This proposal is a request to continue a research project begun in 1987. It addresses the question: """"""""Does knowledge about variability in genes involved in lipid metabolism provide information for the prediction of coronary artery disease (CAD) in the population at large beyond that provided by the continuously distributed plasma measures of lipid metabolism that link the effects of genetic and environmental variation to variation in risk of disease?"""""""" As part of the Rochester Family Heart Study (RFHS) quantitative assays of nine measures of plasma lipids and apolipoproteins (Apos) have been collected on 3,980 living members (ages 5-90) and CAD endpoint information has been collected on 3,831 living (ages 20-90) and deceased members of 576 pedigrees ascertained through school children in Rochester, Minnesota. The first five years of the current project will have completed assays of eight polymorphic genes involved in lipid metabolism on 2,004 of these living individuals. In addition to developing new assays for genotyping candidate genes for CAD, the investigators have developed new statistical methods to identify RFLP haplotypes that carry mutations that affect quantitative measures of lipid metabolism. Analyses of the association between variability in the genes coding for the Apo E, H and AIV molecules and phenotypic variation in the nine measures of lipid metabolism have been completed. Their first studies suggest that allelic variation in the gene coding for the Apo E protein predicts interindividual differences in both quantitative measures of lipid metabolism and CAD endpoints. In this renewal application support is requested to carry out six aims that will: 1) provide new information about four polymorphic genes involved in reverse cholesterol transport; 2) complete the investigators' studies to evaluate the utility of genetic variation in 12 candidate genes for prediction of CAD; 3) identify individuals who carry mutations that have an impact on CAD; and 4) begin molecular studies of these individuals to define the DNA changes that are responsible. New noninvasive measures of CAD in asymptomatic individuals using ultrafast cardiac computed tomography will complement their efforts to evaluate the role of measured genetic variation in predicting CAD.Successful completion of their six aims will establish whether any of the 12 polymorphic genes that play a central role in regulating lipid metabolism predict interindividual variation in CAD once intermediate quantitative measures of lipid metabolism have been considered.
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