Genomic Approach to Gene Discovery in Thrombophilia

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In Project 6 (formerly Project 2), we have been investigating gene-gene interactions in a large, extended (n=800) French Canadian, protein C deficient, thrombophilic family in which we have identified three genomic regions with significant linkage to thrombosis. This kindred has been demonstrated to have a small number of genes (one to three) interacting with protein C to cause thrombosis, thus characterizing thrombophilia in this family as an oligogenic disease. Oligogenic diseases offer attractive models for investigating multigenic diseases, in contrast to polygenic diseases like atherosclerosis which have numerous susceptibility genes, each of small effect. In this family the remaining heritability for thrombosis of 0.40, after correcting for the heritability of the protein C mutation, suggests that the unknown susceptibility gene(s) have an effect of about the same magnitude as protein C. Thus, the effect of the unknown gene(s) should be detectable by modern genomic strategies. In pursuing this strategy we have resequenced 109 candidate genes within the three genomic regions linked with thrombosis (about 50% of the genes in these regions) using a case control design. In our preliminary analysis of this rich database, using SNP genotyping on additional family members based on SNPs identified by resequencing, we have identified an attractive candidate gene by genetic epidemiological analysis with preliminary phenotypic corroboration from microarray experiments which compared endothelial cells cultured from affected family members with normal controls. The goals of this project are to: 1) thoroughly analyze the database of resequenced genes in the Vermont family with respect to an increasingly complex hierarchy of interacting susceptibility genes, 2) validate these findings in independent populations, 3) extend our investigation to the biological pathways implicated by the individual candidate genes identified in the Vermont kindred in cases where individual SNPs identified in the analysis of the family dataset are not reproduced in independent populations using a similar SNP genotyping and resequencing approach and 4) improve risk profiling so that individuals at increased risk for thrombosis due to identified genetic risk factors can receive appropriate intensity and duration of treatment for prophylaxis and for acute events. As candidate genes and the biological pathways they implicate are identified they will be explored in collaboration with the other investigators in the program project group. Relevance: This study will improve individual physician's ability to predict the risk for an individual patient to develop life threatening clots in their veins and therefore allow for more effective treatment of this life threatening disease. It will also decrease the number of serious chronic side effects that result from damage to the blood vessels which contain the clots.