PROJECT 4: Clinical and genetic predictors of myocardial infarction in coronary disease

Mark Hlatky MD, Principal Investigator

The aim of this particular project is to characterize the clinical and genetic determinants of acute myocardial infarction among patients with clinically manifest coronary artery disease. In particular, we seek to identify the risk factors for the steps along the pathway that leads from a stable, quiescent coronary plaque to plaque rupture, superimposed thrombosis, myocardial ischemia, and ultimate myocardial infarction. In order to achieve this aim, we will identify a cohort of new-onset coronary disease patients from a population-based sample drawn from Kaiser Permanente Medical Care Program of Northern California. By capitalizing on the comprehensive medical care provided in the Kaiser system and their sophisticated clinical data systems, we will quickly access a large group of eligible subjects. Thus, we propose:

(1) To recruit patients with acute MI as their initial clinical manifestation of CAD (N=1000) as well as control subjects with angina (N=1000) as their initial clinical manifestation of CAD. We will collect data on cases and controls through chart reviews, clinical interviews and blood sampling.

(2) To collect genomic DNA from blood samples obtained on all cases and controls. Single nucleotide polymorphisms identified in candidate gene loci will be evaluated in all cases and controls (see Project 2 for detailed description of genetic methodology). We will be particularly interested in polymorphisms that are associated with genes that may influence inflammatory response, coagulation and fibrinolytic systems, or myocardial injury. Correlation of the genotype and phenotype will be attempted using sophisticated statistical methodology derived and supported by the Biostatistiscs Core, directed by Dr. Richard Olshen.

These studies will thus, represent a direct test of the hypothesis that variations in the expression or function of genes determine, at least in part, the risk of acute coronary events in patients with pre-existing coronary disease. Elucidation of the role of genes in the modulation of coronary risk should ultimately improve clinical decision-making about treatment and preventive strategies, and identify new avenues for treatments based on a better understanding of the pathophysiology of coronary events.