""""""""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.
