The purpose of the proposed study, Genetics of Coronary and Aortic Calcification (GENCAC), is to identify genetic factors that establish susceptibility to (a) coronary and aortic atherosclerosis and (b) inter-individual variability in the inflammatory response. We propose to quantify coronary and aortic artery calcium volume in 441 selected, informative pedigrees (~ 3,000 individuals) previously examined and extensively genotyped (~400 markers spanning the genome) by the NHLBI Family Heart Study, in order to identify genes associated with human atherosclerosis. An additional 275 African American sibships (~600 individuals, also examined and comparably genotyped) will be included to address these study questions in this high-risk population. Assessment of the inter-individual variability in the inflammatory burden and the host response, and the extensive metabolic, behavioral, and environmental data already collected on these pedigrees will provide enhanced phenotypic homogeneity and increased analytic power in assessing the genetic basis of atherosclerosis. State of the art laboratory and statistical methods will be used to find, localize and characterize the influence of predisposing genes to atherosclerosis and the inflammatory response. Novel genetic analysis methods will be used to address the issues of phenotypic, genetic and population heterogeneity, epistasis, complex interactions among the genetic and environmental risk factors, and to optimize the detection of genomic regions affecting phenotypic susceptibility. The notorious issue of multiple comparisons in genome scans will be bypassed with the use of novel global testing procedures. Based on a cost-efficient design of informative pedigrees and employing novel methodology, this study will contribute currently unavailable information on genetic and environmental determinants of atherosclerosis, with a focus on the prevention of this widely prevalent condition associated with high burden of costs to society.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL067899-03
Application #
6657293
Study Section
Special Emphasis Panel (ZHL1-CSR-L (M1))
Program Officer
Silsbee, Lorraine M
Project Start
2001-09-17
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$365,442
Indirect Cost
Name
Washington University
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Lamina, Claudia; Friedel, Salome; Coassin, Stefan et al. (2016) A genome-wide association meta-analysis on apolipoprotein A-IV concentrations. Hum Mol Genet 25:3635-3646
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Robbins, Jeremy M; Petrone, Andrew B; Ellison, R Curtis et al. (2014) Association of egg consumption and calcified atherosclerotic plaque in the coronary arteries: the NHLBI Family Heart Study. ESPEN J 9:e131-e135
Miedema, Michael D; Petrone, Andrew B; Arnett, Donna K et al. (2014) Adult height and prevalence of coronary artery calcium: the National Heart, Lung, and Blood Institute Family Heart Study. Circ Cardiovasc Imaging 7:52-7
Lai, Y H Lana; Petrone, Andrew B; Pankow, James S et al. (2013) Association of dietary omega-3 fatty acids with prevalence of metabolic syndrome: the National Heart, Lung, and Blood Institute Family Heart Study. Clin Nutr 32:966-9
Arbeev, Konstantin G; Hunt, Steven C; Kimura, Masayuki et al. (2011) Leukocyte telomere length, breast cancer risk in the offspring: the relations with father's age at birth. Mech Ageing Dev 132:149-53

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