INFLUENCE OF GENOTYPE ON FIBRINOGEN STRUCTURE

Fibrinogen is widely regarded as an independent risk factor for cardiovascular disease based on the finding that elevated plasma levels are associated with an increased incidence of ischemic heart disease, stroke and atherosclerosis. In view of this and because heart disease is known to be familial, recent studies have placed considerable emphasis on the role of fibrinogen genotype as a contributor to cardiovascular disease risk. These studies, primarily epidemiologic in design, have focused on 'mutations' that control basal levels of plasma fibrinogen. The consensus appears to be that something about fibrinogen-other than its plasma level alone- is responsible for its role in cardiovascular disease risk. The studies that we would like to undertake are concerned with how fibrinogen genotype affects the protein's structure and function, specifically as it relates to clot formation and dissolution. These processes ultimately determine whether a thrombus formed in response to injury will do its job in staving excessive blood flow and then dissolve in a timely fashion to restore vessel patency or will linger and promote the acute thrombotic events asociated with ischemic heart disease, stroke or atherosclerosis. We propose to perform a series of immunochemical studies to characterize the structure and function (phenotype) of plasma fibrinogen obtained from healthy individuals that represent the varied genotypes possible at two defined sites within the fibrinogen gene(s). Thus, these studies potentially offer a new approach to exploring the question of how fibrinogen might exert its deleterious effect as a risk factor for cardiovascular disease. A control population of healthy adults will serve as the starting point for these studies. Genotyping at two different polymorphic sites in the fibrinogen gene(s) will be performed for each individual in the study population and, based on this intial screening, selected plasmas representing different groups of genotype combinations will be selected for subsequent 'phenotyping'. Plasmas from each group will be analyzed using novel immunochemical methods developed in our laboratory to determine aspects of fibrinogen structure and function (phenotype) related to clot formation and dissolution. Standard statistical procedures will be applied to determine whether the different 'phenotypes' observed are associated with the different groups of genotype combination represented in our study population.