The dramatic rise in obesity may portend an enormous future burden of coronary heart disease (CHD) in women. The proposed study will explore the role of adipocyte-related biomarkers in predicting CHD risk and will build upon our previous work in inflammatory markers in the Nurses'Health Study (NHS) cohort. Adipose tissue may play a key role in vascular disease, through secretion of adipocytokines, including retinol binding protein 4 (RBP4), adiponectin, and resistin, which are involved in inflammation and insulin resistance. Macrophages, a key component of adipose tissue, secrete lipoprotein- associated phospholipase A2 (Lp-PLA2), which hydrolyzes oxidized LDL releasing inflammatory products. Paraoxonase, an HDL- associated enzyme, reduces LDL oxidation. Fatty acid binding protein 4 (FABP4), the lipid binding protein for both adipocytes and macrophages, is an important regulator of lipid and inflammatory cascades. Finally, adiposity and vascular inflammation may lead to premature biological aging as measured by telomere length, with shorter telomere length associated with obesity, insulin resistance, and CHD. This study will examine promising but as-yet- unproven biomarkers that may link adiposity and CHD in a prospective cohort of women in the Nurses'Health Study, currently aged 60-85 years. Blood samples were collected from 32,826 participants in 1989-1990 (with 18,664 fasting), and detailed nutritional, behavioral, and lifestyle variables have been collected biennially. The major aim is to evaluate several biomarkers related to adiposity, vascular inflammation, lipid peroxidation, and related cellular aging with risk of CHD in women. By 2010, more than 600 cases of myocardial infarction will have been confirmed by medical record review among women in the fasting blood cohort. The Nurses'Health Study has a long, established record of important findings for CHD in women. The large size, prospective design, high follow-up rates, detailed and reliable long-term 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 in women. The results of this work may offer important insights for identifying women at high risk of CHD and understanding underlying biology that may lead to new strategies for cardiovascular disease prevention and targeted pharmacologic interventions. Coronary heart disease is the leading cause of death in women. The risk of coronary heart disease has been closely associated with obesity, insulin resistance, and diabetes, and this grant will assess novel risk factors related to obesity including proteins secreted by adipose tissue, inflammatory markers, and markers of cellular aging. These promising biochemical and genetic markers may have implications for improving prevention strategies, enhancing treatment options, and generating additional testable hypotheses for heart disease research.
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