The aims of the project are to:
1. Identify the biochemical signature of atherosclerosis as determined by: (a) Aortic and coronary calcification on CT (data available in 3500 people), (b) aortic plaque burden by MRI (n=2000), (c) carotid intimal-medial thickness by ultrasound (n=3500), (d) clinical atherosclerotic CVD (n=500), and (e) the dynamic balance between arterial calcification and bone demineralization (n=3500).
2. Identify the biochemical signature of metabolic syndrome components including (a) systolic and diastolic blood pressure (n=7000), (b) obesity (n=7000) and visceral adiposity by CT (n=3500), (c) dyslipidemia (n=7000), and (d) impaired fasting glucose, diabetes, and insulin resistance.
Biomarkers for this project will be selected by expert consensus on the basis of (a) a careful review of the literature for biomarkers of atherosclerosis and metabolic syndrome, and (b) genes implicated in atherosclerosis and metabolic syndrome (and their constituent components and pathways), or showing evidence of association with the phenotypes of interest.
Technology:As part of this project, new quantitative tests will be developed to measure circulating biomarker levels using antibody sandwich assays and/or proteomic approaches that are amenable to high throughput application. Critical to this project is the implementation of methods to measure large numbers of biomarkers with minimal sample volume; proteomic, bead-linked immunoassays, and nanotechnology methods may be necessary to accomplish this aim. Pathways to be studied include but are not limited to: Adhesion/chemoattraction, adipokines, cytokines, growth factors, heat shock proteins, inflammation, lipoproteins, neurohormones, thrombosis/fibrinolysis, and vascular calcification. Demonstrated rigorous assay validation using non-FHS samples will be necessary before FHS biospecimens can be used for this project.
Study Sample:The NHLBI's FHS is community-based[N1], which should contribute to the generalizability ofstudy results. Frozen serum/plasma/urine samples and buffy coats for WBC derived RNA are available in two carefully characterized cohorts comprising over 7000 individuals. The presence of young, middle-aged, and elderly subjects will allow a more complete exploration of biomarkers for relevant traits across a wide age range (20-90 years). The FHS main contracts (N01-HC-38038; N01-HC-25195) have provided for the core examinations of the participants that include physical examination, ECG, multidetector CT scans for coronary calcification and visceral adiposity, and blood specimen collection. In addition, buffy coats and purified white blood cell RNA also are available for WBC-derived RNA expression profiling to complement circulating biomarker and genotypic characterization.