Coronary artery disease (CAD) is a major cause of morbidity and mortality in the US. Since half of those who suffer myocardial infarctions and sudden death are previously asymptomatic, studies of individuals with atherosclerosis but without symptoms will contribute to the understanding of preclinical disease. Coronary artery calcification (CAC) provides a potent marker of atherosclerosis because it can identify individuals with mild, non- flow limiting lesions. CAC has been shown to predict future CAD events in asymptomatic adults. Electron beam computed tomography (CT) is an accurate, noninvasive method to quantify and locate CAC in atherosclerotic plaques. Quantity of CAC correlates with plaque area and predicts coronary artery stenosis better than established CAD risk factors. In the first four years of this study, the investigators determined the distribution of quantity of CAC in asymptomatic adults from the Rochester Family Heart Study. Most inter-individual variability in quantity of CAC could not be explained by established CAD risk factors. Notably, they found the first evidence that genetic factors contribute to familial aggregation of quantity of CAC. These findings motivate the aims of this continuation application to localize genes that influence quantity of CAC (CAC genes). This proposed study takes advantage of electron beam CT measures of quantity of CAC, measured CAD risk factors, and stored buffy coats for more than 600 asymptomatic adults, and new data to be collected from 500 of their siblings. The investigators will use robust sibling pair linkage methods and the 100 most discordant sibling pairs for quantity of CAC to determine: (1) whether highly polymorphic tandem repeat loci in or very near to 35 candidate genes involved in calcification and/or the atherosclerotic process are linked to CAC genes (Aim 1), and (2) whether any highly polymorphic anonymous markers evenly spaced throughout the human genome are linked to CAC genes (Aim 2). The investigators also will determine whether any linked markers, anonymous or in candidate genes, explain interindividual variability in quantity of CAC in a sample of 1,100 asymptomatic women and men (Aim 3). Understanding genetic susceptibility to asymptomatic atherosclerosis measured by quantity of CAC will increase understanding of atherosclerosis and improve early identification of individuals who will benefit most from existing or new interventions.
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