Frailty in WHI: Drugs, Inflammatory and Genetic Markers

WHI 中的虚弱：药物、炎症和遗传标记

• 批准号: 6985614
• 负责人: ANDREA Z. LACROIX
• 金额: $ 56.77万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985614
• 关键词: ACE inhibitors; antihypercholesterolemic agent; antihypertensive agents; biomarker; blood coagulation; clinical research; epidemiology; female; frail elderly; genetic markers; genetic susceptibility; human data; human tissue; inflammation; women' s health

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.

描述（由申请人提供）：“脆弱”是一种临床综合征，用于描述体征和症状的星座（例如强度受损，缓慢的步态，不活动，精疲力尽，体重减轻），而男性的频率比男性的频率更高，而男性和同意的风险增加了残疾，住院和死亡的风险。我们使用妇女健康计划的临床试验和观察性研究队列中的数据，我们建议进行一系列研究，以提高人们对人类炎症反应的了解，与脆弱性的发展以及抗炎药在改变这一因果关系方面的作用可能起什么作用。 首先，在这两个大型队列中，2005年平均随访8年，我们建议确定他汀类药物或ACE抑制剂的使用是否与较弱的脆弱发生率和较小的脆弱成分下降有关。 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）在900例出现脆弱的情况下和没有脆弱组件的900例中有所不同。由于观察性研究非常大，因此将在已知与慢性炎症有关的老年妇女中检查这些关联（例如心血管疾病，癌症，糖尿病，严重的骨关​​节炎）。第三，在相同的嵌套病例对照研究中，使用高度多重的基因分型方法，这些方法具有高效，准确，可重复和廉价的基因分型方法，我们建议研究炎症途径中与脆弱性和中等炎症性生物标志物的关系中的26个候选基因，从而提供了最初的大型探索，从而提供了一些大型探索。