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BACKGROUND: The associations of red and processed meat with chronic disease risk remain to be clarified, in part because of measurement error in self-reported diet. OBJECTIVES: We sought to develop metabolomics-based biomarkers for red and processed meat, and to evaluate associations of biomarker-calibrated meat intake with chronic disease risk among postmenopausal women. METHODS: Study participants were women who were members of the Women's Health Initiative (WHI) study cohorts. These participants were postmenopausal women aged 50–79 y when enrolled during 1993–1998 at 40 US clinical centers with embedded human feeding and nutrition biomarker studies. Literature reports of metabolomics correlates of meat consumption were used to develop meat intake biomarkers from serum and 24-h urine metabolites in a 153-participant feeding study (2010–2014). Resulting biomarkers were used in a 450-participant biomarker study (2007–2009) to develop linear regression calibration equations that adjust FFQ intakes for random and systematic measurement error. Biomarker-calibrated meat intakes were associated with cardiovascular disease, cancer, and diabetes incidence among 81,954 WHI participants (1993–2020). RESULTS: Biomarkers and calibration equations meeting prespecified criteria were developed for consumption of red meat and red plus processed meat combined, but not for processed meat consumption. Following control for nondietary confounding factors, hazard ratios were calculated for a 40% increment above the red meat median intake for coronary artery disease (HR: 1.10; 95% CI: 1.07, 1.14), heart failure (HR: 1.26; 95% CI: 1.20, 1.33), breast cancer (HR: 1.10; 95% CI: 1.07, 1.13) for, total invasive cancer (HR: 1.07; 95% CI: 1.05, 1.09), and diabetes (HR: 1.37; 95% CI: 1.34, 1.39). HRs for red plus processed meat intake were similar. HRs were close to the null, and mostly nonsignificant following additional control for dietary potential confounding factors, including calibrated total energy consumption. CONCLUSIONS: A relatively high-meat dietary pattern is associated with somewhat higher chronic disease risks. These elevations appear to be largely attributable to the dietary pattern, rather than to consumption of red or processed meat per se.

Perspective on this Article from Cruciferous Vegetable Feeding Alters UGT1A1 Activity: Diet- and Genotype-Dependent Changes in Serum Bilirubin in a Controlled Feeding Trial

Increased adiposity and diets high in glycemic load (GL) are associated with increased risk of many chronic diseases including cancer. Using plasma from 80 healthy individuals [40 men/40 women, 29 with DXA-derived low fat mass (FM) and 51 with high FM] in a randomized cross-over–controlled feeding trial and arrays populated with 3,504 antibodies, we measured plasma proteins collected at baseline and end of each of two 28-day controlled diets: a low GL diet high in whole grains, legumes, fruits, and vegetables (WG) and a high GL diet high in refined grains and added sugars (RG). Following univariate testing for proteins differing by diet, we evaluated pathway-level involvement. Among all 80 participants, 172 proteins were identified as differing between diets. Stratifying participants by high and low FM identified 221 and 266 proteins, respectively, as differing between diets (unadjusted P < 0.05). These candidate proteins were tested for overrepresentation in Reactome pathways, corresponding to 142 (of 291) pathways in the high-FM group and 72 (of 274) pathways in the low-FM group. We observed that the cancer-related pathways, DNA Repair, DNA Replication, and Cell Cycle, were overrepresented in the high-FM participants while pathways involved in post-translational protein modification were overrepresented in participants with either FM. Although high-GL diets are associated with increased risk of some cancers, our study further suggests that biology associated with consumption of GL diets is variable depending on an individual's adiposity and dietary recommendations related to cancer prevention be made with the additional consideration of an individual's FM.

The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug-metabolizing enzymes that metabolize CY to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post-transplant CY (PT-CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre-HCT), before infusion of the donor allograft (pre-graft), before the first dose of PT-CY (pre-CY), and 24 h after the first dose of PT-CY (24-h post-CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre-CY time point, no EMCs were associated at FDR less than 0.1. At pre-HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre-graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24-h post-CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY.

Research suggests that high intake of supplemental vitamin B12 may be associated with increased risk of cancer, with some evidence that this association may vary by gender and smoking status. This investigation evaluates if similar patterns in association are observed for data for 11,757 adults from the National Health and Nutrition Examination Survey (1999-2006). Survey-weighted multivariable-adjusted linear regression was used to evaluate the association between regular B12 supplement use and log-transformed serum B12 levels. Persons taking vitamin B12 through a multivitamin/multimineral (MVMM) had a median supplemental intake of 12 mcg/day (Q1: 6, Q3: 25), compared to 100 mcg/day (Q1: 22, Q3: 500) for persons reporting supplemental B12 intake through a MVMM-exclusive source. MVMM users had a geometric mean serum B12 26% (95% CI: 23%-30%) higher than nonusers, whereas MVMM-exclusive users' geometric mean was 61% (95% CI: 53%-70%) higher than nonusers (p-trend < 0.001). Although a positive trend (p-trend < 0.001) was observed for both men and women, the association was stronger among women (p-interaction < 0.001). No interaction was observed for smoking status (p-interaction = 0.45). B12 supplementation is associated with higher levels of serum B12, with significant interaction by gender but not smoking. Further work is needed to better understand the interplay of B12 and gender.

Intravenous (IV) busulfan doses are often personalized to a target plasma exposure (targeted busulfan) using an individual's busulfan clearance (BuCL). We evaluated whether BuCL could be predicted by a predose plasma panel of 841 endogenous metabolomic compounds (EMCs). In this prospective cohort of 132 hematopoietic cell transplant (HCT) patients, all had samples collected immediately before to busulfan administration (preBU) and 96 had samples collected two weeks before busulfan (2-week-preBU). BuCL was significantly associated with 37 EMCs after univariate linear regression analysis and controlling for false discovery (0.05) in the 132 preBU samples. In parallel, with preBU samples, we included all 841 EMCs in a Lasso penalized regression which selected 13 EMCs as predominantly associated with BuCL. Then, we constructed a prediction model by estimating coefficients for these 13 EMCs, along with sex, using ordinary least-squares. When the resulting linear prediction model was applied to the 2-week-preBU samples, it explained 40% of the variation in BuCL (adjusted R

Research suggests that high intake of supplemental vitamin B12 may be associated with increased risk of cancer, with some evidence that this association may vary by gender and smoking status. This investigation evaluates if similar patterns in association are observed for data for 11,757 adults from the National Health and Nutrition Examination Survey (1999–2006). Survey-weighted multivariable-adjusted linear regression was used to evaluate the association between regular B12 supplement use and log-transformed serum B12 levels. Persons taking vitamin B12 through a multivitamin/multimineral (MVMM) had a median supplemental intake of 12 mcg/day (Q1: 6, Q3: 25), compared to 100 mcg/day (Q1: 22, Q3: 500) for persons reporting supplemental B12 intake through a MVMM-exclusive source. MVMM users had a geometric mean serum B12 26% (95% CI: 23%−30%) higher than non-users, whereas MVMM-exclusive users’ geometric mean was 61% (95% CI: 53%−70%) higher than non-users (p-trend