The purpose of this study is to define factors contributing to coronary heart disease (CHD) in high risk families. The population includes 859 siblings of patients with proven clinical CHD before age 60, entered into the Johns Hopkins Sibling Study from 1982-1996 representing 490 families. Siblings were 30-59 years old and unaffected at entry. All underwent comprehensive risk factor screening and exercise thallium tomography to identify occult CHD. Follow-up will be performed from 6-15 years after entry (mean 8.7 years) to determine the incidence of (1) acute coronary events (sudden death, myocardial infarction, and unstable angina) and (2) progression of occult CHD (repeat exercise thallium tomography). Blood will be obtained for genomic DNA, which will be tested for polymorphisms of candidate genes which may be associated with premature thrombotic CHD events (platelet proteins GPIIB/IIIa[PlA1/A2 and Baka/b] and GPIbB, endothelial nitric oxide synthase, angiotensin converting enzyme, angiotensinogen, D-fibrinogen, plasminogen activator-1, and methylenetetrahydrofolate reductase). Plasma levels of proteins implicated in the pathogenesis of atherosclerosis and thrombotic CHD events will be measured (fibrinogen, plasminogen activator inhibitor-1, tissue plasminogen activator, homocysteine, lipoprotein (a), and apo(a) isoform size). DNA will also be obtained from living probands and affected siblings to use for genetic linkage studies using affected and unaffected sibling pairs. Statistical analyses will examine (1) whether selected genetic polymorphisms are linked to the occurrence of acute CHD events, and (2) to what extent traditional sociodemographic and biological coronary risk factors or new genetic polymorphisms explain the progression of occult CHD, or the transition from occult to symptomatic CHD events in families with premature CHD. This study will provide important insights into the phenotypic and genetic determinants of clinical and occult CHD in families with premature CHD.
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