GENES AND SEVERE HYPERTENSION AMONG AFRICAN AMERICANS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。非洲裔美国人是世界上高血压发病率最高的人。这种负担的后果是众所周知的，包括非常高的斯托克、心脏病和肾脏疾病的发生率。虽然我们在了解和治疗高血压方面取得了令人印象深刻的进展，但我们还有更多的工作要做，特别是在非洲裔美国人中。多亏了约翰霍普金斯和其他许多研究人员的努力，我们现在知道了许多重要的暴露，但负责高血压易感性及其终末器官效应的等位基因变异仍然难以捉摸。因此，我们设计并开始进行一项以家庭为基础的病例对照研究，以探讨高血压的发病机制，强调遗传易感性，但包括环境和文化背景。我们假设编码G蛋白β 3亚基、内收蛋白细胞骨架蛋白α亚基、β 2肾上腺素能受体、上皮钠通道α和β亚基、血管紧张素转换酶和血管紧张素原的基因的常见等位基因变体与非裔美国人的血压水平相关。 我们正在招募200名患有严重高血压的非裔美国人先证者入住约翰霍普金斯医院，200名无关的血压正常的非裔美国人对照组和病例的兄弟姐妹。包括来自血压谱两端的参与者将最大限度地提高我们检测影响较小的基因的能力。限制从一个环境和文化环境中招募非裔美国人将通过限制表型，环境和文化异质性进一步最大限度地发挥我们的力量。为了控制仍然存在的异质性，我们将进一步描述每个参与者的表型，暴露史和家庭来源。我们将通过获得详细的系谱和使用同胞对照来限制由于群体亚结构和混合而引起的混杂。在这项以家庭为基础的病例对照研究的背景下，我们将使用家庭对照的病例对照分析以及同胞传播/不平衡检验来检验关联和连锁。鉴于血压调节机制的复杂性和非洲裔美国人人口结构的复杂性，这种流行病学方法最有可能揭示高血压的基因组原因。

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 cases. 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.