Genetics of CRP in families with myocardial infarction

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DESCRIPTION (provided by applicant): Coronary artery disease (CAD) and myocardial infarction (MI) are the leading causes of death in the Western world. Numerous epidemiological studies have demonstrated the impact of various risk factors, such as arterial hypertension, hypercholesterolemia and diabetes mellitus. While these risk factors are partly under genetic control, a positive family history remains an additional independent predictor of CAD, suggesting the presence of as yet unidentified susceptibility loci. Given the enormous public health burden of CAD, there is significant interest in identifying its specific genetic foundations. As intensive experimental investigations continue, the inflammatory component of the disease process leading to atherosclerosis evolves as a key aspect in the disease process. Recent evidence demonstrates that systemic markers of inflammation such as C-reactive Protein (CRP) can predict those at high risk of coronary events. CRP emerges with much attention as both a diagnostic marker and therapeutic target with serum levels determined to a significant extent by genetic factors. As the overall objective of this project, we propose to work towards clarifying the genetic basis of CRP and it's genetic influence and relation to CAD/MI through the use of genetic linkage and association studies. In families with MI we have identified a susceptibility locus for MI as well as loci influencing CRP levels. In addition, we have a confirmation of the linkage signals for CRP in a different, independent population. As a mean to elucidate the genetic basis of the inflammatory component of MI and the regulation of CRP, we propose a gene function-oriented evaluation of candidate genes, which map to the above mentioned QTLs. Therefore the specific aims are as follows, 1. We will identify positional candidate genes within regions we have identified for MI and CRP which are functionally related to inflammation and inflammatory processes. We will identify sequence variation in selected candidate genes. 2. We will evaluate the effect of these variants with regard to MI and CRP in two different ethnic populations: our family set of European Caucasians and a population-based, Hispanic family dataset. We will further evaluate the role of CRP as a predictor of cardiovascular events in our study populations. As we have clinical follow up data available on both of our study populations, we will test to what extent CRP contributes to an increased risk for cardiovascular events in the framework of our family analysis.