Grant Number:	2R01CA119171-18 Interpret this number
Primary Investigator:	Neuhouser, Marian
Organization:	Fred Hutchinson Cancer Center
Project Title:	Nutrition and Physical Activity Assessment Study (NPAAS)
Fiscal Year:	2024

PROJECT SUMMARY This competing renewal of CA119171-17 “Nutrition and Physical Activity Assessment Study” (NPAAS) continues to focus on dietary biomarker discovery and application of these biomarkers to investigations of diet and risk of cancer and other chronic diseases in the Women’s Health Initiative (WHI). In our recent funding cycles, we developed novel metabolomics and stable isotope ratio biomarkers of diet in the NPAAS Feeding Study and the NPAAS Observational Study and used these biomarkers to model diet-chronic disease associations in older women. We now turn to the WHI Dietary Modification (WHI-DM) Trial where gaps remain in understanding the biology of the intervention effects (both a priori hypothesized and those observed with further interrogations of the data) and in the interpretation of intervention effects on clinical outcomes. Our goals for this renewal are to use targeted metabolomics to delineate effect biomarkers and biological mechanisms underlying WHI-DM intervention effects and to elucidate the role of the dietary fat reduction intervention component in observed findings. The WHI-DM, a 2-arm randomized controlled trial in 48,835 women, was designed to test whether a low-fat (20% of total kcal) dietary pattern including 5 daily servings of fruits and vegetables and 6 daily servings of grains would reduce risk of invasive breast and colorectal cancers in postmenopausal women. While neither invasive breast nor colorectal cancers were significantly reduced by the ~8.5 y intervention (P=0.09 and P=0.45, respectively), women in the intervention arm experienced numerous clinically meaningful effects on important measures of metabolic health and long-term health and mortality outcomes. Many differences in clinical factors (e.g., metabolic syndrome, body weight) between intervention and comparison groups were detected early in the trial and are risk factors for several cancers. Metabolomic profiling may uncover mechanistic underpinnings of these findings since these small molecules are responsive to diet change and reflect biological phenotype. Our specific aims are 1) Evaluate the effect of the WHI-DM intervention on the targeted serum metabolome and lipidome and biochemical pathways; 2) Investigate how the metabolites mediate intervention effects on body measurements and intermediate biomarkers of metabolic health; and 3) Elucidate the contribution of the trial’s fat reduction to intervention effects. In collaboration with the Northwest Metabolomics Research Center, we will use established targeted metabolomics platforms to interrogate archived serum collected at baseline and year 1 among 1000 WHI-DM women (500 intervention arm/500 comparison arm) and in a subset (n=465) of this 1000 at end of intervention. Results will elucidate biochemical pathways related to downstream risk for breast, colorectal, endometrial, and total cancer, as well as obesity and other chronic diseases. Results are expected to reveal metabolic pathways that explain the clinically meaningful effects from a large low-fat, high fruit and vegetable dietary pattern intervention and to provide insight into the dietary fat reduction in yielding these intervention effects.





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