Frailty in WHI: Drugs, Inflammatory and Genetic Markers

描述(申请人提供)：“虚弱”是一种临床综合征，用于描述一系列体征和症状(例如，力量受损、步态缓慢、缺乏活动、精疲力竭、体重减轻)，这些症状在女性中发生得比男性更频繁，并增加了残疾、住院和死亡的风险。利用妇女健康倡议临床试验和观察性研究队列的数据，我们建议进行一系列研究，以增加对人类炎症反应与虚弱发展的关系的理解，以及抗炎药物在改变这一因果途径中可能发挥的作用。 首先，在2005年平均随访8年的这两个大型队列中，我们建议确定使用他汀类药物或血管紧张素转换酶抑制剂是否与较低的脆弱发生率和较少的脆弱个体成分下降有关。其次，我们建议在WHI观察性研究队列中对65岁及以上的女性进行嵌套病例对照研究，使用已经收集和存储的生物样本，以确定慢性炎症(C-反应蛋白、白介素6、纤维蛋白原或凝血因子VIII)和/或凝血(tPA抗原、D-二聚体、PAI-1活性、ICAM-1、凝血因子VII)的标记物在900例发生脆性事件的患者和900例没有脆性成分的对照组之间是否存在差异。由于WHI的观察性研究规模如此之大，这些相关性将在患有和不患有与慢性炎症相关的已知疾病(例如心血管疾病、癌症、糖尿病、严重骨关节炎)的老年女性中进行检查。第三，在同一项嵌套病例对照研究中，使用高效、准确、可重复性和廉价的高度多元化的基因分型方法，我们提议研究炎症途径中与脆弱和中等炎症生物标记物表型相关的26个候选基因，从而提供一些关于遗传变异和脆弱表型的首次大规模探索。

DESCRIPTION (provided by applicant): "Frailty" is a clinical syndrome that is used to describe a constellation of signs and symptoms (e.g. impaired strength, slow gait, inactivity, exhaustion, weight loss) that occurs more frequently in women than men and confers increased risk of disability, hospitalization and death. Using data from the Women's Health Initiative Clinical Trial and Observational Study cohorts, we propose to conduct a series of studies to increase understanding of how the inflammatory response in humans relates to the development of frailty and what role anti-inflammatory medications may play in altering this causal pathway. First, in these two large cohorts with average follow-up of 8 years in 2005, we propose to determine whether use of statins or ACE inhibitors is associated with a lower incidence of frailty and less decline in the individual components of frailty. Second, we propose to conduct a nested case-control study of women aged 65 and older in the WHI Observational Study cohort using already collected and stored biologic specimens, to determine if markers of chronic inflammation (C-reactive protein, interleukin-6, fibrinogen, or Factor VIII) and/or coagulation (tPA antigen, D-dimer, PAI-1 activity, ICAM-1, Factor VII) differ between 900 cases with incident frailty and 900 controls with no frailty components. Because the WHI Observational Study is so large, these associations will be examined in older women with and without diseases known to be associated with chronic inflammation (e.g. cardiovascular disease, cancer, diabetes, severe osteoarthritis). Third, in the same nested case-control study, using highly multiplexed genotyping methods which are efficient, accurate, reproducible, and inexpensive, we propose to study 26 candidate genes in the inflammatory pathway in relation to frailty and intermediate inflammatory biomarker phenotypes, thereby providing some of the first large-scale exploration of genetic variation and the frailty phenotype.