Nearly one million Americans died of CVD in 1999, and it is predicted that, over one million Americans will have a myocardial infarction (MI) with 650,000 of these experiencing their first MI. Coronary artery disease (CAD) is the leading cause of mortality in the U.S., accounting for 1 of every 5 deaths, or 680,000 of more than 2,000,000 deaths. CAD is also the leading cause of premature, permanent disability in the U.S. labor force, accounting for more than $110 billion in health care costs annually, as compared to $329 billion for all CVD. Risk factors for CAD include high blood pressure, tobacco smoke, abnormal lipids and lipoproteins, physical inactivity, overweight and obesity, diabetes mellitus, increasing age, male sex, heredity, individual response to stress, and menopause in women. Other indicators for increased risk of events include the presence and extent of coronary artery calcification, endothelial dysfunction, and platelet aggregation. Of those who die suddenly from CAD, 50% of men and 63% of women have no previous symptoms. Studies of how specific environmental interventions may interact with genes to influence selected risk factors, especially in individuals with varying extent of vascular calcification, a marker of atherosclerosis, will facilitate the early identification of asymptomatic high-risk individuals who will benefit from existing or new interventions.
The overall objective of this proposal is to identify novel loci (and ultimately genes) that interact with specific environmental exposures to modify risk factors for cardiovascular disease (CVD). To achieve this goal, we will perform four short-term interventions known to modify CVD risk in participants of the Amish Family Calcification Study (AFCS), an ongoing study of the joint genetic determinants of CVD and osteoporosis. Over 1,000 individuals from this ongoing study have already been recruited and are being characterized with respect to CVD risk factors, including blood pressure, body composition, lipids, and coronary artery calcification (by electron beam computerized tomography (EBCT)). From a previous examination, DNA has been collected on all AFCS subjects and a 5-cM genome scan (\~800 short tandem repeat (STR) markers) has been completed by the NHLBI Mammalian Genotyping Service. Thus, this large family study from a unique genetically homogeneous founder population provides an ideal opportunity to identify genes that interact with the environment in shaping risk factors for CVD. The Specific Aims of this proposal are:
1. To perform four focused short-term interventions known to affect cardiovascular function in 1,000 subjects from the AFCS. Responses of relevant CVD-related quantitative traits will be measured. The interventions and responses will be: a. cold pressor stress and changes in blood pressure and changes in endothelial function as assessed by brachial artery dilation (BART); b. a high fat load and changes in brachial artery flow mediated dilation (FMD) and serum lipid levels; c. high salt and low salt diets and changes in blood pressure; and d. aspirin and changes in platelet function and inflammatory markers.
2. To characterize the genetic epidemiology of the responses to each short-term intervention by: a. estimating the heritability of each response to the intervention; b. determining if response to intervention is correlated with coronary artery and aortic calcification and if so, if the association can be explained by common genes or shared environments; and c. determining if response to intervention is correlated with baseline measures of CVD risk factors, and if so, if the association can be explained by common genes or shared environments.
3. To identify specific chromosomal loci that influence CVD-related trait responses to the four short-term interventions by performing genome-wide linkage analysis utilizing a 5 cM density (\~800 STR markers) genetic map already available in 1,000 subjects of the AFCS.
4. To determine if chromosomal regions linked to, or associated with, variation in CVD-related trait responses are also linked to, or associated with, variation in coronary artery or aortic calcification.
5. To fine map the putative chromosomal loci linked to variation in CVD-related trait responses to short-term environmental interventions through linkage disequilibrium mapping with closely spaced single nucleotide polymorphism (SNP) markers.
