Plasma metabolomics profiles in Black and White participants of the Adventist Health Study-2 cohort.

BACKGROUND: Black Americans suffer disparities in risk for cardiometabolic and other chronic diseases. Findings from the Adventist Health Study-2 (AHS-2) cohort have shown associations of plant-based dietary patterns and healthy lifestyle factors with prevention of such diseases. Hence, it is likely that racial differences in metabolic profiles correlating with disparities in chronic diseases are explained largely by diet and lifestyle, besides social determinants of health. METHODS: Untargeted plasma metabolomics screening was performed on plasma samples from 350 participants of the AHS-2, including 171 Black and 179 White participants, using ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and a global platform of 892 metabolites. Differences in metabolites or biochemical subclasses by race were analyzed using linear regression, considering various models adjusted for known confounders, dietary and/or other lifestyle behaviors, social vulnerability, and psychosocial stress. The Storey permutation approach was used to adjust for false discovery at FDR < 0.05. RESULTS: Linear regression revealed differential abundance of over 40% of individual metabolites or biochemical subclasses when comparing Black with White participants after adjustment for false discovery (FDR < 0.05), with the vast majority showing lower abundance in Blacks. Associations were not appreciably altered with adjustment for dietary patterns and socioeconomic or psychosocial stress. Metabolite subclasses showing consistently lower abundance in Black participants included various lipids, such as lysophospholipids, phosphatidylethanolamines, monoacylglycerols, diacylglycerols, and long-chain monounsaturated fatty acids, among other subclasses or lipid categories. Among all biochemical subclasses, creatine metabolism exclusively showed higher abundance in Black participants, although among metabolites within this subclass, only creatine showed differential abundance after adjustment for glomerular filtration rate. Notable metabolites in higher abundance in Black participants included methyl and propyl paraben sulfates, piperine metabolites, and a considerable proportion of acetylated amino acids, including many previously found associated with glomerular filtration rate. CONCLUSIONS: Differences in metabolic profiles were evident when comparing Black and White participants of the AHS-2 cohort. These differences are likely attributed in part to dietary behaviors not adequately explained by dietary pattern covariates, besides other environmental or genetic factors. Alterations in these metabolites and associated subclasses may have implications for the prevention of chronic diseases in Black Americans.

Total energy expenditure as assessed by doubly labeled water and all-cause mortality in a cohort of postmenopausal women.

BACKGROUND: The association of TEE with all-cause mortality is uncertain, as is the dependence of this association on age. OBJECTIVES: To examine the association between TEE and all-cause mortality, and its age interaction, in a Women's Health Initiative (WHI) cohort of postmenopausal United States women (1992-present). METHODS: A cohort of 1131 WHI participants having DLW TEE assessment of ∼10.0 y (median) following WHI enrollment with ∼13.7 y (median) of subsequent follow-up, was used to study the EE associations with all-cause mortality. To enhance the comparability of TEE and total EI, key analyses excluded participants having >5% weight change between WHI enrollment and DLW assessment. The influence of participant age on mortality associations was examined, as was the ability of concurrent and earlier weight and height measurements to explain the results. RESULTS: There were 308 deaths following the TEE assessment through 2021. TEE was unrelated to overall mortality (P = 0.83) in this cohort of generally healthy, older (mean 71 y at TEE assessment) United States women. However, this potential association varied with age (P = 0.003). Higher TEE was associated with a higher mortality rate at the age of 60 y and a lower mortality rate at the age of 80 y. Within the weight-stable subset (532 participants, 129 deaths), TEE was weakly positively related to overall mortality (P = 0.08). This association also varied with age (P = 0.03), with mortality HRs (95% CIs) for a 20% increment in TEE of 2.33 (1.24, 4.36) at the age of 60 y, 1.49 (1.10, 2.02) at 70 y of age, and 0.96 (0.66, 1.38) at 80 y of age. This pattern remained, although was somewhat attenuated, following control for baseline weight and weight changes between WHI enrollment and TEE assessment. CONCLUSIONS: Higher EE is associated with higher all-cause mortality among younger postmenopausal women, only partially explained by weight and weight change. This study is registered with clinicaltrials.gov identifier: NCT00000611.

Enhancing Capacity for Food and Nutrient Intake Assessment in Population Sciences Research.

Nutrition influences health throughout the life course. Good nutrition increases the probability of good pregnancy outcomes, proper childhood development, and healthy aging, and it lowers the probability of developing common diet-related chronic diseases, including obesity, cardiovascular disease, cancer, and type 2 diabetes. Despite the importance of diet and health, studying these exposures is among the most challenging in population sciences research. US and global food supplies are complex; eating patterns have shifted such that half of meals are eaten away from home, and there are thousands of food ingredients with myriad combinations. These complexities make dietary assessment and links to health challenging both for population sciences research and for public health policy and practice. Furthermore, most studies evaluating nutrition and health usually rely on self-report instruments prone to random and systematic measurement error. Scientific advances involve developing nutritional biomarkers and then applying these biomarkers as stand-alone nutritional exposures or for calibrating self-reports using specialized statistics.

Dietary Intake Mediates Ethnic Differences in Gut Microbial Composition.

Background: The human gut microbiome (GM) has been observed to vary by race/ethnicity. Objective: Assess whether racial/ethnic GM variation is mediated by differences in diet. Design: Stool samples collected from 2013 to 2016 from 5267 healthy Multiethnic Cohort participants (age 59−98) were analyzed using 16S rRNA gene sequencing to estimate the relative abundance of 152 bacterial genera. For 63 prevalent genera (>50% in each ethnic group), we analyzed the mediation of GM differences among African Americans, Japanese Americans, Latinos, Native Hawaiians, and Whites by overall diet quality (Healthy Eating Index score (HEI-2015)) and intake amounts of 14 component foods/nutrients assessed from 2003 to 2008. For each significant mediation (p < 1.3 × 10−5), we determined the percent of the total ethnicity effect on genus abundance mediated by the dietary factor. Results: Ethnic differences in the abundance of 12 genera were significantly mediated by one or more of eight dietary factors, most frequently by overall diet quality and intakes of vegetables and red meat. Lower vegetable intake mediated differences in Lachnospira (36% in African Americans, 39% in Latinos) and Ruminococcus-1 (−35% in African Americans, −43% in Latinos) compared to Native Hawaiians who consumed the highest amount. Higher red meat intake mediated differences in Lachnospira (−41%) and Ruminococcus-1 (36%) in Native Hawaiians over African Americans, who consumed the least. Dairy and alcohol intakes appeared to mediate and counterbalance the difference in Bifidobacterium between Whites and Japanese Americans. Conclusions: Overall diet quality and component food intakes may contribute to ethnic differences in GM composition and to GM-related racial/ethnic health disparities.

Assessment of the WAP-Myc mouse mammary tumor model for spontaneous metastasis.

Breast cancer is the most common form of cancer in women. Despite significant therapeutic advances in recent years, breast cancer also still causes the greatest number of cancer-related deaths in women, the vast majority of which (> 90%) are caused by metastases. However, very few mouse mammary cancer models exist that faithfully recapitulate the multistep metastatic process in human patients. Here we assessed the suitability of a syngrafting protocol for a Myc-driven mammary tumor model (WAP-Myc) to study autochthonous metastasis. A moderate but robust spontaneous lung metastasis rate of around 25% was attained. In addition, increased T cell infiltration was observed in metastatic tumors compared to donor and syngrafted primary tumors. Thus, the WAP-Myc syngrafting protocol is a suitable tool to study the mechanisms of metastasis in MYC-driven breast cancer.

The Interaction between Dietary Fiber and Fat and Risk of Colorectal Cancer in the Women's Health Initiative.

Combined intakes of specific dietary fiber and fat subtypes protect against colon cancer in animal models. We evaluated associations between self-reported individual and combinations of fiber (insoluble, soluble, and pectins, specifically) and fat (omega-6, omega-3, and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), specifically) and colorectal cancer (CRC) risk in the Women's Health Initiative prospective cohort (n = 134,017). During a mean 11.7 years (1993-2010), 1952 incident CRC cases were identified. Cox regression models computed multivariate adjusted hazard ratios to estimate the association between dietary factors and CRC risk. Assessing fiber and fat individually, there was a modest trend for lower CRC risk with increasing intakes of total and insoluble fiber (p-trend 0.09 and 0.08). An interaction (p = 0.01) was observed between soluble fiber and DHA + EPA, with protective effects of DHA + EPA with lower intakes of soluble fiber and an attenuation at higher intakes, however this association was no longer significant after correction for multiple testing. These results suggest a modest protective effect of higher fiber intake on CRC risk, but not in combination with dietary fat subtypes. Given the robust results in preclinical models and mixed results in observational studies, controlled dietary interventions with standardized intakes are needed to better understand the interaction of specific fat and fiber subtypes on colon biology and ultimately CRC susceptibility in humans.

Use of a urinary sugars biomarker to assess measurement error in self-reported sugars intake in the nutrition and physical activity assessment study (NPAAS).

BACKGROUND: Measurement error in self-reported sugars intake may be obscuring the association between sugars and cancer risk in nutritional epidemiologic studies. METHODS: We used 24-hour urinary sucrose and fructose as a predictive biomarker for total sugars, to assess measurement error in self-reported sugars intake. The Nutrition and Physical Activity Assessment Study (NPAAS) is a biomarker study within the Women's Health Initiative (WHI) Observational Study that includes 450 postmenopausal women ages 60 to 91 years. Food Frequency Questionnaires (FFQ), four-day food records (4DFR), and three 24-hour dietary recalls (24HRs) were collected along with sugars and energy dietary biomarkers. RESULTS: Using the biomarker, we found self-reported sugars to be substantially and roughly equally misreported across the FFQ, 4DFR, and 24HR. All instruments were associated with considerable intake- and person-specific bias. Three 24HRs would provide the least attenuated risk estimate for sugars (attenuation factor, AF = 0.57), followed by FFQ (AF = 0.48) and 4DFR (AF = 0.32), in studies of energy-adjusted sugars and disease risk. In calibration models, self-reports explained little variation in true intake (5%-6% for absolute sugars and 7%-18% for sugars density). Adding participants' characteristics somewhat improved the percentage variation explained (16%-18% for absolute sugars and 29%-40% for sugars density). CONCLUSIONS: None of the self-report instruments provided a good estimate of sugars intake, although overall 24HRs seemed to perform the best. IMPACT: Assuming the calibrated sugars biomarker is unbiased, this analysis suggests that measuring the biomarker in a subsample of the study population for calibration purposes may be necessary for obtaining unbiased risk estimates in cancer association studies.

Intake of long-chain ω-3 fatty acids from diet and supplements in relation to mortality.

Evidence from experimental studies suggests that the long-chain ω-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid have beneficial effects that may lead to reduced mortality from chronic diseases, but epidemiologic evidence is mixed. Our objective was to evaluate whether intake of long-chain ω-3 fatty acids from diet and supplements is associated with cause-specific and total mortality. Study participants (n = 70,495) were members of a cohort study (the Vitamins and Lifestyle Study) who were residents of Washington State aged 50-76 years at the start of the study (2000-2002). Participants were followed for mortality through 2006 (n = 3,051 deaths). Higher combined intake of eicosapentaenoic acid and docosahexaenoic acid from diet and supplements was associated with a decreased risk of total mortality (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.73, 0.93) and mortality from cancer (HR = 0.77, 95% CI: 0.64, 0.92) but only a small reduction in risk of death from cardiovascular disease (HR = 0.87, 95% CI: 0.68, 1.10). These results suggest that intake of long-chain ω-3 fatty acids may reduce risk of total and cancer-specific mortality.

Use of glucosamine and chondroitin in relation to mortality.

Glucosamine and chondroitin are products commonly used by older adults in the US and Europe. There is limited evidence that they have anti-inflammatory properties, which could provide risk reduction of several diseases. However, data on their long-term health effects is lacking. To evaluate whether use of glucosamine and chondroitin are associated with cause-specific and total mortality. Participants (n = 77,510) were members of a cohort study of Washington State (US) residents aged 50-76 years who entered the cohort in 2000-2002 by completing a baseline questionnaire that included questions on glucosamine and chondroitin use. Participants were followed for mortality through 2008 (n = 5,362 deaths). Hazard ratios (HR) for death adjusted for multiple covariates were estimated using Cox models. Current (baseline) glucosamine and chondroitin use were associated with a decreased risk of total mortality compared to never use. The adjusted HR associated with current use of glucosamine (with or without chondroitin) was 0.82 (95 % CI 0.75-0.90) and 0.86 (95 % CI 0.78-0.96) for chondroitin (included in two-thirds of glucosamine supplements). Current use of glucosamine was associated with a significant decreased risk of death from cancer (HR 0.87 95 % CI 0.76-0.98) and with a large risk reduction for death from respiratory diseases (HR 0.59 95 % CI 0.41-0.83). Use of glucosamine with or without chondroitin was associated with reduced total mortality and with reductions of several broad causes of death. Although bias cannot be ruled out, these results suggest that glucosamine may provide some mortality benefit.

Enhancing recruitment of healthy African American volunteers in a city with a small African American community: results from a dietary supplement crossover trial.

OBJECTIVE: To describe strategies for enhancing recruitment of African Americans to a longterm intervention study requiring frequent blood draws and follow-up visits, in a city with relatively few African Americans. DESIGN: The intervention study was a 14-month, double-blind, crossover study evaluating the effects of three oral folic acid doses on blood homocysteine levels. The goal was to have 40 African Americans complete the study, in addition to 160 participants from other races and ethnicities. RESULTS: Of 707 healthy, adult men and women recruited, 57 were African Americans. Recruitment advice was sought from African American community leaders interested in health research and the advice can be attributable to the success of recruitment. As suggested by the community leaders, our female African American project manager made oral presentations to select community groups. Word-of-mouth support from community leaders and study participants helped recruitment. Although the adult Seattle population is 7.4% African American, the group completing the study comprised 15% African Americans. Retention in the dietary intervention was 74% (31 out of 42) among African Americans, 81% (158 out of 196) among non-African Americans--a statistically non-significant difference. CONCLUSIONS: Advice from African American community leaders about targeting appropriate civic/professional groups, churches, and community organizations can lead to effective recruitment of African Americans. Advice should be sought before beginning recruitment and endorsement for the study should be obtained. Effective retention of African American participants is possible for intervention studies requiring multiple blood draws and follow-up visits.

Prevalence of daidzein-metabolizing phenotypes differs between Caucasian and Korean American women and girls.

Interindividual differences in metabolism of the soy isoflavone, daidzein, to equol and O-desmethylangolensin (ODMA) by human gut bacteria, have been associated with altered risk of cancer and other chronic diseases, according to some studies. Differences have been reported in the prevalence of the equol-producer phenotype among populations, with a higher prevalence in soy-consuming Asian populations than in Western populations. To date, prevalence of the daidzein-metabolizing phenotypes in Asians, compared with Caucasians, has not been evaluated in the context of a standardized phenotyping method. We assessed the prevalence of equol- and ODMA-producer phenotypes in 91 Korean American (KA) women and girls living in the Seattle, Washington area and compared this with previous similarly collected prevalence data in Caucasian American (CA) women and girls (n = 222). We also compared the dietary habits of the 2 groups. Isoflavonoid concentrations in first-void morning urines, collected after a 3-d soy challenge, were used to establish equol-, and ODMA-producer phenotypes (>44 microg/L). The prevalence of the equol-producer phenotype was higher (51 vs. 36%; P = 0.015) and the ODMA-producer phenotype was lower (84 vs. 92%, P = 0.03) in KA than in CA women and girls. KAs consumed approximately 3 times more soy foods than the CAs, but no significant associations were found between the consumption of soy foods and equol-producer phenotype. Our findings support the reports that, compared with Western populations, Asian populations have a higher equol-producer prevalence. The additional observation that the prevalence of the ODMA-producer phenotype is lower in KAs suggests that daidzein-metabolizing patterns in general may differ between KAs and CAs.

Soy isoflavones do not modulate circulating insulin-like growth factor concentrations in an older population in an intervention trial.

Insulin-like growth factors (IGF) are essential for normal growth and maintenance of lean muscle mass; however, high insulin-like growth factor-I (IGF-I) and low IGF binding protein-3 (IGFBP-3) levels are also associated with several cancers. To test the hypothesis that long-term soy isoflavone supplementation decreases circulating IGF-I concentrations, we conducted a controlled, parallel-arm, double-blind intervention study with 150 participants (85% men), 50-80 y old. Participants were randomly assigned to consume a soy beverage powder daily for 12 mo. The active treatment group (+ISO) received soy protein containing 83 mg isoflavones, whereas the comparison group (-ISO) received soy protein containing 3 mg isoflavones. Serum IGF-I and IGFBP-3 were measured by ELISA. Mean change in serum IGF-I concentrations was similar in the two groups (+1.4 nmol/L in +ISO, +1.2 nmol/L in -ISO; P = 0.74, 95% confidence interval -1.1, +1.5 nmol/L for the 0.21 nmol/L difference between groups), indicating no effect of the isoflavone intervention. Similarly, the changes in IGFBP-3 and the IGF-I/IGFBP-3 ratio were similar in both groups, again showing no effect of +ISO treatment. A 12 mo, 83 mg/d soy isoflavone intervention did not modulate serum IGF in an older, mostly male population.