; Evans, Rhobert W et al. (2015) Renal Function and Bone Loss in a Cohort of Afro-Caribbean Men. J Bone Miner Res 30:2215-20
Miljkovic, Iva; Kuipers, Allison L; Cauley, Jane A et al. (2015) Greater Skeletal Muscle Fat Infiltration Is Associated With Higher All-Cause and Cardiovascular Mortality in Older Men. J Gerontol A Biol Sci Med Sci 70:1133-40