GENES AND SEVERE HYPERTENSION AMONG AFRICAN AMERICANS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. African-Americans bear the highest rates of hypertension in the world. The consequences of this burden are well known and include very high rates for stoke, heart disease, and renal disease. While we have made impressive gains in the understanding and treatment of hypertension, we have much more to do, especially among African-Americans. Thanks to the efforts of investigators at Johns Hopkins and many others, we now know many of the important exposures, but the allelic variants responsible for the predisposition to hypertension and its end-organ effects remain elusive. Therefore, we have designed, and begun to carry out, a family-based case-control study into the mechanism of hypertension emphasizing the genetic predisposition but including the environmental and cultural contexts. We hypothesize that common allelic variants of the genes encoding the G protein beta3 subunit, the alpha-subunit of the adducin cytoskeletal protein, the beta2- adrenergic receptor, the alpha and beta-subunits of the epithelial sodium channel, angiotensin-converting enzyme, and angiotensinogen are associated and linked with blood pressure level among African- Americans. We are recruiting 200 African-American probands with severe hypertension admitted to the Johns Hopkins Hospital, 200 unrelated normotensive African-American controls and the siblings of both cases and controls. The inclusion of participants from both ends of the blood pressure spectrum will maximize our ability to detect genes with small effects. Restricting recruitment to African-Americans from one environmental and cultural milieu will further maximize our power by limiting phenotypic, environmental and cultural heterogeneity. To control for the heterogeneity that remains, we will further characterize each participant's phenotype, exposure history, and family origins. We will limit confounding due to population substructure and admixture by obtaining a detailed genealogy and using sibling controls. Within the context of this family-based case-control study, we will test both association and linkage using the case-control analysis with family controls as well the sibling transmission/disequilibrium test. This epidemiological approach has the best chance of uncovering the genomic causes of hypertension given the mechanistic complexity of blood pressure regulation and the complexity of the population structure of African-Americans.