Women's Health Initiative Cohort Research Articles

Chocolate Consumption in Relation to All-Cause and Cause-Specific Mortality in Women: The Women’s Health Initiative

Abstract Objectives To examine the association of chocolate consumption with all-cause and cause-specific mortality. Methods We included 84,709 postmenopausal women free of cardiovascular disease (CVD) and cancer at baseline in the prospective Women's Health Initiative cohort who were enrolled during 1993–1998. Chocolate consumption was assessed using a validated food frequency questionnaire. These women were followed through March 2018. Results During 1608,856 person-years of follow up (19.0 years on average [SD = 4.2]), 25,388 deaths occurred, including 7069 deaths from CVD, 7030 deaths from cancer, and 3279 deaths from dementia. After adjustment for a variety of covariates, compared to no chocolate consumption, the HRs (95% CIs) for all-cause mortality were 0.95 (0.92, 0.98), 0.93 (0.89, 0.96), 0.97 (0.90, 1.04) and 0.90 (0.84, 0.97) for <1 serving/week, 1–3 servings/week, 4–6 servings/week and ≥1 serving/day of chocolate consumption, respectively (P for trend = 0.02). For CVD mortality, compared to no chocolate consumption, the HRs (95% CIs) were 0.96 (0.91, 1.01), 0.88 (0.82, 0.95), 0.96 (0.93, 1.12) and 0.92 (0.80, 1.05) for <1 serving/week, 1–3 servings/week, 4–6 servings/week and ≥1 serving/day of chocolate consumption, respectively (P for trend = 0.45). For dementia mortality, compared to no chocolate consumption, the HRs (95% CIs) were 0.91 (0.84, 0.99), 0.89 (0.80, 0.99), 0.97 (0.79, 1.18) and 0.97 (0.80, 1.08) for <1 serving/week, 1–3 servings/week, 4–6 servings/week and ≥1 serving/day of chocolate consumption, respectively (P for trend = 0.95). Chocolate consumption was not associated with cancer mortality. Conclusions Our results suggested modest inverse association of chocolate consumption with mortality from all-causes, CVD or dementia, specifically for a moderate chocolate consumption of ≤3 servings/week. Funding Sources None.

A gene-diet interaction-based score predicts response to dietary fat in the Women’s Health Initiative

Although diet response prediction for cardiometabolic risk factors (CRFs) has been demonstrated using single genetic variants and main-effect genetic risk scores, little investigation has gone into the development of genome-wide diet response scores. We sought to leverage the multistudy setup of the Women's Health Initiative cohort to generate and test genetic scores for the response of 6 CRFs (BMI, systolic blood pressure, LDL cholesterol, HDL cholesterol, triglycerides, and fasting glucose) to dietary fat. A genome-wide interaction study was undertaken for each CRF in women (n ∼ 9000) not participating in the dietary modification (DM) trial, which focused on the reduction of dietary fat. Genetic scores based on these analyses were developed using a pruning-and-thresholding approach and tested for the prediction of 1-y CRF changes as well as long-term chronic disease development in DM trial participants (n ∼ 5000). Only 1 of these genetic scores, for LDL cholesterol, predicted changes in the associated CRF. This 1760-variant score explained 3.7% (95% CI: 0.09, 11.9) of the variance in 1-y LDL cholesterol changes in the intervention arm but was unassociated with changes in the control arm. In contrast, a main-effect genetic risk score for LDL cholesterol was not useful for predicting dietary fat response. Further investigation of this score with respect to downstream disease outcomes revealed suggestive differential associations across DM trial arms, especially with respect to coronary heart disease and stroke subtypes. These results lay the foundation for the combination of many genome-wide gene-diet interactions for diet response prediction while highlighting the need for further research and larger samples in order to achieve robust biomarkers for use in personalized nutrition.

THE ASSOCIATION BETWEEN HEART FAILURE AND INCIDENT CANCER IN WOMEN: AN ANALYSIS OF THE WOMEN'S HEALTH INITIATIVE

There is conflicting evidence whether heart failure (HF) is associated with incident cancer. Despite population-based cohorts demonstrating this association, no association was found in the Physician's Health Study. We aimed to study this in women. In this Women's Health Initiative cohort, 146,817

The association between DXA-derived body fat measures and breast cancer risk among postmenopausal women in the Women's Health Initiative.

BackgroundMost studies demonstrating an association between excess adiposity and postmenopausal breast cancer have used anthropometric measures, particularly body mass index (BMI). However, more direct body fat measures may more accurately determine the relationship between body fat distribution and breast cancer risk.MethodsCox proportional hazards regression models were created to examine the associations of dual‐energy x‐ray absorptiometry (DXA) body fat measures (at baseline and during follow‐up) with breast cancer risk among 10 931 postmenopausal women from the Women's Health Initiative cohort. A total of 639 incident invasive breast cancer cases (including 484 estrogen receptor positive (ER+) cases) were ascertained after a median follow‐up of 15.0 years.ResultsExcess whole body fat mass and trunk fat mass were positively associated with risk invasive breast cancer risk. These associations persisted even after additional adjustment for standard anthropometric measures. In time‐dependent analyses, we observed that both whole body fat mass and trunk fat mass, in the highest versus lowest category, were associated with a doubling of risk of invasive breast cancer overall (HR: 2.17; 95% CI: 1.54‐3.05 and 2.20; 1.55‐3.14, respectively) and of ER+ breast cancer (2.05; 1.37‐3.05 and 2.03; 1.34‐3.07, respectively). The remaining DXA measures were also positively associated with breast cancer risk in baseline and time‐dependent analyses.ConclusionThese findings suggest that DXA‐derived body fat measures are positively associated with breast cancer risk after adjustment for BMI and other conventional breast cancer risk factors.

Rehabilitation After Total Knee Arthroplasty: Do Racial Disparities Exist?

BackgroundRacial disparities in functional outcomes after total knee arthroplasty (TKA) exist. Whether differences in rehabilitation utilization contribute to these disparities remains to be investigated. MethodsAmong 8349 women enrolled in the prospective Women's Health Initiative cohort who underwent primary TKA between 2006 and 2013, rehabilitation utilization was determined through linked Medicare claims data. Postacute discharge destination (home, skilled nursing facility, and inpatient rehabilitation facility), facility length of stay, and number of home health physical therapy (HHPT) and outpatient physical therapy (OPPT) sessions were compared between racial groups. ResultsNon-Hispanic black women had worse physical function (median score, 65 vs 70) and higher likelihood of disability (13.2% vs 6.9%) than non-Hispanic white women before surgery. After TKA, black women were more likely to be discharged postacutely to an institutional facility (64.3% vs 54.5%) than white women, were more likely to receive HHPT services (52.6% vs 47.8%), and received more HHPT and OPPT sessions. After stratification by postacute discharge setting, the likelihood of receipt of HHPT or OPPT services was similar between racial groups. No significant difference in receipt of HHPT or OPPT services was found after use of propensity score weighting to balance health and medical characteristics indicating severity of need for physical therapy services. ConclusionRehabilitation utilization was generally comparable between black and white women who received TKA when accounting for need. There was no evidence of underutilization of post-TKA rehabilitation services, and thus disparities in post-TKA functional outcomes do not appear to be a result of inequitable receipt of rehabilitation care.

Application of blood concentration biomarkers in nutritional epidemiology: example of carotenoid and tocopherol intake in relation to chronic disease risk

Biomarkers provide potential to objectively measure the intake of nutrients and foods, and thereby to strengthen nutritional epidemiology association studies. However, there are only a few established intake biomarkers, mostly based on recovery of nutrients or their metabolites in urine. Blood concentration measures provide a potential biomarker source for many additional nutritional variables, but their use in disease-association studies requires further development. The aim of this study was to apply recently proposed serum-based carotenoid and tocopherol intake biomarkers and to examine their association with the incidence of major cardiovascular diseases, cancers, and diabetes in a subset of Women's Health Initiative (WHI) cohorts. Serum concentrations of α- and β-carotene, lutein plus zeaxanthin (L+Z), and α-tocopherol were routinely measured at baseline in a subset of 5488 enrollees in WHI cohorts. Intake biomarkers for these 4 micronutrients, obtained by combining serum concentrations with participant characteristics, were recently proposed using a 153-woman feeding study within WHI. These biomarker equations are augmented here to include pertinent disease risk factors and are associated with subsequent chronic disease incidence in this WHI subset. HRs for a doubling of micronutrient intake differed only moderately from the null for the outcomes considered. However, somewhat lower risks of specific cardiovascular outcomes, breast cancer, and diabetes were associated with a higher intake of α- and β-carotene, lower risk of diabetes was associated with higher L+Z intake, and elevated risks of certain cardiovascular outcomes were associated with a higher intake of α-tocopherol. These patterns remained following the exclusion of baseline users of dietary supplements. Concentration biomarkers can be calculated from blood specimens obtained in large epidemiologic cohorts and applied directly in disease-association analyses, without relying on self-reported dietary data. Observed associations between carotenoid and tocopherol biomarkers and chronic disease risk could be usefully evaluated further using stored serum specimens on the entire WHI cohort. This study was registered at www.clinicaltrials.gov as NCT00000611.

The Impact of APOL1 on Chronic Kidney Disease and Hypertension.

Essential hypertension is a clinical diagnosis based on the presence of an elevated systemic blood pressure on physical examination without a clear inciting cause. It has multiple etiologies and is not a homogeneous disorder. Hypertension contributes to the development and progression of atherosclerotic cardiovascular diseases, and antihypertensive treatment reduces the risk of fatal and nonfatal myocardial infarction, stroke, and congestive heart failure. Although hypertension is frequently present in nondiabetic individuals with low levels of proteinuria and chronic kidney disease, reducing blood pressures in this population does not reliably slow nephropathy progression. Many of these patients with recent African ancestry have the primary kidney disease "solidified glomerulosclerosis" that is strongly associated with renal-risk variants in the apolipoprotein L1 gene (APOL1). This kidney disease contributes to secondarily elevated blood pressures. The APOL1-associated spectrum of nondiabetic nephropathy also includes proteinuric kidney diseases, idiopathic focal segmental glomerulosclerosis, collapsing glomerulopathy, severe lupus nephritis, and sickle cell nephropathy. This article reviews relationships between mild to moderate essential hypertension and chronic kidney disease with a focus on the role of APOL1 in development of hypertension. Available evidence strongly supports that APOL1 renal-risk variants associate with glomerulosclerosis in African Americans, which then causes secondary hypertension, not with essential hypertension per se.

Metabolic syndrome and risk of endometrial cancer in postmenopausal women: a prospective study.

Obesity is a strong risk factor for endometrial cancer, but it is unclear whether metabolic syndrome (MetS) contributes to endometrial cancer risk over and above the contribution of obesity. We examined the association of MetS and its components with risk of endometrial cancer in a sub-cohort of 24,210 women enrolled in the Women's Health Initiative cohort study. Two variants of the National Cholesterol Education Program Adult Treatment Panel III definition of the MetS were used: one including and one excluding waist circumference (WC). Cox proportional hazards models were used to estimate the association of the study exposures with disease risk. When WC was included in the definition, MetS showed an approximately two-fold increase in endometrial cancer risk (HR 2.20; 95% CI 1.61-3.02); however, when WC was excluded, MetS was no longer associated with risk. We also observed that women with hyperglycemia, dyslipidemia and hypertension, in combination, had almost a twofold increased risk of endometrial cancer, independent of WC (HR 1.94; 95% CI 1.09, 3.46). Glucose, and, in particular, WC and body mass index were also positively associated with risk. Our findings suggest that MetS may predict risk of endometrial cancer independent of obesity among women with the remaining four Mets components.

Serum Nitrogen and Carbon Stable Isotope Ratios Meet Biomarker Criteria for Fish and Animal Protein Intake in a Controlled Feeding Study of a Women's Health Initiative Cohort

Natural abundance stable isotope ratios are candidate biomarkers of dietary intake that have not been evaluated in a controlled feeding study in a US population. Our goals were to evaluate dietary associations with serum carbon (CIR), nitrogen (NIR), and sulfur (SIR) isotope ratios in postmenopausal women, and to evaluate whether statistical models of dietary intake that include multiple isotopes and participant characteristics meet criteria for biomarker evaluation. Postmenopausal women from the Women's Health Initiative (n=153) were provided a 2-wk controlled diet that approximated each individual's habitual food intake. Dietary intakes of animal protein, fish/seafood, red meat, poultry, egg, dairy, total sugars, added sugars, sugar-sweetened beverages (SSBs), and corn products were characterized during the feeding period with the use of the Nutrition Data System for Research (NDS-R). The CIR, NIR, and SIR were measured in sera collected from fasting women at the beginning and the end of the feeding period. Linear models based on stable isotope ratios and participant characteristics predicted dietary intake. The criterion used for biomarker evaluation was R2≥0.36, based on the study's power to detect true associations with R2≥0.50. The NIR was associated with fish/seafood intake and met the criterion for biomarker evaluation (R2=0.40). The CIR was moderately associated with intakes of red meat and eggs, but not to the criterion for biomarker evaluation, and was not associated with intake of sugars (total, added, or SSB). A model of animal protein intake based on the NIR, CIR, and participant characteristics met the criterion for biomarker evaluation (R2=0.40). Otherwise, multiple isotopes did not improve models of intake, and improvements from including participant characteristics were modest. Serum stable isotope ratios can, with participant characteristics, meet biomarker criteria as measures of fish/seafood and animal protein intake in a sample of postmenopausal women. This trial was registered at clinicaltrials.gov as NCT00000611.

Abstract 4944: Insulin resistance and long-term cancer-specific and all-cause mortality: The Women's Health Initiative (WHI)

Abstract Background: Elevated insulin resistance has been associated with multiple morbid conditions. To our review, only one cohort study has evaluated insulin resistance and all-cause mortality in a general population (Pyorala 2000). Objective: To examine associations of insulin resistance with long-term cancer-specific and all-cause mortality in postmenopausal women. Methods: Included were 22,837 postmenopausal women aged 50-79 from the WHI cohort without prior cancer and with available fasting glucose and insulin levels. Using multivariate Cox proportional hazard models, we compared cancer-specific and all-cause mortality across quartiles of insulin resistance estimated by the homeostasis model assessment-insulin resistance (HOMA-IR) index. Results: Women in the highest HOMA-IR quartile were less educated, had higher BMI and waist circumference, were more likely to be Black, and were more likely to have hypertension than those in lower HOMA-IR quartiles. Women in the highest quartile were also significantly more likely to have a history of treated diabetes than those in lower quartiles (23.5% in Q4 versus 0.6% in Q1). After a median follow-up of 18.1 years, cancer-specific and all-cause mortality were significantly higher in the highest HOMA-IR quartile compared to the lowest (HR 1.25, 95% CI 1.07-1.46 and HR 1.62, 95% CI 1.50-1.75, respectively) (Table 1). In a sensitivity analysis excluding women with treated diabetes (remaining n=21,104), all-cause mortality findings were similar (HR 1.36, 95% CI 1.25-1.48, p<0.0001). Specific causes of the 7,194 total deaths were cancer (1,786, 25%), cardiovascular disease (2,458, 34%), Alzheimer's/dementia (549, 8%), other (2,041, 28%), and unknown (360, 5%). Conclusion: Insulin resistance by HOMA-IR index identifies a substantial, previously under-recognized population of postmenopausal women at increased risk for cancer-specific and all-cause mortality who could potentially benefit from early intervention. Table 1. Adjusted* HRs for cancer-specific and all-cause mortality by HOMA-IR quartilesHOMA-IR QuartilesNCancer Specific Mortality HR (95% CI) P valueAll Cause Mortality HR (95% CI) P valueQ1: 0.04-1.0857071.0 (reference)0.04311.0 (reference)<0.0001Q2: 1.09-1.7657131.11 (0.97-1.28)1.13 (1.05-1.21)Q3: 1.77-3.0257161.17 (1.01-1.36)1.20 (1.11-1.29)Q4: 3.03-40357011.25 (1.07-1.46)1.62 (1.50-1.75)*Adjusted for education level, BMI, age at menopause, parity, alcohol consumption, and Gail score Citation Format: Kathy Pan, Rebecca Nelson, Jean Wactawski-Wende, Delphine J. Lee, JoAnn E. Manson, Joanne E. Mortimer, Lawrence S. Phillips, Thomas Rohan, Gloria Y. Ho, Nazmus Saquib, Aladdin H. Shadyab, Rami Nassir, Jinnie J. Rhee, Arti Hurria, Rowan T. Chlebowski. Insulin resistance and long-term cancer-specific and all-cause mortality: The Women's Health Initiative (WHI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4944.

Chocolate intake and heart disease and stroke in the Women's Health Initiative: a prospective analysis

Three recent meta-analyses found significant prospective inverse associations between chocolate intake and cardiovascular disease risk. Evidence from these meta-analyses suggests that such inverse associations may only apply to elderly individuals or those with pre-existing major chronic disease. We assessed the association between habitual chocolate intake and subsequent incident coronary heart disease (CHD) and stroke, and the potential effect of modification by age. We conducted multivariable Cox regression analyses using data from 83,310 postmenopausal women free of baseline pre-existing major chronic disease in the prospective Women's Health Initiative cohort. Chocolate intake was assessed using a food-frequency questionnaire. Physician-adjudicated events or deaths were ascertained up to 30 September 2013. After exclusions, there were 3246 CHD and 2624 stroke events or deaths, representing incidence rates of 3.9% and 3.2% during 1,098,091 and 1,101,022 person-years (13.4 y), respectively. We found no association between consumption of chocolate and risk of CHD (P for linear trend=0.94) or stroke (P=0.24). The results for CHD and stroke combined were similar (P=0.30), but were significantly modified by age (P for interaction=0.02). For women age <65 y at baseline, those who ate 1 oz (28.35 g) of chocolate <1/mo, 1 to <1.5/mo, 1.5 to <3.5/mo, 3.5/mo to <3/wk, and ≥3/wk had HRs (95% CIs) of 1.00 (referent), 1.17 (1.00, 1.36), 1.05 (0.90, 1.22), 1.09 (0.94, 1.25), and 1.27 (1.09, 1.49), respectively (P for linear trend=0.005). No association was apparent for older women. We observed no association between chocolate intake and risk of CHD, stroke, or both combined in participants free of pre-existing major chronic disease. The relation for both combined was modified by age, with a significant positive linear trend and an increased risk in the highest quintile of chocolate consumption among women age <65 y. This trial was registered at clinicaltrials.gov as NCT03453073.

Genome-Wide DNA Methylation in Prediagnostic Blood and Bladder Cancer Risk in the Women's Health Initiative.

Background: Differential DNA methylation as measured in blood is a promising marker of bladder cancer susceptibility. However, previous studies have exclusively used postdiagnostic blood samples, meaning that observed associations may be markers of disease rather than susceptibility.Methods: Genome-wide methylation was measured in prediagnostic blood samples, using the Illumina Infinium HumanMethylation450 Bead Array, among 440 bladder cancer cases with the transitional cell carcinoma (TCC) subtype and 440 matched cancer-free controls from the Women's Health Initiative cohort. After normalization and probe filtering, we used conditional logistic regression models to test for associations between methylation measurements at 361,184 CpG sites and bladder cancer risk.Results: Increased methylation at cg22748573, located in a CpG island within the 5'-UTR/first exon of the CITED4 gene, was associated with an 82% decreased risk of bladder cancer after adjusting for race/ethnicity, smoking status, pack-years of smoking, and leukocyte cell profile and accounting for multiple testing (OR = 0.18, q-value = 0.05). The result was robust to sensitivity analyses accounting for time between enrollment and diagnosis, race, tumor subtype, and secondhand smoke exposure.Conclusions: Although results need to be confirmed in additional prospective studies, differential methylation in CITED4, as measured in blood, is a promising marker of bladder cancer susceptibility.Impact: Identification of biomarkers of bladder cancer susceptibility in easily accessible tissues may allow targeting of screening efforts so as to improve bladder cancer prognosis. This is particularly important among women, who tend to have poorer bladder cancer outcomes than men. Cancer Epidemiol Biomarkers Prev; 27(6); 689-95. ©2018 AACR.

Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort.

Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk. We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women. Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset. Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50-2.42). The incremental change in c-index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041-0.109) for incident melanoma. Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort. Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available.

Accelerometer-Measured Physical Activity and Mortality in Women Aged 63 to 99.

To prospectively examine associations between accelerometer-measured physical activity (PA) and mortality in older women, with an emphasis on light-intensity PA. Prospective cohort study with baseline data collection between March 2012 and April 2014. Women's Health Initiative cohort in the United States. Community-dwelling women aged 63 to 99 (N = 6,382). Minutes per day of usual PA measured using hip-worn triaxial accelerometers, physical functioning measured using the Short Physical Performance Battery, mortality follow-up for a mean 3.1 years through September 2016 (450 deaths). When adjusted for accelerometer wear time, age, race-ethnicity, education, smoking, alcohol, self-rated health, and comorbidities, relative risks (95% confidence intervals) for all-cause mortality across PA tertiles were 1.00 (referent), 0.86 (0.69, 1.08), 0.80 (0.62, 1.03) trend P = .07, for low light; 1.00, 0.57 (0.45, 0.71), 0.47 (0.35, 0.61) trend P < .001, for high light; and, 1.00, 0.63 (0.50, 0.79), 0.42 (0.30, 0.57) trend P < .001, for moderate-to-vigorous PA (MVPA). Associations remained significant for high light-intensity PA and MVPA (P < .001) after further adjustment for physical function. Each 30-min/d increment in light-intensity (low and high combined) PA and MVPA was associated, on average, with multivariable relative risk reductions of 12% and 39%, respectively (P < .01). After further simultaneous adjusting for light intensity and MVPA, the inverse associations remained significant (light-intensity PA: RR = 0.93, 95% CI = 0.89-0.97; MVPA: RR = 0.67, 95% CI = 0.58-0.78). These relative risks did not differ between subgroups for age or race and ethnicity (interaction, P ≥ .14, all). When measured using accelerometers, light-intensity and MVPA are associated with lower mortality in older women. These findings suggest that replacing sedentary time with light-intensity PA is a public health strategy that could benefit an aging society and warrants further investigation.

Chocolate intake and diabetes risk in postmenopausal American women.

Recent long-term prospective cohort studies found inverse associations between chocolate consumption and the risk of type 2 diabetes, but provided conflicting evidence on the nature of the association among women. To assess this association in a large cohort of American women. Multivariable Cox regression was used with the data from 92 678 postmenopausal women in the prospective Women's Health Initiative study. Chocolate intake was assessed by food frequency questionnaire. Incidence of type 2 diabetes was determined by self-report of the first treatment with oral medication or insulin. Among women free of diabetes at baseline, there were 10 804 cases, representing an incidence rate of 11.7% during 13.1 years and 1 164 498 person-years of follow-up. There was no significant linear association between long-term chocolate intake and type 2 diabetes risk, but there was significantly reduced risk at moderate levels of intake. Compared to women who ate 1 oz. of chocolate <1 time per month, those who ate this amount 1-<1.5 times per month, 1.5-<3.5 times per month, 3.5 times per month to <3 times per week and ⩾3 times per week had hazard ratios of 0.97 (95% confidence interval: 0.92, 1.04), 0.92 (0.87, 0.98), 0.93 (0.88, 0.98) and 0.98 (0.92, 1.04) (P for linear trend=0.79). There was only evidence of such inverse associations for women with below-median physical activity (P for interaction <0.0001) and those with age<65 years (P=0.01). We only found an inverse association between chocolate consumption and type 2 diabetes at moderate levels of consumption in two subgroups of postmenopausal women in the Women's Health initiative cohort.

Dietary Long‐Chain Fatty Acids and Carbohydrate Biomarkers Evaluation in a Controlled Feeding Study in Participants from the Women's Health Initiative Cohort

We used an individualized controlled feeding study to assess the utility of serum phospholipid fatty acids (PLFA) as biomarkers of dietary intake of fatty acids, total fat, and carbohydrate. 153 postmenopausal women from the Women's Health Initiative were provided a 2‐wk controlled diet that mimicked each participant's habitual food intake as estimated from 4‐d food records and adjusted for estimated energy requirement using established methods (1; 2). 41 PLFA were measured using gas chromatography in end‐of‐feeding‐period fasting serum samples and expressed in both relative (weight percentage of total) and absolute (μg/ml) concentrations. R2 from linear regression of (ln‐transformed) consumed fatty acids (individual, groups, and broad categories) on (ln‐transformed) corresponding measures of serum PLFA ranged from 0.2% for consumed cis mono‐unsaturated fatty acid (MUFA) 16:1 to 47.1% for poly‐unsaturated fatty acid (PUFA) 22:6 (DHA) when using relative concentration of PLFA as a potential biomarker, and ranged from &lt;0.1% for PUFA 22:5 and % energy from PUFA to 38.3% for PUFA 20:5 (EPA) when using absolute concentration of PLFA. These linear regression models were further enriched by other important participant‐related variables (age, race/ethnicity, BMI, season of study participation, education level, and estimated energy intake from doubly labeled water). EPA and DHA were the only fatty acids that achieved R2 &gt;36% — benchmark set by established urinary recovery biomarkers of energy and protein — with or without additional covariates; incorporation of the additional covariates increased R2 to 46.5% and 50.3% respectively for EPA and DHA using their relative serum PLFA concentrations, and to 41.2% and 39.8% respectively using their absolute serum PLFA concentrations. When all 41 PLFA and the other participant‐related variables were initially included in the selection model, cross‐validated R2 achieved &gt;36% for consumed total carbohydrate (41.6% using relative PLFA concentration and 37.1% using absolute PLFA concentration), total saturated fatty acids (SFA, 39.8% and 39.9%), % energy from SFA (45.2% and 47.2%), and total trans fatty acids (37.5% and 36.4%) with potential PLFA biomarkers in either concentration metric. These serum PLFA biomarkers performed similarly to established energy and protein urinary recovery biomarkers in describing intake variations for several nutrients, and thus appear suitable for application in this population of postmenopausal women. This approach represents an important methodological contribution toward the utilization of nutritional biomarkers to assess macronutrient intake.Support or Funding InformationThis work was supported by National Cancer Institute (NCI) grant R01 CA119171. WHI is supported by National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts, HHSN268201100046C (Fred Hutch), HHSN268201100001C (SUNY Buffalo), HHSN268201100002C (The Ohio State University), HHSN268201100003C (Stanford), HHSN268201100004C (Wake Forest), and HHSN271201100004C (WHI Memory Study). R2 from linear regression models with consumed nutrient as dependent variable. Serum PLFA biomarkers were measured in both relative and absolute concentrations. wt% serum PLFA μg/ml serum PLFA Consumed Nutrient R2 (%) Model 1 R2 (%) Model 2 Cross‐validated R2 (%) Model 3 R2 (%) Model 1 R2 (%) Model 2 Cross‐validated R2 (%) Model 3 PUFA 20:5 (EPA), g/d 44.1 46.5 na 38.3 41.2 na PUFA 22:6 (DHA), g/d 47.1 50.3 na 35.0 39.8 na Total carbohydrate, g/d na na 41.6 na na 37.1 Total SFA, g/d na na 39.8 na na 39.9 % energy from SFA na na 45.2 na na 47.2 Total trans fatty acids, g/d na na 37.5 na na 36.4 PLFA, phospholipid fatty acid; PUFA, poly‐unsaturated fatty acid; SFA, saturated fatty acid; na, not applicable Model 1 independent variable: corresponding measure of serum PLFA Model 2 independent variables: corresponding measure of serum PLFA, participant age, race/ethnicity, BMI, season of study participation, education level, and estimated energy intake from doubly labeled water Model 3 independent variables: all 41 serum PLFA, participant age, race/ethnicity, BMI, season of study participation, education level, and estimated energy intake from doubly labeled water

Serum lipid changes following the onset of depressive symptoms in postmenopausal women.

A cross-sectional association between depression and serum low-density lipoprotein cholesterol (LDL-c) has been noted in psychiatric literature, raising the question of temporality: does low LDL-c predict depression, does depression lead to changes in LDL-c levels, or is this relationship bidirectional? In a previous longitudinal analysis of postmenopausal women ages 50-79 who participated in the Women's Health Initiative (WHI), we detected an association between low LDL-c and the subsequent onset of depressive symptoms (HR=1.25, 95% CI 1.05-1.49, p=0.01). This current study uses the WHI cohort to explore the question of temporality in the opposite direction, examining the influence of depressive symptoms on subsequent changes in LDL-c levels. This study provides no evidence to suggest an association between depression and subsequent changes in LDL-c level (-2.78mg/dL, 95% CI=-7.49 to 1.92, p=0.25), nor was any association detected for total cholesterol, HDL, or triglyceride changes over time. Further, this study demonstrates that the relationship between depression and serum LDL changes is not mediated by changes in weight, exercise, or energy intake.

Genetic Variant in ACVR2B Is Associated with Lean Mass.

Low lean mass (LM) is a risk factor for chronic disease, a major cause of disability and diminished quality of life, and is a heritable trait. However, relatively few specific genetic factors have been identified as potentially influencing this trait. In this study, we selected 1493 single-nucleotide polymorphisms (SNP) in 155 candidate genes involved in anabolic, catabolic, growth hormone, and other related pathways and examined their association with LM, assessed by dual-energy x-ray absorptiometry, in a sample of 2760 non-Hispanic and Hispanic white postmenopausal women from the Women's Health Initiative (WHI) Observational Study. We assessed the replication of our top findings in a meta-analysis of 20 genome-wide association studies (n = 38,292) conducted by the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Musculoskeletal Working Group. We identified 32 SNPs that had nominally significant associations with LM in the WHI cohort. In the replication stage, we find that SNP rs2276541 in the activin A receptor, type IIB (ACVR2B), was significantly associated with LM (β = 0.15, P = 2.17 × 10). ACVR2B codes for a receptor for a negative regulator of skeletal muscle, myostatin, and has previously been identified in a candidate gene study as a determinant of skeletal muscle mass. Our findings support a previously proposed role of ACVR2B allelic variation as a determinant of muscle mass and extend prior findings in men and women. Additional large-scale studies will be needed to confirm our findings in different populations.

Participation in Physical Activity and Risk for Amyotrophic Lateral Sclerosis Mortality Among Postmenopausal Women.

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease with no known cause. Case studies primarily of athletes and several case-control studies have suggested that high levels of strenuous physical activity (PA) may increase the risk for ALS. This relationship has yet to be evaluated among women in population-based cohort studies. To evaluate the relationship between PA and risk for ALS mortality in a large cohort of postmenopausal women. The Women's Health Initiative (WHI) enrolled 161 809 postmenopausal women, aged 50 to 79 years (mean [SD] age, 63.6 [7.24] years), between 1993 and 1998 into either a clinical trial or an observational study at 40 clinical research centers across the United States. We conducted a cohort study from November 2014 to September 2015 using baseline and mortality data during an average of 9.6 years of follow-up from the entire WHI cohort, through September 1, 2013 (with 1.1% lost to follow-up), to address whether there is a relationship between PA and ALS mortality. The WHI assessed frequency and duration of mild, moderate, and strenuous PA at baseline via self-administered questionnaire. Underlying cause of death from ALS collected from death certificates. The WHI enrolled 161 809 women, of whom 165 died of ALS; women who died of ALS were older (median age, 66 years; interquartile range, 61-69 years) compared with the total WHI study population (median age, 63 years; interquartile range, 57-69 years). Age-adjusted ALS mortality rates varied from 7.4 (95% CI, 5.5-9.9)/100 000 person-years for no strenuous PA to 10.6 (95% CI, 5.6-20.0)/100 000 person-years for strenuous PA 3 or more days per week (P = .07). Adjusted for age and body mass index (calculated as weight in kilograms divided by height in meters squared), the odds ratio for death from ALS for participants with strenuous PA 3 or more days per week compared with no reported strenuous PA was 1.56 (95% CI, 1.02-2.37; P = .04). To our knowledge, this is the first cohort study to report an increased risk for ALS mortality associated with strenuous PA in postmenopausal women. The association between strenuous PA and ALS risk observed does not compromise the overall benefit of strenuous PA for total mortality, coronary heart disease, and breast cancer reported in other WHI investigations, but it may provide an important clue to the etiology of ALS, if replicated by other studies.

Aging Well: Observations From the Women's Health Initiative Study.

As the proportion of the population aged 80 and over accelerates, so does the value of understanding the processes of aging well. The purposes of this article are to: (a) review contemporary theoretical and conceptual perspectives on aging well, (b) describe indicators of aging well that reflect key concepts and perspectives as assessed in the Women's Health Initiative (WHI) and (c) characterize the status of aging among women aged 80 and older using data obtained from WHI participants at the WHI Extension 2 follow-up. Data from the Lifestyle Questionnaire, which was administered from 2011 to 2012 during the WHI Follow-up Study (Extension 2), were analyzed to provide a profile of the WHI cohort with respect to aging well. Data revealed substantial diversity in the cohort with respect to the various measures of aging well. Although many reported physical functioning levels consistent with disability, most rated their health as good or better. Most reported moderately high levels of resilience, self-control, and self-mastery but lower levels of environmental mastery. Finally, the cohort reported high levels of optimal aging as reflected by their high levels of emotional well-being and moderately high levels of life satisfaction and social support, but more modest levels of personal growth and purpose in life. The wide range of some dimensions of aging well suggest that further examination of predictors of positive coping and resilience in the face of aging-related disability could identify opportunities to support and facilitate aging well among U.S. women.