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National Institutes of Health

National Heart, Lung, and Blood Institute: Circulating Biomarkers of Cardiovascular Risk in the NHLBI's Framingham Heart Study

AGENCY: National Heart, Lung, and Blood Institute, NIH, HHS.
ACTION: Notice.
SUMMARY: Background:Despite steady declines in CVD mortality, CVD remains the leading cause of death in the developed world. The NHLBI's Framingham Heart Study (FHS) has been instrumental in the identification and elucidation of key modifiable risk factors for CVD, which in turn have facilitated modern approaches to the prevention and treatment of CVD. Because of its prospective study design, the NHLBI's FHS is ideally positioned to enable identification of novel risk factors for CVD. The availability of frozen serum/plasma/urine samples from over 7000 FHS participants in the Offspring and Third Generation cohorts, in concert with new high-throughput quantitative biomarker technology available from commercial collaborators, provides a unique opportunity to explore the biochemical signatures of key CVD phenotypes. In addition, by the end of 2007 genotyping of 550k SNPs will be completed in nearly all the FHS participants as part of the NHLBI's SHARe project and these data will permit analysis of the associations of gene variants with biomarker levels.

Scientific Scope:The proposed study will measure 150 or more evolving and novel biomarkers from the FHS in 7000 FHS subjects for whom subclinical and clinical CVD and its risk factors have been carefully characterized. Analyses will be conducted for association of biomarkers--individually and collectively--with clinically relevant phenotypes.

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.

DATES: Effective Dates:Inquiries regarding this Notice and scientific matters may be forwarded at any time. Confidential, written letters of interest, preferably two pages or less, must be submitted to NHLBI on or before January 19, 2007. Guidelines on next steps will be communicated shortly thereafter to all respondents with whom initial confidential discussions will have established sufficient mutual interest.
ADDRESSES: Interest regarding this notice should be forwarded to: Ms. Lili Portilla, NHLBI Office of Technology Transfer and Development, 6705 Rockledge Drive, Suite 6018 MSC 7992, Bethesda, MD 20892-7992 ( Scientific inquiries should be submitted to Daniel Levy, M.D., FACC, Director, Framingham Heart Study, Center for Population Studies, National Heart, Lung, Blood Institute, 73 Mt. Wayte Avenue, Suite 2, Framingham, MA 01702 (
Dated: November 3, 2006. Suzanne Freeman, NHLBI Project Clearance Liaison, National Institutes of Health. Dated: November 3, 2006. Daniel Levy, Director of the NHLBI Framingham Heart Study, National Institutes of Health.