Oxidation is fundamental to the etiology of atherosclerosis and coronary heart disease. The breakthrough discovery of scavenger receptors on macrophages that facilitate the rapid influx of oxidized lipid particles to produce foam cells and early atherosclerotic lesions has been instrumental in the basic understanding of atherogenesis. Recent studies of circulating oxidation-related molecules have defined promising mechanistic pathways with the greatest potential for prevention or therapeutic intervention. The proposed study will explore the role of several broad markers of oxidation or susceptibility to oxidation in predicting CHD risk in the Health Professionals Follow-Up Study. These markers include: 1) CD36, a complex multifunctional protein that acts as a scavenger receptor for oxidized LDL on macrophage and can now be measured in circulating plasma;2) Telomere length, a novel marker of somatic cell aging and oxidative damage that will be measured in circulating leukocytes and 3) Fluorescent oxidation products (FLOx), a novel marker of systemic oxidation, that reflect underlying global oxidative burden. Finally, we will assess haptoglobin 2-2 phenotype, a genetic marker of intravascular oxidation susceptibility, to identify individuals at highest oxidation risk. In addition to these biomarkers, we propose to examine prospectively the risk of CHD and ischemic stroke associated with dietary antioxidants - specifically total dietary flavonoids (and 5 sub classes) and dietary pattern scores derived through principal component factor analyses. These dietary measures also will be examined within the subset of men at highest risk based on several biomarkers of oxidative susceptibility noted above and a summary oxidation susceptibility score. This study will examine these promising but as-yet-unproven biomarkers that may link global oxidation to CHD in a prospective cohort of men from the Health Professionals Follow-Up Study, aged 40-75 years at baseline in 1986. Blood samples were collected from 18,140 participants in 1994 and detailed nutritional, behavioral, and lifestyle variables have been collected biennially. By 2010, we project 840 incident confirmed cases of myocardial infarction (matched to 1680 controls) among men in the blood cohort and over 3500 incident CHD cases and 843 occlusive strokes in the whole cohort. The Health Professionals Follow-Up Study has a long, established record of important findings for CHD. The large size, prospective design, high follow-up rates, detailed and reliable long-term repeated exposure and outcome information, and the availability of blood specimens on a large subgroup, combined with the relatively low cost, make this cohort a valuable and unique resource for studying biochemical determinants of cardiovascular risk. The results of this work may offer important insights for identifying men at intermediate to high risk of CHD and understanding underlying biology that may lead to new strategies for cardiovascular disease prevention and targeted pharmacologic interventions.

Public Health Relevance

Oxidation is fundamental to the etiology of coronary heart disease. We propose to assess blood and genetic markers of oxidation and identify participants at highest risk of incident coronary disease in an ongoing 22-year prospective study of over 50,000 male health professionals. Results from the proposed study will help us to understand biological pathways of oxidative damage as well as to identify nutritional or other behavioral characteristics that may prevent or lead to treatment for oxidation-related causes of coronary heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035464-23
Application #
8296608
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Loria, Catherine
Project Start
1985-12-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
23
Fiscal Year
2012
Total Cost
$680,994
Indirect Cost
$152,474
Name
Harvard University
Department
Nutrition
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
Ma, Wenjie; Heianza, Yoriko; Huang, Tao et al. (2018) Dietary glutamine, glutamate and mortality: two large prospective studies in US men and women. Int J Epidemiol 47:311-320
Jiang, Lai; Penney, Kathryn L; Giovannucci, Edward et al. (2018) A genome-wide association study of energy intake and expenditure. PLoS One 13:e0201555
Liu, Gang; Li, Yanping; Hu, Yang et al. (2018) Influence of Lifestyle on Incident Cardiovascular Disease and Mortality in Patients With Diabetes Mellitus. J Am Coll Cardiol 71:2867-2876
Mehta, Raaj S; Abu-Ali, Galeb S; Drew, David A et al. (2018) Stability of the human faecal microbiome in a cohort of adult men. Nat Microbiol 3:347-355
Lopez, David S; Liu, Lydia; Rimm, Eric B et al. (2018) Coffee Intake and Incidence of Erectile Dysfunction. Am J Epidemiol 187:951-959
Hagan, Kaitlin A; Harrington, Laura B; Kim, Jihye et al. (2018) Adiposity throughout the life course and risk of venous thromboembolism. Thromb Res 172:67-73
Li, Yanping; Pan, An; Wang, Dong D et al. (2018) Impact of Healthy Lifestyle Factors on Life Expectancies in the US Population. Circulation 138:345-355
Rist, Pamela M; Jiménez, Monik C; Tworoger, Shelley S et al. (2018) Plasma Retinol-Binding Protein 4 Levels and the Risk of Ischemic Stroke among Women. J Stroke Cerebrovasc Dis 27:68-75
Tsang, Sabrina H; Peisch, Samuel F; Rowan, Brendan et al. (2018) Association between Trichomonas vaginalis and prostate cancer mortality. Int J Cancer :
Bailey, Jessica N Cooke; Gharahkhani, Puya; Kang, Jae H et al. (2018) Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets. Invest Ophthalmol Vis Sci 59:629-636

Showing the most recent 10 out of 440 publications