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

描述(申请人提供)：高血压(HTN)及其合并症的遗传解剖，主要是通过传统的连锁分析进行的，到目前为止在识别特定的遗传变异方面大多没有成功。现有证据表明，一些遗传效应受年龄和肥胖的影响，受此激励，研究人员开发了合适的新基因发现方法。这项修订后的应用解决了这样的假设，即基因-年龄和基因-肥胖症的交互作用在基因-表型相关性中很重要。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HTN和血压的遗传效应变得尤为重要。这项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。这项研究将使用之前在大家庭血压计划(FBPP)中收集的表型和基因数据进行，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，包括11,040人。我们拟议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。这项拟议的研究将调查年龄变异在遗传效应中的作用，以及肥胖如何通过使用我们最近被证明非常有效的方法进行连锁分析来调节HTN和血压的遗传效应。这项研究的独特之处在于，还可以调查种族差异对调制效果的影响。目前的探索性拨款是基于新的建模概念和HTN上收集到的最大样本之一。确定基因变异发挥最大影响的适当特定种族年龄(以及临界肥胖水平)，在寻找特定基因变异、最佳干预时机以及针对年龄、肥胖和种族特点开发新的药物治疗方面，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确定具有HTN可改变遗传风险的个人，并可以实施有效和适当的生活方式改变和/或药物治疗来进行初级预防。 公共卫生相关性：不同年龄或肥胖水平或不同种族之间的高血压风险并不是恒定的；有理由认为遗传效应也不是一成不变的。我们的新连锁方法结合了种族特定的基因年龄和肥胖年龄交互作用作为高血压兄弟姐妹中的调节因素，具有识别具有可修改的遗传风险的个人、确定最佳干预时机和开发有针对性的药物治疗的潜力。

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.