AS755 - Nutrition and Physical Activity Assessment Study (Competitive renewal)

Investigator Names and Contact Information

Marian Neuhouser (mneuhous@fredhutch.org)

Johanna Lampe

Introduction/Intent

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 with risk of cancer and other chronic diseases in the Women’s Health Initiative (WHI). Our recent cycles of funding have focused on dietary biomarkers in the NPAAS Feeding Study and the NPAAS Observational Study. We now turn to the WHI Dietary Modification Trial where gaps remain in understanding the biology of intervention effects (both a priori hypothesized and those observed with further interrogations of the data). Our overall goal for this renewal is to delineate biological mechanisms underlying intervention effects of the WHI Dietary Modification (DM) Trial. Specifically, we will use metabolomics to interrogate archived biospecimens collected at baseline, Year 1, and end of study among women in the intervention and comparison groups to elucidate pathways related to downstream risk for breast, colorectal, endometrial, and total cancer, as well as obesity and other chronic diseases. The WHI-DM randomized 48,835 postmenopausal women to an intervention group (DM-I) whose participants followed a low-fat/high fruit and vegetable dietary pattern (n=19,541) or a usual diet comparison group (DM-C) (n=29,294).1 Recruitment and randomization took place 1993-1998 at 40 US clinical centers (CCs) and ended in 2005 after a mean 8.5 year intervention period. Neither invasive breast cancer nor colorectal cancer were statistically significantly reduced by the intervention (P=0.09 and P=0.45, respectively),2, 3 but women in the low-fat/high fruit and vegetable intervention were less likely to have colon polyps – a cancer precursor lesion.3 All-cause mortality after a breast cancer diagnosis was significantly reduced for those diagnosed during the intervention period (P=0.02).4 Additionally, intervention women who reduced fat by increasing plant protein had a coronary heart disease (CHD) hazard ratio of 0.39 (95%CI 0.22-0.71) compared to women who did not make these changes.5 Further, after nearly 20 years of long-term follow-up, there was a sustained reduction in mortality after breast cancer for those who were in the DM-I compared to the DM-C (HR=0.85, 95%CI 0.74-0.96, p<0.01).6 Other novel and important clinical findings for the DM-I compared to DM-C were reductions in body weight even though the trial did not instruct on weight loss and had no weight loss goals,7 more favorable lean and fat measures of body composition,8 less urinary incontinence,9 and suggestively less age-related cognitive impairment.10 In terms of metabolic health, women in the WHI DM-I arm did not have higher Type 2 diabetes (T2D) risk (a potential concern with a higher carbohydrate diet), and among those who did develop T2D during the trial, intervention arm women were less likely to have disease progression requiring insulin.11 Three years into the trial, intervention effects yielded lower diastolic blood pressure, Factor VIIC, total and LDLcholesterol, body weight, waist circumference and body mass index (BMI),12 and the intervention had notable effects on risk of metabolic syndrome.13 Taken together, the WHI-DM had clinically meaningful intervention effects on important measures of metabolic health and on long term health and mortality outcomes. Gaps remain in identifying specific biological pathways affected by the WHI-DM, gaps that will be filled with this proposal. We will utilize baseline and year 1 biospecimens from the WHI-DM blood draw cohort, and end of trial specimens from the Nutritional Biomarkers Study (NBS, W8) whose participants were enrolled in the DM at 12 CCs.

The specific aims for the upcoming grant period are:

1. Evaluate the effect of the WHI Dietary Modification Trial intervention on the targeted plasma metabolome and lipidome and metabolic pathways in WHI-DM participants. 1a. Measure metabolomics at baseline and year 1 in 500 DM-I and 500 DM-C participants (blood draw cohort) 1b. Measure metabolomics at end of trial in n=272 DM-I and n=272 DM-C participants (NBS) Hypothesis: WHI participants in the DM-I will have metabolomics profiles downregulated in pathways related to insulin resistance and metabolic syndrome compared to WHI participants in DM-C.
2. Investigate how the metabolites mediate the effects of the intervention on intermediate biomarkers and body measurements of metabolic health. 2a. Measure the mediation effect of metabolites on weight, waist circumference and BMI (blood draw cohort). 2b. Measure the mediation effect of metabolites on existing measure of glucose, insulin, computed HOMA-IR, and lipids (blood draw cohort with core analytes). Hypothesis: Metabolites will mediate the intervention effects on body measurements and on glucose, insulin, and lipids favoring the DM-I compared to the DM-C.

**Expected Impact: **This study is expected to reveal specific metabolites and metabolic pathways that explain the clinically meaningful effects from a large low-fat, high fruit and vegetable diet pattern intervention in postmenopausal women.