The current proposal is part of an ongoing collaborative project aiming at the study of genetic factors associated with cardiovascular disease in the Brazilian population. In this scenario, different undergraduate and graduate students from both the University of São Paulo and Harvard Medical School are already conducting research and experiments using this collaborative resource under the supervision of Prof. Alexandre Pereira on the Brazilian side, and Prof Christine Seidman on the Harvard side.We plan to undertake, during the one-year in-residence period, analysis dealing with understanding the different roles of genetic factors, local genetic ancestry, and socio-economic factors in a Brazilian cohort of patients. Specifically, I will extend previous studies from the Seidman lab by determining if renina-angiotensin-aldosterone (RAA) rare variants also contribute to treatment responses in the hypertensive Brazilian population. I will sequence the nine RAA genes in 200 Brazilian hypertensive subjects, selected based on their ancestry and response to anti-hypertensive medication. The clinical part of this work has already been conducted and is part of the ReHot trial, a 2,000 patient, multi-center, randomized, clinical trial coordinated by our group at the University of São Paulo. These analyses will test the hypothesis that subsets of the Brazilian hypertensive patients, like African Americans, are enriched for deleterious RAA variants and will be less responsive to ACEi treatment. By associating genetic admixture of Brazilian hypertensive patients with rare deleterious RAA, we will gain insights into the origins of these variants and as well improve the selection of hypertension treatment. While previous studies that propose a race-based approach to the selection of the most efficacious antihypertensive therapy use race as an important proxy, these preliminary findings suggest that RAA genotype, not race, account for the individual therapeutic response. While there are current technical and economic barriers to individualized sequence-based approaches, the public health benefit in terms of both decreased cardiovascular disease burden and decreased medical costs may outweigh these barriers. A 10mmHg decrease in SBP using pharmacological therapy results in a 22% reduction in coronary heart disease and 41% reduction in stroke. Given the population scale burden of coronary heart disease and stroke, the additional cost of a sequence-based pharmacogenomic test to select initial antihypertensive medication may be a worthwhile investment.
News published in Agência FAPESP Newsletter about the scholarship: