The results of the early-terminated WHI hormone trials (WHI-HT) led to a dramatic 50% reduction in hormone use by post-menopausal women in the ensuing 5 years since the trial was terminated. Yet, controversy persists, and several important clinical and scientific questions remain unresolved. Individuals are known to vary considerably in response to drug therapy and other interventions, both in magnitude of treatment effect and in risk of adverse events. Much of this variation in drug response has been hypothesized to have a genetic basis. Based on previous data from animal models, observational human studies, and accruing candidate gene and plasma biomarker and proteomic data from WHI-HT, estrogen and progesterone have multi-factorial effects on atherosclerotic and metabolic traits. Nonetheless, the specific genetic factors that govern the overall risk of vascular and metabolic disorders in response to hormone therapy are largely unknown. Because it requires fewer a priori assumptions, a genome-wide approach may increase the likelihood of identifying risk variants and may reveal novel mechanisms. Moreover, the breadth and depth of genomic linkage disequilibrium coverage on current 1 million SNP whole-genome platforms allow for more focused analysis and follow-up of candidate genes based on prior biologic hypotheses. Therefore, a comprehensive evaluation of SNPs using current generation genome-wide association (GWA) technology is the next logical step to screening susceptible populations. As such, the value of using existing epidemiologic data and biologic specimens from the large, population-based randomized hormone trials of WHI will be substantially increased by the addition of GWA genotyping studies through this proposal. We hypothesize that it is possible to identify common variants that reproducibly alter risk of vascular events (CHD, stroke, and VTE) and diabetes after exposure to estrogen with or without progestin in postmenopausal women. Public Health Relevance: Information generated from this study will be critical to determine the health impact of genetic variants on the balance of benefits and risks associated with hormone therapy in post-menopausal women. Findings may also provide valuable insights into disease pathways and mechanisms, and identify novel targets for disease screening, prevention, and treatment of cardiovascular events and diabetes in women.
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