Coronary artery disease (CAD) is the single largest killer of Americans. Relative to European Americans, African Americans have higher mortality rates from CAD, particularly in women and younger men. A high prevalence of risk factors (e.g., hypertension) and associated co-morbidities (e.g., end stage renal disease and left ventricular hypertrophy), poor risk factor control, and reduced access to care are likely contributors to some, but not all, ethnic disparities in CAD events. Atherosclerosis is the major cause of CAD and extent of coronary atherosclerosis is the most powerful predictor of subsequent clinical events. Non-invasive imaging of coronary artery calcification (CAC) has emerged as a useful method to assess CAD risk, especially in intermediate risk patients. Quantity of CAC measured by computed tomography correlates directly with quantity of coronary atherosclerotic plaque and CAC quantity in asymptomatic adults predicts risk for future clinical events. Asymptomatic African Americans with evidence of subclinical coronary atherosclerosis, as assessed by CAC quantity, are the highest risk ethnic minority population when European Whites are the reference group. Identification of CAD susceptibility genes in African Americans will provide insights into disease biology and suggested targets for novel therapeutic approaches. In this revised application, we propose to build upon the resources of the Genetic Epidemiology Network of Arteriopathy (GENOA) Study, part of the Family Blood Pressure Program. The GENOA Study is a population-based cohort of hypertensive sibships extensively characterized through two exams conducted between 1995 and 2004. GENOA has conducted studies to identify genes for hypertension and target-organ damage. We will extend those efforts by assessing CAC quantity in 900 African American siblings from the GENOA Field Center in Jackson, MS. 381 marker loci spanning the genome, already measured in GENOA will be used to localize genes influencing CAC quantity (for Aim 1). These same marker loci will then be used to localize genes with pleiotropic effects on CAC quantity and each of the CAD traditional and novel risk factors (Aim 2). We propose to follow-up the genome-wide linkage analysis for CAC quantity by localizing positional candidate genes under the most compelling LOD score peaks (from Aims 1 and 2) and evaluate the relationship of nucleotide variation in the identified candidate genes with CAC quantity. Genetic studies in African American populations will advance knowledge of mechanisms of subclinical atherosclerosis as well as lead to improved strategies for early identification of individuals at risk for CAD events, and development of new, more efficacious treatments tailored to those most likely to respond.
