Women's Health Initiative Observational Study Research Articles

Abstract 4147625: Cardiometabolic Syndrome and Incident Alzheimer’s Disease: The Predicative Value of Age and CMS Using Cox and Machine Learning Models

Background: Cardiometabolic syndrome (CMS) poses a significant public health concern. The study aimed to investigate the predictive value of age and CMS for incident Alzheimer’s disease (AD) in women aged≥50. Methods: A cohort of women aged 50-79 ( n = 63,117) who participated in the Women’s Health Initiative Observational Study (WHIOS) in 1993-1998, without baseline AD and followed through to March 1, 2019, were analyzed. CMS was defined as having ≥3 of five CMS components: large waist circumference, HBP, elevated triglycerides, elevated glucose, and low HDL-cholesterol. AD was classified by physician-diagnoses of incident AD. Hazards ratios (HR) of AD risk associated with CMS by age were analyzed using Cox’s proportional hazards regression analysis. Machine learning (ML)-XGBoost and Lasso Cox models clustered individuals with low, mild, moderate, and severe risk of incident AD. Results: During a median follow-up of 20 years (range: 3.36 to 23.36 years), 8340 developed incident AD. The incident rate (95%CI) of AD was 8.6 (8.1-9.1) per 1000 person-years (PY) in women with CMS, and 7.0 (6.9-7.2) per 1000 PY in those without CMS (p<0.001). Multivariate Cox’s regression analysis indicated that women with CMS versus non-CMS had significantly higher risks of AD in those aged 50-59 [HR (95%CI): 1.37(1.12-1.68)], followed by in those aged 60-69 [1.26 (1.14-1.40)], but nonsignificant in those aged≥70 [1.00 (0.87-1.14)]. Elevated glucose concentration ranked as the top predictor for AD, followed by triglyceride and HBP. Four levels (low to severe) of AD risk were significantly clustered using ML-XGBoost and Lasso Cox models. Conclusions: Women aged 50-69 with CMS vs those without CMS had significantly higher relative risks of AD, but the risk was not significant in those aged≥70. The application of ML prediction models holds potential promise in the early identification of AD risk among U.S. adults.

Accuracy of self-reported treated hypertension in the women's health initiative: Comparisons with medication inventories.

Few studies have reported on the accuracy of self-reported hypertension history among older postmenopausal women, which was this study's objective. Participants were postmenopausal women enrolled in the Osteoporosis and Periodontal Disease (OsteoPerio) study, an ancillary investigation of the Women's Health Initiative Observational Study (WHI-OS) at the Buffalo, New York, clinical site. Participants self-reported their history of physician diagnosed hypertension treated with medication at WHI-OS enrollment (1993-1998; n=1342, mean age 63 years), then 3 years later at OsteoPerio enrollment (1997-2001; n=1342), and again at OsteoPerio Year 5 follow-up (2002-2005; n=1020). At each time point, medication inventories were recorded and served as the criterion with which self-report was compared in the present study. Physician diagnosed-treated hypertension was also self-reported annually on mailed health update questionnaires in the WHI-OS and were compared against medication inventory at the subsequent clinic exam. Of those participants who self-reported a history of hypertension at WHI enrollment, OsteoPerio enrollment, and OsteoPerio Year 5 follow-up, 41.2%, 90.3%, and 94.4%, respectively, had anti-hypertensive pills in their medication inventory. Across the three time points, sensitivity and specificity ranged from 0.72 to 0.98 and from 0.85 to 0.95, and kappa coefficients ranged from 0.52 to 0.79 when comparing self-report with medication inventory. For self-reported newly physician-diagnosed and treated hypertension on the annual health update questionnaire, 88.4% and 95.2% of those reporting hypertension had anti-hypertensive pills in the subsequent medication inventory. In general, sensitivity and kappa were lower in women aged ≥70 versus<70 years and in those with history of cardiovascular disease and diabetes compared to those without these comorbidities. In this cohort of postmenopausal women, self-reported physician diagnosed and treated hypertension demonstrated moderate to high accuracy when compared against anti-hypertensive medication use documented by pill inventory, particularly for those who were younger and managing fewer comorbidities.

Diet and Chronic Disease Research in the Women’s Health Initiative

The Women’s Health Initiative (WHI) has been a major contributor to diet and chronic disease research among postmenopausal US women over its 30+ year history (1993 to present). The WHI program included full-scale randomized trials of a low-fat dietary pattern high in fruits, vegetables, and grains, and of calcium and vitamin D supplementation, each with designated primary and secondary chronic disease outcomes. The history of these trials will be briefly reviewed here, along with principal findings that included evidence for breast cancer-related benefits for each of the 2 interventions. In recent years, WHI investigators have developed an active research program in nutritional biomarker development and in the application of these biomarkers in WHI cohorts, among various other nutritional epidemiology uses of WHI observational study resources. The intake biomarker work, which primarily relies on blood and urine metabolomics profiles, lends support to the low-fat dietary pattern trial results, and supports chronic disease benefits of higher carbohydrate diets more generally, especially through the fiber component of carbohydrate.

Energy-Adjusted Dietary Inflammatory Index and Diabetes Risk in Postmenopausal Hispanic Women

BackgroundType 2 diabetes is a major public health concern in the United States and worldwide. The dietary inflammatory index (DII) and the energy-adjusted DII (E-DII) are tools that assess dietary inflammation. Previous evidence suggests that obesity can modify the association between inflammation and disease. ObjectiveThe aim of this study was to evaluate the association between the DII/E-DII and incident diabetes in self-identified Hispanic women from the Women’s Health Initiative (WHI). The secondary aim was to evaluate whether obesity modifies the association between the DII/E-DII scores and incident diabetes. DesignParticipants were from the WHI Observational Study and the Clinical Trial Components (except women from the treatment arm in the Dietary Modification Trial) conducted among postmenopausal women in the United States. DII/E-DII scores were calculated from a self-administered food frequency questionnaire at baseline that included 122 food items, of which 12 are representative of Hispanic eating patterns. Participants/settingsParticipants included 3,849 postmenopausal women who self-identified as Hispanic that were recruited for the WHI from 1993 to 1998 at 40 US clinical centers. Main outcome measuresThe outcome was incident diabetes. Statistical analysis performedCox regression models were used to assess the association between DII/E-DII and incident diabetes. Models were adjusted for age at baseline, lifestyle-related risk factors, known type 2 diabetes mellitus (T2DM) risk factors, and neighborhood socioeconomic status. Interaction was tested between the DII/E-DII scores and obesity. ResultsThe incidence of diabetes was 13.1% after a median follow-up of 13 years. Higher E-DII scores were associated with a higher risk of incident diabetes (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.04–1.14). There was no interaction between E-DII scores and obesity (P = 0.73). ConclusionsPro-inflammatory diets, as measured by higher E-DII scores, were associated with a higher risk of incident diabetes. Future research is needed for understanding how the inflammatory potential of diets can be decreased.

Genetic admixture and cardiovascular disease risk in postmenopausal Hispanic women

BackgroundHispanics are a heterogeneous population with differences in the prevalence of cardiovascular disease (CVD) and its related risk factors among ethnic sub-groups. This study evaluated the association of genetic admixture and CVD in self-identified Hispanic women from the Women's Health Initiative (WHI). MethodsData came from the WHI Observational Study and the Clinical Trial Components conducted among postmenopausal women. The CVD outcomes included coronary heart disease (CHD) and stroke. The proportions of European (EUR), sub-Saharan African (AFR), and Amerindian (AMI) admixture were estimated using 92 ancestry-informative markers. Cox regression models were used to assess the relationship between genetic admixture and CVD adjusting for age, lifestyle risk factors, known risk factors, and neighborhood socioeconomic status. ResultsAmong 5195 participants EUR ancestry was associated with a lower CHD risk after adjusting for age (HR 0.41, p = 0.02), and in the fully adjusted model (HR 0.40, p = 0.03). AFR ancestry was associated with a higher CHD risk after adjusting for age (HR 2.91, p = 0.03), but it only showed a trend in in the fully adjusted model (HR 2.46, p = 0.10). AMI ancestry was not statistically significantly associated with CHD and none of the genetic admixture proportions were statistically significantly associated with stroke (p > 0.05). ConclusionEUR ancestry was associated with a lower risk of CHD in Hispanic women. This highlights the need to account for genetic admixture in future CVD studies to consider different heritage groups to understand the role that genetic, neighborhood socioeconomic status, and environmental factors contribute to CVD health disparities in Hispanic women.

Association of Tea-drinking Habits with the Risk of Non-Hodgkin Lymphoma - A Prospective Cohort Study among Postmenopausal Women.

Although, biological evidence suggests that tea consumption may protect against non-Hodgkin lymphoma (NHL), epidemiologic evidence has been unclear. The aim of this study was to examine the association between tea-drinking habits and the risk of NHL in a large nationwide prospective cohort of postmenopausal US women. 68,854 women who were enrolled from 1993 through 1998 in the Women's Health Initiative Observational Study (WHI-OS) and responded to year 3 annual follow-up questionnaire comprised the analytic cohort. Newly diagnosed NHL cases after the year 3 visit were confirmed by medical and pathology reports. Multivariable-adjusted Cox proportional hazards models were performed to assess the associations of tea-drinking habits (specifically, the amounts of caffeinated/herbal/decaffeinated tea intake) with the overall risk of NHL and 3 major subtypes (Diffuse large B-cell lymphoma, DLBCL, (n=195, 0.3%), follicular lymphoma, FL, (n=128, 0.2%), and chronic lymphocytic leukemia/small lymphocytic lymphoma, CLL/SLL, (n=51, 0.1%)). Among 62,622 participants, a total of 663 (1.1%) women developed NHL during a median follow-up of 16.51(SD±6.20) years. Overall, different amounts of type-specific tea intake were not associated with the risk of NHL regardless of its histologic subtypes after adjustment for confounders. Our findings suggest that tea intake at the current consumption level does not influence the risk of NHL, regardless of its histologic types.

Hormone therapy formulation, dose, route of delivery, and risk of hypertension: findings from the Women's Health Initiative Observational Study (WHI-OS).

Using data from the Women's Health Initiative Observational Study (WHI-OS), to determine the role of estrogen formulation, dose, route of delivery, and its combination with different progestogens on the risk for hypertension in the WHI-OS. After excluding women with diagnosed hypertension, receiving antihypertensive medication, presenting with elevated blood pressure ( ≥ 140/90), and those not taking menopausal hormone therapy at baseline, 19,986 women remained eligible for the analyses. Using hierarchal modeling, proportional hazard rate calculation, and linear and logistic regression analyses, we evaluated incident treated hypertension and mean systolic and diastolic blood pressure changes at 3 years. Multivariable models were adjusted for age, race/ethnicity, education, smoking, physical activity, body mass index, history of treated diabetes, history of prescription medicines for high cholesterol, alcohol intake, hysterectomy, and bilateral oophorectomy. At 3 years, and compared with conjugated estrogens (CEE) with or without a progestin, the odds for newly treated hypertension were lower in women who used transdermal estradiol (0.85, 95% CI, 0.73-1.00) or oral estrone sulphate dominant preparations (0.83, 0.72-0.96). The odds of incident treated hypertension after 3 years did not vary according to dose of estrogen. The mean measured systolic blood pressure was minimally lower with transdermal estradiol (-1.20, 95% CI, -1.97 to -0.44) mm Hg and other oral Estrone dominant preparations (-0.83, 95% CI, -1.51 to -0.16) mm Hg at 3 years. For a given estrogen type, the magnitudes of the hazard ratio were similar for estrogen-alone compared with estrogen plus a progestogen. For women 10 or more years past menopause when they entered, the HR for incident self-reported treated hypertension was 1.26 (95% CI, 1.09-1.46) with higher dose CEE compared with 0.625 mg CEE. It was 0.87 (95% CI, 0.68-1.13) when given to women who were < 10 years after menopause when they entered the WHI-OS. The risk of treated hypertension differed by formulation, dose, and years since menopause.

Associations of Job Strain, Stressful Life Events, and Social Strain With Coronary Heart Disease in the Women's Health Initiative Observational Study.

BackgroundThe association between psychosocial stress and coronary heart disease (CHD) may be stronger in women than men and may differ across types of stressors. In this study, we assessed associations of psychosocial stressors, including job strain, stressful life events, and social strain with the incidence of CHD in women.Methods and ResultsWe used longitudinal data from 80 825 WHI‐OS (Women's Health Initiative Observational Study) participants with a mean age of 63.4 years (7.3 years) at baseline. Job strain was assessed through linkage of Standard Occupational Classification codes to the Occupational Information Network. Stressful life events and social strain were assessed via validated self‐reported questionnaires. Cox proportional hazard models were used to evaluate associations of each stressor with CHD separately and jointly. A total of 3841 (4.8%) women developed CHD during an average of 14.7 years of follow‐up. After adjustment for age, other stressors, job tenure, and socioeconomic factors, high stressful life events score was associated with a 12% increased CHD risk, and high social strain was associated with a 9% increased CHD risk. Job strain was not independently associated with CHD risk, but we observed a statistically significant interaction between job strain and social strain (P=0.04), such that among women with high social strain, passive job strain was associated with a 21% increased CHD risk.ConclusionsHigh stressful life events and social strain were each associated with higher CHD risk. Job strain and social strain work synergistically to increase CHD risk.

Impact of diabetes mellitus and cardiometabolic syndrome on the risk of Alzheimer's disease among postmenopausal women.

BACKGROUNDIn spite of an increase in the incidence and prevalence of diabetes mellitus (DM) and Alzheimer’s disease (AD) in the aging population worldwide, limited attention has been paid to their potential association.AIMTo investigate the association of DM and cardiometabolic syndrome (CMS, a precursor to DM) with risk of incident AD among postmenopausal women.METHODSPostmenopausal women aged 50-79 (n = 63117) who participated in the U.S. Women’s Health Initiative Observational Study (WHIOS), recruited in 1993-1998, without baseline AD and followed up through March 1, 2019, were analyzed. AD was classified by participant-reported history of doctor-diagnosis of incident AD in the WHIOS. DM was defined by participant-report or treated because of diabetes or serum glucose concentrations ≥ 126 mg/dL. CMS was defined as having ≥ 3 of five CMS components: large waist circumference, high blood pressure, elevated triglycerides, elevated glucose, and low high-density lipoprotein cholesterol. The associations of DM and CMS with AD were analyzed using Cox’s proportional hazards regression analysis.RESULTSDuring a median follow-up of 20 years (range: 3.36 to 23.36 years), of 63117 participants, 8340 developed incident AD. Women with DM had significantly higher incidence of AD [8.5, 95% confidence interval (CI): 8.0-9.0 per 1000 person-years (PY)] than those without DM (7.1, 95%CI: 6.9-7.2 per 1000 PY). Multivariate Cox’s regression analysis indicated that women with DM or CMS had a significantly higher risk of AD than those without DM or CMS. The corresponding hazard ratios [HR (95%CI)] were 1.22 (1.13-1.31, P < 0.001) in subjects with DM, and 1.18 (1.09-1.27, P < 0.001) in subjects with CMS. The HRs diminished with age and became non-significant in the oldest age group.CONCLUSIONDuring a median follow-up of 20 years, DM and CMS were significantly associated with the risk of AD among postmenopausal women. More specifically, women aged 50-69 with DM or CMS vs those without these conditions had significantly higher relative risks of AD than the relative risks of AD in those aged 70-79 with DM or CMS vs those without DM or CMS.

Metabolomic Effects of Hormone Therapy and Associations With Coronary Heart Disease Among Postmenopausal Women.

In the WHI-HT trials (Women's Health Initiative Hormone Therapy), treatment with oral conjugated equine estrogens and medroxyprogesterone acetate (CEE+MPA) resulted in increased risk of coronary heart disease (CHD), whereas oral conjugated equine estrogens (CEE) did not. Four hundred eighty-one metabolites were measured at baseline and at 1-year in 503 and 431 participants in the WHI CEE and CEE+MPA trials, respectively. The effects of randomized HT on the metabolite profiles at 1-year was evaluated in linear models adjusting for baseline metabolite levels, age, body mass index, race, incident CHD, prevalent hypertension, and diabetes. Metabolites with discordant effects by HT type were evaluated for association with incident CHD in 944 participants (472 CHD cases) in the WHI-OS (Women's Health Initiative Observational Study), with replication in an independent cohort of 980 men and women at high risk for cardiovascular disease. HT effects on the metabolome were profound; 62% of metabolites significantly changed with randomized CEE and 52% with CEE+MPA (false discovery rate-adjusted P value<0.05) in multivariable models. Concerted increases in abundance were seen within various metabolite classes including triacylglycerols, phosphatidylethanolamines, and phosphatidylcholines; decreases in abundance was observed for acylcarnitines, lysophosphatidylcholines, quaternary amines, and cholesteryl/cholesteryl esters. Twelve metabolites had discordant effects by HT type and were associated with incident CHD in the WHI-OS; a metabolite score estimated in a Least Absolute Shrinkage and Selection Operator regression was associated with CHD risk with an odds ratio of 1.47 per SD increase (95% CI, 1.27-1.70, P<10-6). All twelve metabolites were altered in the CHD protective direction by CEE treatment. One metabolite (lysine) was significantly altered in the direction of increased CHD risk by CEE+MPA; the remaining 11 metabolites were not significantly changed by CEE+MPA. The CHD associations of a subset of 4 metabolites including C58:11 triacylglycerol, C54:9 triacylglycerol, C36:1 phosphatidylcholine and sucrose replicated in an independent dataset of 980 participants in the PREDIMED trial (Prevención con Dieta Mediterránea). Randomized treatment with oral HT resulted in large metabolome shifts that generally favored CEE alone over CEE+MPA in term of CHD risk. Discordant metabolite effects between HT regimens may partially mediate the differences in CHD risk between the 2 WHI-HT trials.

The association between weight-promoting medication use and weight gain in postmenopausal women: findings from the Women's Health Initiative

With the rise in obesity, there has been a concomitant increase in prescription medications associated with weight gain. The objective of this study is to quantify the magnitude of association between putative weight-promoting medications and 3-year weight change in a diverse cohort of postmenopausal women in the Women's Health Initiative (WHI). This is a prospective observational cohort study, considering 40 sites in the WHI and a cohort of seventy six thousand two hundred fifty-two postmenopausal women aged 50-79 years, with weight measured at both baseline and 3 years, in the WHI-Observational Study. Body mass index (BMI) and waist circumference (WC) were measured at baseline and 3 years. An in-clinic medication inventory identified prescribed medications, including antidepressants, beta-blockers, insulin, and/or glucocorticosteroids. Generalized linear models evaluated if intermittent or persistent use of weight-promoting drugs was associated with increased BMI and WC during a 3-year follow up. Women with overweight or obesity at baseline were more likely to be taking antidepressants, beta-blockers, and/or insulin. Taking at least one putative weight-promoting medication was associated with a greater increase in BMI (0.37 vs 0.27 kg/m, P = 0.0045) and WC (1.10 cm vs 0.89 cm, P = 0.0077) over the course of 3 years compared to women not on these medications. Both BMI and WC increased with the number of weight-promoting drugs prescribed (P for trend per medication used < 0.00001 for both variables). Those who took either antidepressants or insulin, or a combination of antidepressants and beta-blockers, were most likely to have a significant increase in BMI compared to nonusers. Antidepressants, beta-blockers, and insulin were associated with weight gain in postmenopausal women. This information may help to inform clinical decision-making and efforts to mitigate medication-related weight gain. : Video Summary:http://links.lww.com/MENO/A617.

Associations of depression status with plasma levels of candidate lipid and amino acid metabolites: a meta-analysis of individual data from three independent samples of US postmenopausal women.

Recent animal and small clinical studies have suggested depression is related to altered lipid and amino acid profiles. However, this has not been examined in a population-based sample, particularly in women. We identified multiple metabolites associated with depression as potential candidates from prior studies. Cross-sectional data from three independent samples of postmenopausal women were analyzed, including women from the Women's Health Initiative-Observational Study (WHI-OS, n=926), the WHI-Hormone Trials (WHI-HT; n=1,325), and the Nurses' Health Study II Mind-Body Study (NHSII-MBS; n=218). Positive depression status was defined as having any of the following: elevated depressive symptoms, antidepressant use, or depression history. Plasma metabolites were measured using liquid chromatography-tandem mass spectrometry (21 phosphatidylcholines [PCs], 7 lysophosphatidylethanolamines, 5 ceramides, 3 branched chain amino acids and 9 neurotransmitters). Associations between depression status and metabolites were evaluated using multivariable linear regression; results were pooled by random-effects meta-analysis with multiple testing adjustment using the Benjamini-Hochberg false discovery rate (FDR). Prevalence rates of positive depression status were 24.4% (WHI-OS), 25.7% (WHI-HT) and 44.7% (NHSII-MBS). After multivariable adjustment, positive depression status was associated with higher levels of glutamate and PC 36:1/38:3, and lower levels of tryptophan and GABA-to-glutamate and GABA-to-glutamine ratio (FDR-p<0.05). Positive associations with LPE 18:0/18:1 and inverse associations with valine and serotonin were also observed, although these associations did not survive FDR adjustment. Associations of positive depression status with several candidate metabolites including PC 36:1/38:3 and amino acids involved in neurotransmission suggest potential depression-related metabolic alterations in postmenopausal women, with possible implications for later chronic disease.

Reproductive history and osteoarthritis in the Women’s Health Initiative

Objective: To investigate the relationship between self-reported osteoarthritis (OA) and reproductive factors in the Women’s Health Initiative (WHI). Method: We used multivariable logistic regression to study the association of self-reported OA and reproductive factors in the WHI Observational Study and Clinical Trial cohorts of 145 965 postmenopausal women, in a retrospective cross-sectional format. Results: In our cohort, we observed no clinically significant associations between reproductive factors and OA given small effect sizes. The following factors were associated with statistically significant increased likelihood of developing OA: younger age at menarche (p < 0.001), history of hysterectomy [adjusted odds ratio (aOR) 1.013, 95% confidence interval (CI) 1.004–1.022, p = 0.04 vs no hysterectomy], history of unilateral oophorectomy (aOR 1.015, 95% CI 1.004–1.026, p < 0.01 vs no oophorectomy), parity (aOR 1.017, 95% CI 1.009–1.026, p < 0.001), ever use of oral contraceptives (aOR 1.008, 95% CI 1.001–1.016, p < 0.01 vs never use), and current use of hormonal therapy (reference current users, aOR 0.951, 95% CI 0.943–0.959 for never users; aOR 0.981, 95% CI 0.972–0.989 for past users; global p < 0.001). Age at menopause, first birth, and pregnancy were not associated with OA. Among parous women, no clear pattern was observed with number of pregnancies, births, or duration of breastfeeding in relation to OA. Conclusion: Our study showed that reproductive factors did not have significant clinical associations with OA after controlling for confounders. This may be due to complex hormonal effects. Additional investigation is warranted in prospective cohort studies. The Women’s Health Initiative is registered under ClinicalTrials.gov. Trial registration ID: NCT00000611.

Metabolic signatures associated with Western and Prudent dietary patterns in women

The Western dietary pattern (WD) is positively associated with risk of coronary artery disease (CAD) and cancer, whereas the Prudent dietary pattern (PD) may be protective. Foods may influence metabolite concentrations as well as oxidative stress and lipid dysregulation, biological mechanisms associated with CAD and cancer. The aim was to assess the association of 2 derived dietary pattern scores with serum metabolites and identify metabolic pathways associated with the metabolites. We evaluated the cross-sectional association between each dietary pattern (WD, PD) and metabolites in 2199 Women's Health Initiative (WHI) participants. With FFQ and factor analysis, we determined 2 dietary patterns consistent with WD and PD. Metabolites were measured with LC-tandem MS. Metabolite discovery among 904 WHI Observational Study (WHI-OS) participants was replicated among 1295 WHI Hormone Therapy Trial (WHI-HT) participants. We analyzed each of 495 metabolites with each dietary score (WD, PD) in linear regression models. The PD included higher vegetables and fruit intake compared with the WD with higher saturated fat and meat intake. Independent of energy intake, BMI, physical activity, and other confounding variables, 45 overlapping metabolites were identified (WHI-OS) and replicated (WHI-HT) with an opposite direction of associations for the WD compared with the PD [false discovery rate (FDR) P<0.05]. In metabolite set enrichment analyses, phosphatidylethanolamine (PE) plasmalogens were positively enriched for association with WD [normalized enrichment score (NES)=2.01, P=0.001, FDR P=0.005], and cholesteryl esters (NES = -1.77, P=0.005, FDR P=0.02), and phosphatidylcholines (NES = -1.72, P=0.01, P=0.03) were negatively enriched for WD. PE plasmalogens were positively correlated with saturated fat and red meat. Phosphatidylcholines and cholesteryl esters were positively correlated with fatty fish. Distinct metabolite signatures associated with Western and Prudent dietary patterns highlight the positive association of mitochondrial oxidative stress and lipid dysregulation with a WD and the inverse association with a PD.

Dietary Manganese, Plasma Markers of Inflammation, and the Development of Type 2 Diabetes in Postmenopausal Women: Findings From the Women's Health Initiative.

To examine the association between manganese intake and the risk of type 2 diabetes in postmenopausal women and determine whether this association is mediated by circulating markers of inflammation. We included 84,285 postmenopausal women without a history of diabetes from the national Women's Health Initiative Observational Study (WHI-OS). Replication analysis was then conducted among 62,338 women who participated in the WHI-Clinical Trial (WHI-CT). Additionally, data from a case-control study of 3,749 women nested in the WHI-OS with information on biomarkers of inflammation and endothelial dysfunction were examined using mediation analysis to determine the relative contributions of these known biomarkers by which manganese affects type 2 diabetes risk. Compared with the lowest quintile of energy-adjusted dietary manganese, WHI-OS participants in the highest quintile had a 30% lower risk of type 2 diabetes (hazard ratio [HR] 0.70 [95% CI 0.65, 0.76]). A consistent association was also confirmed in the WHI-CT (HR 0.79 [95% CI 0.73, 0.85]). In the nested case-control study, higher energy-adjusted dietary manganese was associated with lower circulating levels of inflammatory biomarkers that significantly mediated the association between dietary manganese and type 2 diabetes risk. Specifically, 19% and 12% of type 2 diabetes risk due to manganese were mediated through interleukin 6 and hs-CRP, respectively. Higher intake of manganese was directly associated with a lower type 2 diabetes risk independent of known risk factors. This association may be partially mediated by inflammatory biomarkers.

The Buffalo OsteoPerio Studies: Summary of our findings and the unique contributions of Robert J. Genco, DDS, PhD.

Robert ("Bob") Genco was a member of the research team that established the Buffalo Osteoporosis and Periodontal Disease (OsteoPerio) study. Here we detail the scientific discoveries emanating from this enduring collaboration. OsteoPerio is ancillary to the Women's Health Initiative Observational Study (WHI-OS). WHI-OS is a longitudinal study of 93,000 postmenopausal women aged 50-79 enrolled at 40 U.S. centers (enrolled 1993-1998). OsteoPerio enrolled 1342 women 3 years later (1997-2001) from the Buffalo WHI-OS participants to study the association of osteoporosis and periodontal disease. OsteoPerio has 5-year (N=1026) and 17-year (N=518) follow-up examinations. In addition to information on health status from the WHI-OS, OsteoPerio further included comprehensive oral examinations assessing probing pocket depth, clinical attachment loss, gingival bleeding, alveolar crestal height, and DMFT. Systemic bone density (measured by DXA), blood, saliva and plaque also were collected at all three visits. Findings from these studies are summarized here.

COPD and lung cancer incidence in the Women’s Health Initiative Observational Study: A brief report

ObjectivesLung cancer is the leading cause of cancer mortality in both men and women in the United States. COPD is associated with lung cancer independently of cigarette smoking, but remains understudied in women. Utilizing data from the Women’s Health Initiative Observational Study (WHI-OS), this report investigates the association between COPD and development of lung cancer, with a focus on ethnicity and cancer subtype. Materials and methodsThe WHI-OS, part of the larger Women’s Health Initiative (WHI), is comprised of postmenopausal women between ages 50 and 79 years old at enrollment. Self-administered questionnaires were utilized to gather baseline demographic, socioeconomic, and behavioral information from participants. For this analysis, COPD status was determined at study entry (baseline) and on annual survey (incident). Information on the primary outcome of interest, diagnosis of lung cancer, was also collected annually. Results and conclusionOf the 92,789 women examined, 1,536 developed lung cancer. Overall, women with COPD were 1.64 times more likely to develop lung cancer than those without COPD, after adjusting for smoking status and intensity, ethnicity, education, body mass index, and income (HR = 1.64, 95 % CI: 1.43, 1.89). The relationship between COPD and lung cancer was not found to be significantly different between ethnic groups (p-value = 0.697). The associations between COPD and lung cancer was similar across subtypes (HR range 1.31–2.16), after adjusting for smoking status and intensity.COPD increases risk of lung cancer in women, thus they may benefit from more intensive surveillance compared to similar women without COPD.

Identifying Metabolomic Profiles of Insulinemic Dietary Patterns.

The food-based empirical dietary index for hyperinsulinemia (EDIH) score assesses the insulinemic potential of diet. This cross-sectional study evaluated associations between EDIH scores from food frequency questionnaires with c-peptide concentrations and with 448 metabolites, from fasting plasma samples, in multivariable linear regression analyses. Metabolites were measured with liquid chromatography tandem mass spectroscopy. Using a robust two-stage study design, discovery of metabolite associations was conducted among 1109 Women’s Health Initiative (WHI) Hormone Therapy (HT) trial participants and results replicated in an independent dataset of 810 WHI Observational Study (OS) participants. In both discovery and replication datasets, statistical significance was based on the false-discovery rate adjusted P < 0.05. In the multivariable-adjusted analyses, EDIH was significantly associated with c-peptide concentrations among 919 women (HT & OS) with c-peptide data. On average, c-peptide concentrations were 18% higher (95% CI, 6%, 32%; P-trend < 0.0001) in EDIH quintile 5 compared to quintile 1. Twenty-six metabolites were significantly associated with EDIH in the discovery dataset, and 19 of these were replicated in the validation dataset. Nine metabolites were found to decrease in abundance with increasing EDIH scores and included: C14:0 CE, C16:1 CE, C18:1 CE, C18:3 CE, C20:3 CE, C20:5 CE, C36:1 PS plasmalogen, trigonelline, and eicosapentanoate, whereas the 10 metabolites observed to increase with increasing EDIH scores were: C18:2 SM, C36:3 DAG, C36:4 DAG-A, C51:3 TAG, C52:3 TAG, C52:4, TAG, C54:3 TAG, C54:4 TAG, C54:6 TAG, and C10:2 carnitine. Cholesteryl esters, phospholipids, acylglycerols, and acylcarnitines may constitute circulating metabolites that are associated with insulinemic dietary patterns.

Identifying metabolomic profiles of inflammatory diets in postmenopausal women

We previously showed that a food-based empirical dietary inflammatory pattern (EDIP) score is associated with circulating inflammatory biomarkers. Metabolomic profiling of inflammatory diets may therefore provide insights on mechanisms contributing to disease etiology and prognosis. We aimed to elucidate metabolites associated with inflammatory diets among postmenopausal women, utilizing a robust study design that incorporates independent discovery and validation datasets. This baseline cross-sectional investigation evaluated associations between continuous EDIP scores calculated from food frequency questionnaires and 448 log-transformed plasma metabolites as outcomes in multivariable-adjusted linear regression analyses. Metabolites were measured with liquid chromatography tandem mass spectroscopy. Metabolite discovery was conducted among 1109 Women's Health Initiative (WHI) Hormone Therapy trial participants and results were replicated in an independent dataset of 810 WHI Observational Study participants. Secondary analyses were stratified by standard body mass index (BMI, kg/m2) categories. In discovery and replication datasets statistical significance was based on false-discovery rate adjusted P<0.05. After adjusting for energy intake, BMI, physical activity, and other confounding variables, 23 metabolites were significantly associated with EDIP score in the discovery dataset. Of these, the following ten were replicated: trigonelline, caffeine, acethylamino-6-amino-3-methyluracil, 7-methylxanthine, 1,7-dimethyluric acid, 3-methylxanthine, C18:3CE, glycine, associated with lower dietary inflammatory potential; whereas C52:3 triacylglycerol and linoleate associated with higher dietary inflammatory potential. Four of the ten were associated [glycine (inversely), caffeine, 1,7-dimethyluric acid, C52:3 triacylglycerol, (positively)], with C-reactive protein levels. In secondary analyses, associations showed differences by BMI category. Four metabolites, related to coffee/caffeine metabolism were inversely associated among normal weight women, and 83 metabolites associated with EDIP among overweight/obese women, including 40 (48%) that were also associated with C-reactive protein. Metabolites associated with coffee/caffeine and lipid metabolism may reflect the inflammatory potential of diet. Potential differences by BMI and the linkage to disease outcomes, require further study.

Identifying Metabolomic Profiles of Insulinemic Dietary Patterns (OR31-03-19)

ObjectivesThe empirical dietary index for hyperinsulinemia (EDIH) is a food-based score derived from correlations with plasma c-peptide. Our aim is to use the EDIH to discover metabolites associated with insulinemic dietary patterns. MethodsThis baseline cross-sectional study evaluated associations between continuous EDIH scores from food frequency questionnaires and 448 log-transformed plasma metabolites as outcomes in multivariable linear regression analyses. Metabolites were measured with liquid chromatography tandem mass spectroscopy. Metabolite discovery was conducted among 1109 Women’s Health Initiative (WHI) Hormone Therapy trial participants and results replicated in an independent dataset of 810 WHI Observational Study participants. In both discovery and replication datasets statistical significance was based on false-discovery rate adjusted P < 0.05. Secondary analyses were conducted in body mass index (BMI: <25, >=25 kg/m2) categories. ResultsAfter adjustment for energy intake, BMI, physical activity, and other confounding variables, 26 metabolites were significantly associated with EDIH in the discovery dataset, and included: trigonelline, C14:0 CE, C16:1 CE, C18:1 CE, C18:3 CE, C20:3 CE. C20:5 CE, C36:1 PS plasmalogen and eicosapentaenoate were associated with lower dietary insulinemic potential, whereas C36:3 DAG, C51:3 TAG, C52:3 TAG, C52:4 TAG, C54:2 TAG, C54:3 TAG, C54:4 TAG, C54:6 TAG, C36:4 DAG-A, cystathionine, isoleucine, N4-acetylcytidine, C10:2 carnitine, cAMP, C18:2 SM, C4-OH carnitine, and myristoleic acid were associated with higher dietary insulinemic potential. 25 out of the 26 metabolites replicated in the validation dataset except myristoleic acid. In secondary analyses within BMI strata, Associations differed by BMI category: 12 metabolites were significant among normal weight women whereas 64 metabolites were associated with EDIH among overweight/obese women. ConclusionsCholesterol esters, triglycerides, carnitines and amino acids may constitute metabolites that are associated with insulinemic dietary patterns. Funding SourcesR00CA207736, NHLBI HHSN268201300008C.