EXPLORING A NEW DIRECTION TO GENE DISCOVERY FOR HYPERTENSION IN THE LARGE FBPP

描述（由申请人提供）：高血压（HTN）和合并症的基因剖析主要通过传统的连锁分析进行，迄今为止在识别特定的遗传变异方面大多不成功。现有证据表明一些遗传效应受到年龄和肥胖的调节，研究人员开发了适当的基因发现新方法。该修订后的申请提出了基因年龄和基因肥胖相互作用在基因型-表型相关性中很重要的假设。全球范围内日益严重的肥胖流行使得研究肥胖是否以及在多大程度上调节对高血压和血压的遗传影响变得尤为重要。拟议的发育研究的主要目标是了解基因如何与年龄和肥胖相互作用以产生血压和高血压。该研究将使用先前在大型家庭血压计划 (FBPP) 中收集的表型和基因型数据进行，该计划包括来自 3 个网络的非裔美国人、白人和西班牙裔高血压家庭，共 11,040 人。我们提出的研究具有很高的成本效益，因为它充分利用了这些已经存在的非凡资源。拟议的研究将通过使用我们最近的方法进行连锁分析来调查年龄变化在遗传效应中的作用，以及肥胖如何调节高血压和血压中的遗传效应，该方法已被证明是非常强大的。这项研究的独特之处在于还可以研究调节效应的种族差异。当前的探索性资助基于新颖的建模概念，也是 HTN 上收集的最大样本之一。确定遗传变异影响最大时的适当种族特定年龄（和临界肥胖水平），为寻找特定遗传变异和最佳干预时机以及开发针对年龄、肥胖和种族特质的新药物治疗方法开辟了新的研究途径。从公共卫生的角度来看，可以在疾病发展之前识别具有可改变的高血压遗传风险的个体，并可以实施有效和适当的生活方式改变和/或药物治疗以进行一级预防。 公共卫生相关性：高血压风险在不同年龄或肥胖水平或不同种族之间并不恒定；可以合理地假设遗传效应也不是静态的。我们的新颖连锁方法将种族特异性基因年龄和肥胖年龄相互作用作为高血压兄弟姐妹的调节剂，有可能识别具有可改变遗传风险的个体，确定最佳干预时机并开发有针对性的药物治疗。

DESCRIPTION (provided by applicant): Genetic dissection of hypertension (HTN) and co-morbidities, carried out largely through traditional linkage analysis, has mostly been unsuccessful to date in identifying specific genetic variants. Motivated by existing evidence that some of the genetic effects are modulated by age and obesity, the investigators have developed appropriate new methods for gene discovery. This revised application addresses the hypothesis that gene-age and gene-obesity interactions are important in the genotype-phenotype correlations. The growing obesity epidemic world-wide makes it particularly important to investigate whether and to what extent obesity modulates genetic effects on HTN and blood pressure. The primary goal of the proposed developmental research is to understand how genes interact with age and obesity in producing blood pressure and HTN. The research will be carried out using the phenotypic and genotypic data previously collected in the large Family Blood Pressure Program (FBPP) that includes African American, White and Hispanic hypertensive families from 3 Networks, incorporating 11,040 individuals. Our proposed study is highly cost effective because it takes full advantage of these extraordinary resources which exist already. The proposed research will investigate the role of age variation in genetic effects and how obesity modulates genetic effects in HTN and blood pressure by performing linkage analysis using our recent method which has been shown to be very powerful. This study is unique in that ethnic differences in the modulation effects also can be investigated. The current exploratory grant is based on novel modeling concepts and one of the largest samples ever collected on HTN. Identifying appropriate ethnic-specific ages (and the critical obesity levels) when genetic variants exert the most influence opens up new avenues of research in terms of finding specific genetic variants and the optimal timing of interventions as well as the development of new pharmaceutical treatments targeted toward the idiosyncrasies of age, obesity and ethnicity. From a public health perspective, individuals with a modifiable genetic risk of HTN could be identified prior to disease development, and effective and appropriate lifestyle modifications and/or pharmaceutical treatments could be implemented for primary prevention. PUBLIC HEALTH RELEVANCE: Risk for hypertension is not constant across age or obesity levels or between ethnic groups; it is reasonable to assume that genetic effects also are not static. Our novel linkage approach incorporating ethnic-specific gene- age and obesity-age interactions as modulators in hypertensive siblings has the potential to identify individuals with modifiable genetic risk, determine optimal timing of intervention and develop targeted drug treatments.