[Federal Register Volume 71, Number 223 (Monday, November 20, 2006)]
[Notices]
[Pages 67148-67149]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-19522]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

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.

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SUMMARY: National Heart, Lung, and Blood Institute (NHLBI) seeks 
partners in a biomarker consortium to promote research on novel serum/
plasma/urine biomarkers of cardiovascular disease (CVD) and related 
risk factors including atherosclerosis, obesity, insulin resistance, 
hypertension, and metabolic syndrome. An immediate consequence of this 
project will be the development of new diagnostic tests to identify 
individuals at high risk for CVD and its risk factors at a time when 
intervention is most feasible. A downstream result of the 
identification of novel biomarkers of CVD (and its risk factors) will 
be the discovery of disease promoting pathways, which may serve as new 
therapeutic targets for treating and preventing our nation's leading 
cause of death.
    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 of

[[Page 67149]]

study 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.

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 (E-
mail: [email protected]). 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 (E-mail: [email protected]).

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.

    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.
[FR Doc. E6-19522 Filed 11-17-06; 8:45 am]
BILLING CODE 4140-01-P