PATHOBIOLOGICAL DETERMINANTS OF ATHEROSCLEROSIS IN YOUTH

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The overall goal of this competitive renewal proposal (yrs 06-10) remains the same as the original grant (yrs 01-05); that is, to identify genetic factors that influence the extent and severity of atherosclerotic lesions in autopsied young persons. This genetic project is a component of two nationwide multicenter studies that collect and measure lesions in arterial tissues from victims of accidents, homicide, and suicide (ages 15-34). The initial multicenter study was entitled "Pathobiological Determinants of Atherosclerosis in Youth (PDAY)," and collected a total of 1,532 cases from eight forensic pathology laboratories throughout the country. To obtain additional cases (particularly females), the PDAY collection was continued in a project titled "Risk Factors of Early Human Atherosclerosis (RFEHA)." The total number of PDAY-RFEHA cases is projected to be 2,654. PDAY-RFEHA studies also measure known risk factors of atherosclerotic diseases, including postmortem serum levels of lipids and lipoproteins, thiocyanate (measure of smoking), and glycosylated hemoglobin (measure of diabetes). Other measurements include medical thickness of renal arterioles (measure of hypertension) and subcutaneous fat (measure of obesity). The 1988 PDAY genetic study began by collection of liver samples (50 g) from each case. A small portion of each sample (0.5 g) is used to extract DNA, and the remainder is stored at -80 degrees C as a national resource for future genetic studies. The hepatic DNA is used to determine genotypes for polymorphisms in candidate genes of atherosclerosis. The genotypes are used for statistical and population genetic analyses to determine their effects on measured risk factors and arterial lesions. The PDAY genetic study is unique in its ability to identify genes that affect lesions, even in the absence of measured physiological intermediates. In years 0-1-05, this project focused on genes involved in cholesterol metabolism (apolipoproteins and the LDL receptor), resulting in the first published reports of the effects of genetic polymorphisms on direct measures of atherosclerosis. In years 06-10, we propose to continue our studies of genes involved in cholesterol metabolism, and to begin a new initiative to examine effects of genes that are directly involved in lesions in the arterial wall. The aims of this competitive renewal proposal are to (1) continue acquisition of PDAY-RFEHA liver samples and extraction of DNA to increase numbers of cases (particularly females) for statistical analyses, (2) continue typing of genes involved in lipid metabolism, (3) identify and type polymorphisms in genes involved in lesions in the arterial wall, (4) apply new techniques that do not rely on differences in restriction enzyme cleavage sites to detect polymorphisms, (5) perform statistical and population genetic analyses to determine effects of candidate gene polymorphisms on measured risk factors and extent and severity of atherosclerosis, and (6) determine the underlying nucleotide sequence differences that are responsible for genotype associations.