The purpose of the proposed study, Genetics of Coronary and Aortic Calcification (GENCAC), is to identify genetic factors that establish susceptibility to (a) coronary arid aortic atherosclerosis and (b) inter- individual variability in the inflammatory response. We propose to quantity 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 Fancily 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, arid 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 measurement and laboratory methodology, this study will contribute currently unavailable information on genetic and environmental susceptibility to subclinical atherosclerosis, a widely prevalent condition associated with high costs to society. This application corresponds to the GENCAC Central Biochemistry Laboratory submitted by the University of Minnesota as part of tire GENCAC genetic epidemiology network.
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