NFkb Related Genetic Influences on Inflammation and Poor Health in Older Adults

描述（由申请人提供）：本研究的长期目标是确定与炎症相关的基因和生物学途径，这些基因和生物学途径影响老年人功能的快速下降，影响虚弱和死亡率。促炎蛋白NFkB的不适当激活在这一过程中起着重要的作用。我们已经确定了一组与NFkB相关的炎症介质，并预测了不良的健康结果。我们假设这组细胞因子代表了一种促炎表型，而触发或传播NFkB活性的基因变异导致了促炎状态，因此在一些老年人中观察到健康状况不佳。在此，我们建议进一步完善老年人的炎症表型，随后进行验证步骤，我们将测量心血管健康研究中储存血清中最重要的表型贡献者，并确定这些标志物是否与相同的不良健康结果相关。然后，我们将在CHS参与者的病例对照研究中确定NFkB相关候选基因中潜在的有意义的基因变异，并确定这些多态性中的任何一个或这些多态性的组合是否影响炎症和不良的健康结果。最后，我们将选择在CHS研究中确定的最具影响力的候选基因，并在整个CHS人群和in CHIANTI中进行测试，以确定这些基因是否可以预测相同的不良医疗结果。具有临床意义的基因型将突出潜在的生物学途径，用于干预老年人一系列不良健康结局。

DESCRIPTION (provided by applicant): The long-term goal of this study is to identify genes and biologic pathways related to inflammation that influence the rapid decline in function and influence frailty and mortality in a subset of older adults. Inappropriate activation of the pro-inflammatory protein NFkB acts as an important gateway in this process. We have identified a cluster of inflammatory mediators that are related to NFkB and that predict poor health outcomes. We hypothesize that this cluster of cytokines represents a pro-inflammatory phenotype, and that variation in genes that trigger or propagate NFkB activity contributes to the pro-inflammatory state and hence to the poor health comes observed in some older adults. We propose here to further refine the inflammatory phenotype in the In Chianti population of older adults, followed by a validation step in which we will measure the most important contributors to this phenotype in stored serum from the Cardiovascular Health Study and determine if these markers are related to the same poor health outcomes. We will then identify potentially meaningful gene variants within NFkB related candidate genes in a case control study of CHS participants, and determine if any of these polymorphisms, or combination of these polymorphisms influence inflammation and poor health outcomes. Finally, we will pick the most influential candidate genes determined in the CHS study, and test them in the entire CHS population and in In CHIANTI and determine if these genes are predictive of the same poor health care outcomes. Clinically meaningful genotypes will highlight potential biologic pathways for interventions into a range of poor health outcomes in older adults.