We propose to investigate gene-gene and gene-environmental interactions in venous thrombosis with the goal of better defining individualized clinical risk profiles, optimal, optimal clinical management practices and underlying pathophysiology. Our study population is a group of extended, related thrombophilic pedigrees of French/French Canadian descent (n=1400), living in France, Quebec and Vermont, which share type I protein C deficiency due to a rare 3363 C insertion mutation. The mutation exhibits haplotypic identity across the Quebec, Vermont and probably French families. Thus, the abnormal allele is identical across the population with respect to not only protein C coding and intronic sequence but also related nearby regulatory or co-regulated elements. Therefore, our study population creates a unique opportunity to study the multicausal nature of thrombosis with one of the major modifying loci held constant. Some of these families have been studied by investigators for up to 15 years. We will study the following hypotheses in this study population by a combination of an ambispective longitudinal familial cohort study and molecular biologic strategies focused on gene discovery: 1. The risk for venous thrombosis is a function of a definable subset of oligogenic and environmental factors and their interaction. 2. Clinical management will be improved by better understanding of individual global risk profiles. 3. Quality of life will be affected to varying degrees by the knowledge of an individual's risk profile as well as the presence of disease. 4. Expression of many individual and composite biochemical risk factors, characterized as continuous variables, will reflect the inheritance of single genes that can be localized within the genome. This collaborative clinical study will bring together complementary expertise from five major academic centers, with existing collaborative relationships, in North America and Europe.
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