GENES AND SEVERE HYPERTENSION AMONG AFRICAN AMERICANS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。非裔美国人的高血压发病率是世界上最高的。这种负担的后果是众所周知的，包括中风、心脏病和肾病的发病率非常高。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，但我们还有很多工作要做，特别是在非洲裔美国人当中。由于约翰霍普金斯大学和其他许多研究者的努力，我们现在知道了许多重要的暴露，但导致高血压易感性及其最终器官影响的等位基因变异仍然难以理解。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，以研究高血压的发病机制，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、内缩蛋白细胞骨架蛋白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变异与非裔美国人的血压水平相关。我们正在招募200名被约翰霍普金斯医院收治的患有严重高血压的非裔美国人先证，200名非裔美国人的无血缘关系的正常血压控制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小影响基因的能力。限制招收来自同一环境和文化背景的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化我们的权力。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、暴露史和家庭起源。我们将通过获得详细的家谱和使用兄弟对照来限制由于种群子结构和混合而引起的混淆。在这个基于家庭的病例对照研究的背景下，我们将使用病例对照分析和家庭对照以及兄弟姐妹传播/不平衡检验来检验关联和联系。鉴于血压调节机制的复杂性和非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.