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）和合并症的遗传解剖，主要通过传统的连锁分析进行，迄今为止在鉴定特定的遗传变异方面大多不成功。受现有证据的启发，一些遗传效应受到年龄和肥胖的调节，研究人员已经开发出合适的新方法来发现基因。该修订后的申请解决了基因-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。全球范围内日益增长的肥胖流行使得研究肥胖是否以及在多大程度上调节HTN和血压的遗传效应变得尤为重要。拟议的发展研究的主要目标是了解基因如何与年龄和肥胖相互作用，产生血压和HTN。这项研究将使用以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个网络的非洲裔美国人，白色和西班牙裔高血压家庭，共纳入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。拟议的研究将调查年龄变化在遗传效应中的作用，以及肥胖如何通过使用我们最近的方法进行连锁分析来调节HTN和血压的遗传效应，该方法已被证明非常强大。这项研究的独特之处在于，种族差异的调制效果也可以调查。目前的探索性资助是基于新的建模概念和HTN上收集的最大样本之一。确定遗传变异发挥最大影响力的适当种族特定年龄（和临界肥胖水平）开辟了新的研究途径，可以找到特定的遗传变异和干预的最佳时机，以及开发针对年龄，肥胖和种族特质的新药物治疗。从公共卫生的角度来看，可以在疾病发展之前确定具有可改变的HTN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：高血压的风险在不同年龄、肥胖程度或种族群体之间并不恒定;有理由假设遗传效应也不是静态的。我们的新的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同胞的调节剂，有可能识别具有可改变遗传风险的个体，确定干预的最佳时机并开发靶向药物治疗。

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.