Human exomics genotyping-driven discovery and characterization of proteins related to clinical thrombosis, blood coagulation and thrombin generation

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7. PROJECT SUMMARY/ABSTRACT Advancing basic and clinical knowledge about thrombosis is the major goal of this Project. Excessive thrombin generation causes thrombosis, including venous thromboembolism (VTE) which is a complex disease. Genomics-based research should be a powerful tool for discovery of VTE risk factors, but GWAS had added few new insights. In contrast to GWAS that is centered on common gene variations, new exome genotyping arrays permit interrogation of rare functional variants throughout the genome. Race-specific causal factors for VTE in Caucasian, Japanese and Chinese populations involve rare variants in coagulation proteins. The missing heritability of VTE risk may be attributed, in part, to rare or low frequency variants. Exome genotyping can interrogate > 250,000 variations for rare missense variants that might alter a protein's functional activity. Our initial application of exome array technology to one cohort of European Americans and one cohort of African Americans yielded surprising findings which will be confirmed and extended by this project. While identification of new genetic variants linked to VTE represents significant and valuable genetic associations, it is critical to determine whether and how the biological activities of the newly implicated candidate gene's product may contribute to thrombosis. Our initial exome genotyping implicated certain structural protein genes as being linked to VTE risk, including some myosin heavy chain genes. This surprising discovery led to the discovery that some myosins have procoagulant activity. We propose to characterize the mechanisms by which myosin promotes thrombin generation by its interactions with clotting factors. We also propose to clarify mechanisms by which the constitutive plasma protein, serum amyloid A 4, interacts with clotting factors to promote thrombin generation. A major goal of this project is to discover new genetic rare variants that are linked to VTE among the understudied African American population for whom no genetic risk factor has yet been widely recognized. Our initial exome genotyping data significantly identified a set of VTE- linked rare variants unique to African Americans and another set of VTE-linked rare variants unique to Caucasian Americans. For this project, we propose to study seven cohorts from key collaborating centers wherein these studies will include circa 3,000 Caucasians and 2,000 African Americans. These cohorts will enable replication of our initial exome genotyping-based discoveries and will facilitate efforts for further discoveries of exomic rare variants linked to VTE. If successful, new knowledge from this project will include discovery of thrombosis-related rare genetic variants and revelation of new proteins that may contribute to thrombosis risks. This new knowledge about new genes and previously unrecognized proteins will significantly extend our concepts about VTE pathophysiology and will have potential implications for new diagnostic or therapeutic applications.