SUMMARY
Genetic epidemiology of thrombophilia/bleeding disorders in women.
The long-term objective of my research program is to describe the epidemiology, including genetic epidemiology, of the multifactorial disease, venous thromboembolism (VTE, thrombophilia). Using the resources of the Rochester Epidemiology Project, we have identified the 30-year inception cohort of Olmsted County residents with a first lifetime episode of deep vein thrombosis or pulmonary embolism. With this inception cohort, we described trends in the incidence of VTE over this 30-year period, as well as outcomes after VTE, including survival and VTE recurrence as well as predictors of survival and recurrence. We also identified an Olmsted County resident without VTE matched to each VTE case on age, gender, and medical record number, and performed a nested case-control study. We tested over 25 baseline characteristics as potential risk factors for VTE. In a subset of cases and controls, we collected plasma
and DNA samples. We have developed an automated method for rapidly screening genomic DNA for unknown mutations using denaturing high-pressure liquid chromatography (DHPLC). In addition, we have developed assays for rapidly screening for known mutations (allele detection) using allele-specific hybridization. With these assays and plasma samples, we are performing candidate-gene, case-control studies to identify single nucleotide polymorphisms ("mutations") which predict a change in either protein expression or function and are associated with VTE (either causative or protective), test for the independence of these mutations as risk factors for deep vein thrombosis or pulmonary embolism, and test for interaction of these mutations with other environmental exposures. With this information, we will be able to better stratify patients into high and lowrisk for VTE and either modify risk factors or target prophylaxis to those patients who would benefit most. More over, we are testing these mutations and exposures as predictors of VTE recurrence.
With this information, we will also target longterm anticoagulation therapy to those patient who would benefit most.
My second research program which has recently been funded addresses bleeding disorders among women. Specifically, this program addresses potential disorders of platelet function as the etiology of idiopathic menorrhagia among women of reproductive age. In addition to assessing the role of platelet dysfunction, this program also address novel therapies for menorrhagia (e.g., antifibrinolytic therapy or DDAV P therapy) as an alternative to hysterectomy or endometrial ablation. Drs. Whyte Owen (Extrinsic Hemostasis Research Laboratory), David Fass (Intrinsic Hemostasis Research Laboratory), William L. Nichols (Special Coagulation Diagnostic Laboratory), and Rajiv Pruthi (Hemophilia Treatment Center) are co-investigators for this program.