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1.  Periodontal disease and breast cancer: Prospective cohort study of postmenopausal women 
Periodontal disease (PD) has been consistently associated with chronic disease; there are no large studies of breast cancer although oral-associated microbes are present in breast tumors.
In the Women’s Health Initiative Observational Study, a prospective cohort of postmenopausal women, 73,737 women without previous breast cancer were followed. Incident, primary, invasive breast tumors were verified by physician adjudication. PD was by self-report. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards, adjusted for breast cancer risk factors. Because the oral microbiome of those with PD differs with smoking status, we examined associations stratified by smoking.
2,124 incident, invasive breast cancer cases were identified after mean follow-up of 6.7 years. PD, reported by 26.1% of women, was associated with increased breast cancer risk (HR 1.14, 95% CI 1.03 to 1.26), particularly among former smokers who quit within 20 years (HR 1.36; 95% CI 1.05 to 1.77). Among current smokers, the trend was similar (HR 1.32; 95% CI 0.83 to 2.11); there were few cases (n=74) and the CI included the null. The population attributable fraction was 12.06% (95% CI 1.12 to 21.79) and 10.90% (95% CI 10.31 to 28.94) for PD among former smokers quitting within 20 years and current smokers, respectively.
PD, a common chronic inflammatory disorder, was associated with increased risk of postmenopausal breast cancer, particularly among former smokers who quit in the past 20 years.
Understanding a possible role of the oral microbiome in breast carcinogenesis could impact prevention.
PMCID: PMC4713270  PMID: 26689418
Breast neoplasms; periodontal disease; postmenopausal women; inflammation; microbiome; epidemiology
2.  Physical impairment and body weight history in postmenopausal women: The Women's Health Initiative 
Public health nutrition  2016;19(17):3169-3177.
To examine whether weight history and weight transitions over adult lifespan contribute to physical impairment among postmenopausal women.
Body mass index (BMI; kg/m2) categories were calculated among postmenopausal women who reported their weight and height at age 18. Multiple-variable logistic regression was used to determine the association between BMI at age 18 and BMI transitions over adulthood on severe physical impairment (SPI), defined as scoring < 60 on the Physical Functioning Subscale of the Random 36-Item Healthy Survey.
Participants were part of the Women's Health Initiative Observational study (WHI OS), where participants’ health were followed over time via questionnaires and clinical assessments.
Postmenopausal women (n=76,016; 63.5 ± 7.3 years)
Women with overweight (BMI=25.0-29.9) or obesity (BMI≥30) at 18 years had greater odds of SPI [odds ratio (OR) = 1.51, 95% confidence interval (CI): 1.35-1.69 and 2.14, 95% CI: 1.72-2.65, respectively] than normal weight (BMI=18.5-24.9) counterparts. Transitions from normal weight to overweight/obese or to underweight (BMI <18.5) were associated with greater odds of SPI (1.97 [1.84-2.11] and 1.35 [1.06-1.71], respectively) compared to weight stability. Shifting from underweight to overweight/obese also had increased odds of SPI (1.52 [1.11-2.09]). Overweight/obese to normal BMI transitions resulted in a reduced SPI odds (0.52 [0.39-0.71]).
Higher weight history and transitions into higher weight classes were associated with higher likelihood of severe physical impairment, while transitioning into lower weight classes for those with overweight/obesity was protective among postmenopausal women.
PMCID: PMC5135627  PMID: 27269298
Body weight; weight change; body mass index; physical impairment; physical function; disability
3.  Prospective Analysis of Health and Mortality Risk in Veteran and non-Veteran Participants in the Women’s Health Initiative 
The health of post-menopausal women Veterans is a neglected area of study. A stronger empirical evidence base is needed, and would inform the provision of health care for the nearly 1 million U.S. women Veterans currently 50 years of age or older. To this end, the present work compares salient health outcomes and risk of all-cause mortality among Veteran and non-Veteran participants of the Women’s Health Initiative (WHI).
This study features prospective analysis of long-term health outcomes and mortality risk (average follow-up 8 years) among the 3,706 women Veterans and 141,009 non-Veterans who participated in the WHI Observational Study or Clinical Trials. Outcome measurements included confirmed incident cases of cardiovascular disease (CVD), cancer, diabetes, hip fractures, and all-cause mortality.
We identified 17,968 cases of CVD; 19,152 cases of cancer; 18,718 cases of diabetes; 2,817 cases of hip fracture; and 13,747 deaths. In Cox regression models adjusted for age, sociodemographic, and health risk factors, Veteran status was associated with significantly increased risk of all-cause mortality (HR: 1.13; 95% CI: 1.03 – 1.23), but not with risk of CVD (HR: 1.00; CI 95%: 0.90 – 1.11); cancer (HR: 1.04; 95% CI: 0.95 – 1.14); hip fracture (HR: 1.16; 95% CI: 0.94 – 1.43); or diabetes (HR: 1.00; 95% CI: 0.89 – 1.1).
Women Veterans’ post-menopausal health, particularly risk for all-cause mortality, warrants further consideration. In particular, efforts to identify and address modifiable risk factors associated with all-cause mortality are needed.
PMCID: PMC4641800  PMID: 26432346
Women; Veterans; Mortality; Postmenopausal Health
4.  Adequate vitamin D status is associated with the reduced odds of prevalent diabetic retinopathy in African Americans and Caucasians 
Vitamin D status has been hypothesized to protect against development of diabetic retinopathy via its anti-inflammatory and anti-angiogenic properties. Additionally, in vitro and in vivo studies suggest vitamin D favorably influences blood pressure and blood glucose control, strong risk factors for diabetic retinopathy. We examined the association between vitamin D status and prevalent diabetic retinopathy in participants with diabetes from a population-based cohort.
Among participants in the Atherosclerosis Risk in Communities (ARIC) study with diabetes at visit 3 (1993–1995), 1339 (906 Caucasians, 433 African Americans) had serum 25-hydroxyvitamin (25[OH]D) concentrations assessed at visit 2 (1989–1992) and nonmydriatic retinal photographs taken at visit 3. Dietary intake of vitamin D was assessed at visit 1 (1987–1989). Logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for diabetic retinopathy by categories of season-adjusted 25(OH)D (<30 [referent], 30–<50, 50–<75 and ≥75 nmol/L), by quartile of vitamin D intake (IU/day), and use of vitamin D or fish oil supplements (yes/no). P for trend was estimated using continuous 25(OH)D or vitamin D intake. ORs were adjusted for race, and duration of diabetes. We further adjusted for HBA1c and hypertension to examine if 25(OH)D influenced diabetic retinopathy via its effects on either glycemic control or blood pressure.
ORs (95 % CIs) for retinopathy, adjusted for race and duration, were 0.77 (0.45–1.32), 0.64 (0.37–1.10), and 0.39 (0.20–0.75), p for trend = 0.001, for participants with 25(OH)D of 30–<50, 50–<75, and ≥75 nmol/L, respectively. Further adjustment for hypertension minimally influenced results (data not show), but adjustment for HBA1c attenuated the OR among those with 25(OH)D ≥75 (0.47 [0.23–0.96], p for trend = 0.030). No statistically significant association was observed between vitamin D intake from foods or supplements and retinopathy.
25(OH)D concentrations ≥75 nmol/L were associated with lower odds of any retinopathy assessed 3 years later. We speculate this may be due in part to vitamin D’s influence on blood glucose control.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-016-0434-1) contains supplementary material, which is available to authorized users.
PMCID: PMC5009647  PMID: 27586865
Vitamin D; 25-hydroxy vitamin D; Diabetic retinopathy; Retinal diseases; Epidemiology; Cohort studies
5.  Vitamin D Status and Five Year Changes in Periodontal Disease Measures among Postmenopausal Women: The Buffalo OsteoPerio Study 
Journal of periodontology  2014;85(10):1321-1332.
Vitamin D is hypothesized to prevent periodontal disease progression through its immune modulating properties and its role in maintaining systemic calcium concentrations. We investigated associations between plasma 25(OH)D (collected 1997–2000) and the five-year change in periodontal disease measures from baseline (1997–2000) to follow-up (2002–2005) among 655 postmenopausal women in a Women’s Health Initiative Observational Study ancillary study. Exploratory analyses were conducted in 628 women who also had 25(OH)D measures at follow-up.
Four continuous measures of five-year change in periodontal disease were assessed using alveolar crestal height (ACH), clinical attachment level (CAL), probing pocket depth (PD), and percent of gingival sites that bled upon assessment. Linear regression was used to estimate beta-coefficients (β), standard errors (SE), and p-values corresponding to change in periodontal disease (either a 1 mm change in ACH, CAL or PD, or 1 unit change in the percent of gingival sites that bled) for a 10 nmol/L difference in 25(OH)D. Models were adjusted for age, education, dental visit frequency, smoking, diabetes status, current medications affecting bone health, baseline measures of periodontal disease, body mass index, and recreational physical activity.
No statistically significant associations were observed between baseline 25(OH)D and change in periodontal disease measures, overall or in a subset (n=442) of women with stable 25(OH)D concentrations (women whose 25(OH)D changed less than ± 20 nmol/L from baseline to follow-up). Results also did not vary significantly in analyses that were stratified by baseline periodontal disease status.
No association between baseline 25(OH)D and the subsequent five-year change in periodontal disease measures was observed. Vitamin D status may not influence periodontal disease progression. More studies are needed to confirm these results.
Study summary
In our prospective study in postmenopausal women, baseline vitamin D status, assessed using 25-hydroxyvitamin D concentrations, was not associated with the five-year progression of periodontal disease defined as changes in alveolar bone, clinical attachment, probing pocket depth, or gingival bleeding.
PMCID: PMC4861231  PMID: 24794688
vitamin D; periodontal diseases; postmenopausal period; epidemiology; alveolar bone loss
6.  Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: Results from the women’s health initiative 
International journal of cancer  2015;138(8):1915-1927.
Findings from studies of metformin use with risk of cancer incidence and outcome provide mixed results; with few studies examined associations by recency of diabetes diagnosis or duration of medication use. Thus, in the Women’s Health Initiative, we examined these associations and further explored whether associations differ by recency of diabetes and duration of metformin use. Cox regression models were used to estimate hazard ratios (HR) and their 95% confidence intervals. Diabetes was associated with higher risk of total invasive cancer (HR, 1.13; p < 0.001) and of several site-specific cancers (HR, 1.2–1.4, and up to over twofold). Diabetes was also associated with higher risk of death from cancer (HR, 1.46; p < 0.001). There was no overall difference in cancer incidence by diabetes therapy (p = 0.66). However, there was a lower risk of death from cancer for metformin users, compared to users of other medications, relative to women without diabetes, overall (HRs, 1.08 vs. 1.45; p = 0.007) and for breast cancer (HRs, 0.50 vs. 1.29; p = 0.05). Results also suggested that lower cancer risk associated with metformin may be evident only for a longer duration of use in certain cancer sites or subgroup populations. We provide further evidence that postmenopausal women with diabetes are at higher risk of invasive cancer and cancer death. Metformin users, particularly long-term users, may be at lower risk of developing certain cancers and dying from cancer, compared to users of other anti-diabetes medications. Future studies are needed to determine the long-term effect of metformin in cancer risk and survival from cancer.
PMCID: PMC4830266  PMID: 26616262
diabetes; metformin; invasive cancer; incidence; mortality
7.  Association of Serum 17β-Estradiol Concentration, Hormone Therapy, and Alveolar Crest Height in Postmenopausal Women 
Journal of periodontology  2015;86(4):595-605.
Declines in endogenous estrogen levels after menopause can lead to systemic bone loss, including loss of oral bone and alveolar crest height (ACH). However, few studies have assessed both serum 17β-estradiol (E2) and exogenous hormone therapy (HT) use in relation to oral bone loss.
This study examines the associations among serum E2, HT use, and ACH in 613 postmenopausal women from the Buffalo OsteoPerio study. Baseline ACH levels and 5-year ACH were assessed for groups according to E2 level (undetectable, >5.00 to ≤18.00, >18.00 to ≤46.07, and >46.07 pg/mL) and among HT use (never, ever) using analysis of variance and analysis of covariance. Logistic regression was used to analyze the association of ACH loss with serum E2 and HT use.
In cross-sectional analyses, no association was found of serum E2 with whole-mouth mean or worst-site ACH. However, history of HT use was associated with ACH. Women who had never used HT had more ACH loss assessed as a whole-mouth mean ACH (P = 0.01) and as worst-site ACH loss (P = 0.03). In logistic regression analyses of baseline ACH loss severity, HT never-users had two-fold higher odds of being in the severe ACH loss category compared to ever-users (odds ratio, 2.00; 95% confidence interval, 1.11 to 3.62). No association was observed of 5-year change in ACH with baseline serum E2 or HT use.
Although this study did not detect an association with current serum E2 level and ACH, HT use was found to be associated with less ACH loss in postmenopausal women.
PMCID: PMC4469131  PMID: 25594424
Epidemiology; osteoporosis; periodontitis; women's health
8.  Calibrating physical activity intensity for hip-worn accelerometry in women age 60 to 91 years: The Women's Health Initiative OPACH Calibration Study 
Preventive medicine reports  2015;2:750-756.
We conducted a laboratory-based calibration study to determine relevant cutpoints for a hip-worn accelerometer among women ≥60 years, considering both type and filtering of counts.
Two hundred women wore an ActiGraph GT3X+ accelerometer on their hip while performing eight laboratory-based activities. Oxygen uptake was measured using an Oxycon portable calorimeter. Accelerometer data were analyzed in 15-second epochs for both normal and low frequency extension (LFE) filters. Receiver operating characteristic (ROC) curve analyses were used to calculate cutpoints for sedentary, light (low and high), and moderate to vigorous physical activity (MVPA) using the vertical axis and vector magnitude (VM) counts.
Mean age was 75.5 years (standard deviation 7.7). The Spearman correlation between oxygen uptake and accelerometry ranged from 0.77 to 0.85 for the normal and LFE filters and for both the vertical axis and VM. The area under the ROC curve was generally higher for VM compared to the vertical axis, and higher for cutpoints distinguishing MVPA compared to sedentary and light low activities. The VM better discriminated sedentary from light low activities compared to the vertical axis. The area under the ROC curves were better for the LFE filter compared to the normal filter for the vertical axis counts, but no meaningful differences were found by filter type for VM counts.
The cutpoints derived for this study among women ≥60 years can be applied to ongoing epidemiologic studies to define a range of physical activity intensities.
PMCID: PMC4625400  PMID: 26527313
Calibration; Indirect calorimetry; Low frequency extension filter; Oxygen uptake; Physical activity; Sedentary behavior; Validity
9.  Comparison of Lifestyle Based to Traditional CVD Prediction in a Multiethnic Cohort of Non-Smoking Women 
Circulation  2014;130(17):1466-1473.
Healthy levels of lifestyle factors can reduce risk of CVD. However, except for smoking status, often considered a traditional risk factor, their effect on cardiovascular risk prediction is unclear.
Methods and Results
We used a case-cohort design of post-menopausal non-smokers in the multiethnic Women’s Health Initiative Observational Study (1587 cases and 1808 sub-cohort participants) with a median follow-up of 10 years in non-cases. Compared to non-smokers with no other healthy lifestyle factors (healthy diet, recreational physical activity, moderate alcohol use, and low adiposity), the risk of cardiovascular disease was lower for each additional factor (hazard ratio for trend 0.82; 95% CI 0.76, 0.89), with a 45% reduction in risk with all factors (95% CI 0.36, 0.84). When lifestyle factors were added to traditional risk factor models (variables from the Pooled Cohort and Reynolds risk scores), only recreational physical activity remained independently associated with risk of cardiovascular disease. The addition of detailed lifestyle measures to traditional models showed a change in the integrated discrimination improvement and continuous net reclassification improvement (p < 0.01 for both), but had little impact on more clinically relevant risk stratification measures.
While lifestyle factors have important effects on CVD risk factors and subsequent risk, their addition to established CVD risk models does not result in clear improvement in overall prediction.
PMCID: PMC4206581  PMID: 25156990
lifestyle; risk prediction; primary prevention; cardiovascular diseases
Journal of hypertension  2014;32(10):2071-2081.
Mean and visit-to-visit variability (VVV) of blood pressure are associated with an increased cardiovascular disease risk. We examined the effect of hormone therapy on mean and VVV of blood pressure in postmenopausal women from the Women’s Health Initiative (WHI) randomized controlled trials.
Blood pressure was measured at baseline and annually in the two WHI hormone therapy trials in which 10,739 and 16,608 postmenopausal women were randomized to conjugated equine estrogens (CEE, 0.625 mg/day) or placebo, and CEE plus medroxyprogesterone acetate (MPA, 2.5 mg/day) or placebo, respectively.
At the first annual visit (Year 1), mean systolic blood pressure was 1.04 mmHg (95% CI 0.58, 1.50) and 1.35 mmHg (95% CI 0.99, 1.72) higher in the CEE and CEE+MPA arms respectively compared to corresponding placebos. These effects remained stable after Year 1. CEE also increased VVV of systolic blood pressure (ratio of VVV in CEE vs. placebo, 1.03, P<0.001), whereas CEE+MPA did not (ratio of VVV in CEE+MPA vs. placebo, 1.01, P=0.20). After accounting for study drug adherence, the effects of CEE and CEE+MPA on mean systolic blood pressure increased at Year 1, and the differences in the CEE and CEE+MPA arms vs. placebos also continued to increase after Year 1. Further, both CEE and CEE+MPA significantly increased VVV of systolic blood pressure (ratio of VVV in CEE vs. placebo, 1.04, P<0.001; ratio of VVV in CEE+MPA vs. placebo, 1.05, P<0.001).
Among postmenopausal women, CEE and CEE+MPA at conventional doses increased mean and VVV of systolic blood pressure.
PMCID: PMC4180281  PMID: 24991872
hypertension; blood pressure; postmenopause; women; hormone therapy
11.  Calibrating physical activity intensity for hip-worn accelerometry in women age 60 to 91 years: The Women's Health Initiative OPACH Calibration Study 
Preventive Medicine Reports  2015;2:750-756.
We conducted a laboratory-based calibration study to determine relevant cutpoints for a hip-worn accelerometer among women ≥ 60 years, considering both type and filtering of counts.
Two hundred women wore an ActiGraph GT3X + accelerometer on their hip while performing eight laboratory-based activities. Oxygen uptake was measured using an Oxycon portable calorimeter. Accelerometer data were analyzed in 15-second epochs for both normal and low frequency extension (LFE) filters. Receiver operating characteristic (ROC) curve analyses were used to calculate cutpoints for sedentary, light (low and high), and moderate to vigorous physical activity (MVPA) using the vertical axis and vector magnitude (VM) counts.
Mean age was 75.5 years (standard deviation 7.7). The Spearman correlation between oxygen uptake and accelerometry ranged from 0.77 to 0.85 for the normal and LFE filters and for both the vertical axis and VM. The area under the ROC curve was generally higher for VM compared to the vertical axis, and higher for cutpoints distinguishing MVPA compared to sedentary and light low activities. The VM better discriminated sedentary from light low activities compared to the vertical axis. The area under the ROC curves were better for the LFE filter compared to the normal filter for the vertical axis counts, but no meaningful differences were found by filter type for VM counts.
The cutpoints derived for this study among women ≥ 60 years can be applied to ongoing epidemiologic studies to define a range of physical activity intensities.
•Vector magnitude counts (VM) performed better than vertical axis counts.•The low frequency extension (LFE) and normal filter performed similarly for VM.•The LFE performed better than the normal filter for vertical axis counts.•Cutpoints generated from this work can be used to classify intensity.
PMCID: PMC4625400  PMID: 26527313
AUC, area under the intensity-specific ROC curve; kg/m2, kilograms per meters squared; LFE, low frequency extension; mL·min− 1·kg− 1, milliliters of oxygen per minute per kilogram; mm Hg, millimeters of mercury; MET, metabolic equivalent; mph, miles per hour; MVPA, moderate to vigorous physical activity; OPACH, Objective Physical Activity and Cardiovascular Health; ROC, receiver operating characteristic; RPE, rating of perceived exertion; SCC, Spearman correlation coefficients; VM, vector magnitude; VO2, oxygen uptake; WHI, Women's Health Initiative; Calibration; Indirect calorimetry; Low frequency extension filter; Oxygen uptake; Physical activity; Sedentary behavior; Validity
12.  History of periodontal disease diagnosis and lung cancer incidence in the Women’s Health Initiative Observational Study 
Cancer causes & control : CCC  2014;25(8):1045-1053.
While some evidence suggests that periodontal disease (PD) might be positively associated with lung cancer, prospective studies in women are limited. Previous findings may reflect residual confounding by smoking. The study aims to determine whether history of PD diagnosis is associated with incident lung cancer in a large cohort of postmenopausal women.
Prospective analyses were conducted in a cohort of 77,485 postmenopausal women enrolled in the Women’s Health Initiative Observational Study. History of PD (prevalence of 26.1%) was self-reported and 754 incident lung cancer cases occurred during an average 6.8 (SD ±2.6) years of follow-up. Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
Overall, PD was positively associated with lung cancer risk after adjusting for detailed smoking history including smoking status and pack-years of smoking (HR=1.24, 95% CI: 1.07–1.45). There was a positive additive interaction between PD with pack-years of smoking (P=0.02), suggesting a potential synergistic effect between PD and smoking intensity on lung cancer. The association between PD and lung cancer was stronger in former smokers. When restricted to never-smokers, PD was not associated with lung cancer (HR=1.02, 95% CI: 0.68–1.53).
PD was not independently associated with lung cancer in non-smoking postmenopausal women. However, smoking and PD jointly increased lung cancer risk beyond that expected from the sum of the each effect separately. The potential synergism between PD and smoking on lung cancer warrants further examination.
PMCID: PMC4117379  PMID: 24913780
lung cancer; periodontal disease; postmenopause; smoking; chronic inflammation; interaction
13.  Association of plasma 25-hydroxyvitamin D concentrations and pathogenic oral bacteria in postmenopausal women 
Journal of periodontology  2013;85(7):944-955.
Previous findings of an association between 25-hydroxyvitamin D (25(OH)D) concentrations and periodontal disease, may be partially explained by vitamin D’s antimicrobial properties. To our knowledge, no study has investigated the association between 25(OH)D and pathogenic oral bacteria, a putative cause of periodontal disease.
We examined the association between plasma 25(OH)D concentrations and pathogenic oral bacteria among postmenopausal women in the Buffalo Osteoporosis and Periodontal Disease Study (1997–2000), an ancillary study of the Women’s Health Initiative Observational Study. Subgingival plaque samples were assessed using immunofluorescence for the presence of Porphyromonas gingivalis, Tannerella forsythensis, Fusobacterium nucleatum, Prevotella intermedia and Campylobacter rectus. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for prevalent bacteria by quintile (Q) of 25(OH)D concentrations adjusting for age and body mass index.
Of the 855 participants, 288 (34%) had deficient/inadequate (<50 nmol/L) 25(OH)D concentrations and 497 (58%) had at least one species of pathogenic bacteria. No significant association was found between 25(OH)D and presence of any of these bacteria (adjusted OR for high (Q5) compared to low (Q1) 25(OH)D=0.96; 95% CI: 0.61–1.50, p for trend=0.50). Inverse, although not statistically significant, associations were found between 25(OH)D and more than one species of pathogenic bacteria (adjusted OR for adequate compared to deficient/inadequate 25(OH)D=0.85; 95% CI: 0.60–1.19).
No association was observed between pathogenic oral bacteria and 25(OH)D concentrations in postmenopausal women. This may be due to the species of bacteria assessed, small effect size or a true absence of an association.
PMCID: PMC4029869  PMID: 24261910
vitamin D; 25-hydroxyvitamin D; periodontal diseases; dental plaque; periodontitis; postmenopause
14.  Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations 
Yoneyama, Sachiko | Guo, Yiran | Lanktree, Matthew B. | Barnes, Michael R. | Elbers, Clara C. | Karczewski, Konrad J | Padmanabhan, Sandosh | Bauer, Florianne | Baumert, Jens | Beitelshees, Amber | Berenson, Gerald S. | Boer, Jolanda M.A. | Burke, Gregory | Cade, Brian | Chen, Wei | Cooper-Dehoff, Rhonda M. | Gaunt, Tom R. | Gieger, Christian | Gong, Yan | Gorski, Mathias | Heard-Costa, Nancy | Johnson, Toby | Lamonte, Michael J. | Mcdonough, Caitrin | Monda, Keri L. | Onland-Moret, N. Charlotte | Nelson, Christopher P. | O'Connell, Jeffrey R. | Ordovas, Jose | Peter, Inga | Peters, Annette | Shaffer, Jonathan | Shen, Haiqinq | Smith, Erin | Speilotes, Liz | Thomas, Fridtjof | Thorand, Barbara | Monique Verschuren, W. M. | Anand, Sonia S. | Dominiczak, Anna | Davidson, Karina W. | Hegele, Robert A. | Heid, Iris | Hofker, Marten H. | Huggins, Gordon S. | Illig, Thomas | Johnson, Julie A. | Kirkland, Susan | König, Wolfgang | Langaee, Taimour Y. | Mccaffery, Jeanne | Melander, Olle | Mitchell, Braxton D. | Munroe, Patricia | Murray, Sarah S. | Papanicolaou, George | Redline, Susan | Reilly, Muredach | Samani, Nilesh J. | Schork, Nicholas J. | Van Der Schouw, Yvonne T. | Shimbo, Daichi | Shuldiner, Alan R. | Tobin, Martin D. | Wijmenga, Cisca | Yusuf, Salim | Hakonarson, Hakon | Lange, Leslie A. | Demerath, Ellen W | Fox, Caroline S. | North, Kari E | Reiner, Alex P. | Keating, Brendan | Taylor, Kira C.
Human Molecular Genetics  2013;23(9):2498-2510.
Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20–80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10−6). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10−9) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10−7) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10−6). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10−6) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10−6), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
PMCID: PMC3988452  PMID: 24345515
15.  Body mass index, physical activity, and mortality in women diagnosed with ovarian cancer: Results from the Women’s Health Initiative 
Gynecologic oncology  2014;133(1):4-10.
Ovarian cancer is often diagnosed at late stages and consequently the 5-year survival rate is only 44%. However, there is limited knowledge of the association of modifiable lifestyle factors, such as physical activity and obesity on mortality among women diagnosed with ovarian cancer. The purpose of our study was to prospectively investigate the association of (1) measured body mass index (BMI), and (2) self-reported physical activity with ovarian cancer-specific and all-cause mortality in postmenopausal women enrolled in the Women’s Health Initiative (WHI).
Participants were 600 women diagnosed with primary ovarian cancer subsequent to enrollment in WHI. Exposure data, including measured height and weight and reported physical activity from recreation and walking, used in this analysis were ascertained at the baseline visit for the WHI. Cox proportional hazard regression was used to examine the associations between BMI, physical activity and mortality endpoints.
Vigorous-intensity physical activity was associated with a 26% lower risk of ovarian cancer specific-mortality (HR=0.74; 95% CI: 0.56–0.98) and a 24% lower risk of all-cause mortality (HR=0.76; 95% CI: 0.58–0.98) compared to no vigorous-intensity physical activity. BMI was not associated with mortality.
Participating in vigorous-intensity physical activity, assessed prior to ovarian cancer diagnosis, appears to be associated with a lower risk of ovarian cancer mortality.
PMCID: PMC4064800  PMID: 24680584
ovarian cancer; obesity; weight; physical activity; exercise; prognosis; mortality; survival
16.  Obesity and Survival to Age 85 Years without Major Disease or Disability in Older Women 
JAMA internal medicine  2014;174(1):98-106.
The impact of obesity on late-age survival without disease or disability in women is unknown.
To investigate if higher baseline body mass index and waist circumference affects women’s survival to age 85 years without major chronic disease (coronary disease, stroke, cancer, diabetes, or hip fracture) and mobility disability.
Design, Setting, Participants
Examination of 36,611 women from the Women’s Health Initiative who could have reached age 85 years or older if they survived to the last outcomes evaluation on September 17, 2012. Recruitment was from 40 US Clinical Centers from October 1993–December 1998. Multinomial logistic regression models were used to estimate odds ratios and 95% confidence intervals for the association of baseline body mass index and waist circumference with the outcomes, adjusting for demographic, behavioral, and health characteristics.
Main Outcome Measures
Mutually-exclusive classifications: 1) survived without major chronic disease and without mobility disability (“healthy”); 2) survived with ≥1 major chronic disease at baseline, but without new disease or disability (“prevalent diseased”); 3) survived and developed ≥1 major chronic disease but not disability during study follow-up (“incident diseased”); 4) survived and developed mobility disability with or without disease (“disabled”); and 5) did not survive (“died”).
Mean (SD) baseline age was 72.4 (3.0) years (range: 66–81). The distribution of women classified as healthy, prevalent diseased, incident diseased, disabled, and died was 19%, 15%, 23%, 18%, and 25%, respectively. Compared to normal-weight women, underweight and obese women were more likely to die before age 85 years. Overweight and obese women had higher risks of incident disease and mobility disability. Disability risks were striking. Relative to normal-weight women, adjusted odds ratios (95% confidence intervals) of mobility disability was 1.6 (1.5–1.8) for overweight women and 3.2 (2.9–3.6), 6.6 (5.4–8.1), and 6.7 (4.8–9.2), for class I, II, and III obesity, respectively. Waist circumference >88 centimeters was also associated with higher risk of earlier death, incident disease, and mobility disability.
Overall and abdominal obesity were important and potentially modifiable factors associated with dying or developing mobility disability and major chronic disease before age 85 years in older women.
PMCID: PMC3963496  PMID: 24217806
17.  Change in physical activity after a diabetes diagnosis: opportunity for intervention 
Moderate intensity physical activity is recommended for individuals with diabetes to control glucose and prevent diabetes-related complications. The extent to which a diabetes diagnosis motivates patients to increase physical activity is unclear. This study used data from the Women’s Health Initiative Observational Study (baseline data collected from 1993-1998) to examine change in physical activity and sedentary behavior in women who reported a diabetes diagnosis compared to women who did not report diabetes over 7 years of follow-up (up to 2005).
Participants (n=84,300) were post-menopausal women who did not report diabetes at baseline [mean age=63.49; standard deviation (SD)=7.34; mean BMI=26.98 kg/m2; SD=5.67]. Linear mixed model analyses were conducted adjusting for study year, age, race/ethnicity, BMI, education, family history of diabetes, physical functioning, pain, energy/fatigue, social functioning, depression, number of chronic diseases and vigorous exercise at age 18. Analyses were completed in August 2012.
Participants who reported a diabetes diagnosis during follow-up were more likely to report increasing their total physical activity (p=0.002), walking (p<0.001) and number of physical activity episodes (p<0.001) compared to participants who did not report a diabetes diagnosis. On average, participants reporting a diabetes diagnosis reported increasing their total physical activity by 0.49 MET-hours/week, their walking by 0.033 MET-hours/week and their number of physical activity episodes by 0.19 MET-hours/week. No differences in reported sedentary behavior change were observed (p=0.48).
A diabetes diagnosis may prompt patients to increase physical activity. Healthcare professionals should consider how best to capitalize on this opportunity to encourage increased physical activity and maintenance.
PMCID: PMC4028702  PMID: 23860414
type 2 diabetes; exercise; sedentary behavior; sedentary activity; Women’s Health Initiative
18.  All-Cause, Cardiovascular, and Cancer Mortality Rates in Postmenopausal White, Black, Hispanic, and Asian Women With and Without Diabetes in the United States 
American Journal of Epidemiology  2013;178(10):1533-1541.
Using data from the Women's Health Initiative (1993–2009; n = 158,833 participants, of whom 84.1% were white, 9.2% were black, 4.1% were Hispanic, and 2.6% were Asian), we compared all-cause, cardiovascular, and cancer mortality rates in white, black, Hispanic, and Asian postmenopausal women with and without diabetes. Cox proportional hazard models were used for the comparison from which hazard ratios and 95% confidence intervals were computed. Within each racial/ethnic subgroup, women with diabetes had an approximately 2–3 times higher risk of all-cause, cardiovascular, and cancer mortality than did those without diabetes. However, the hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups. Population attributable risk percentages (PARPs) take into account both the prevalence of diabetes and hazard ratios. For all-cause mortality, whites had the lowest PARP (11.1, 95% confidence interval (CI): 10.1, 12.1), followed by Asians (12.9, 95% CI: 4.7, 20.9), blacks (19.4, 95% CI: 15.0, 23.7), and Hispanics (23.2, 95% CI: 14.8, 31.2). To our knowledge, the present study is the first to show that hazard ratios for mortality outcomes were not significantly different between racial/ethnic subgroups when stratified by diabetes status. Because of the “amplifying” effect of diabetes prevalence, efforts to reduce racial/ethnic disparities in the rate of death from diabetes should focus on prevention of diabetes.
PMCID: PMC3888272  PMID: 24045960
diabetes; health disparities; menopause; mortality; obesity; women's health
19.  Modifying effect of obesity on the association between sitting time and incident diabetes in post-menopausal women 
Obesity (Silver Spring, Md.)  2013;22(4):1133-1141.
To evaluate the association between self-reported daily sitting time and the incidence of type II diabetes in a cohort of postmenopausal women.
Design and Methods
Women (N = 88,829) without diagnosed diabetes reported the number of hours spent sitting over a typical day. Incident cases of diabetes were identified annually by self-reported initiation of using oral medications or insulin for diabetes over 14.4 years follow-up.
Each hour of sitting time was positively associated with increased risk of diabetes (Risk ratio (RR): 1.05; 95% confidence interval (CI): 1.02–1.08]. However, sitting time was only positively associated with incident diabetes in obese women. Obese women reporting sitting 8–11 (RR: 1.08; 95% CI 1.0–1.1), 12–15 (OR: 1.13; 95% CI 1.0–1.2), and ≥16 hours (OR: 1.25; 95% CI 1.0–1.5) hours per day had an increased risk of diabetes compared to women sitting ≤ 7 hours per day. These associations were adjusted for demographics, health conditions, behaviors (smoking, diet and alcohol intake) and family history of diabetes. Time performing moderate to vigorous intensity physical activity did not modify these associations.
Time spent sitting was independently associated with increased risk of diabetes diagnosis among obese women— a population already at high risk of the disease.
PMCID: PMC3968183  PMID: 24123945
sedentary; glucose control; overweight; glycemia
20.  Obesity, Physical Activity, and Their Interaction in Incident Atrial Fibrillation in Postmenopausal Women 
Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased risk of stroke and death. Obesity is an independent risk factor for AF, but modifiers of this risk are not well known. We studied the roles of obesity, physical activity, and their interaction in conferring risk of incident AF.
Methods and Results
The Women's Health Initiative (WHI) Observational Study was a prospective observational study of 93 676 postmenopausal women followed for an average of 11.5 years. Incident AF was identified using WHI‐ascertained hospitalization records and diagnostic codes from Medicare claims. A multivariate Cox's hazard regression model adjusted for demographic and clinical risk factors was used to evaluate the interaction between obesity and physical activity and its association with incident AF. After exclusion of women with prevalent AF, incomplete data, or underweight body mass index (BMI), 9792 of the remaining 81 317 women developed AF. Women were, on average, 63.4 years old, 7.8% were African American, and 3.6% were Hispanic. Increased BMI (hazard ratio [HR], 1.12 per 5‐kg/m2 increase; 95% confidence interval [CI], 1.10 to 1.14) and reduced physical activity (>9 vs. 0 metabolic equivalent task hours per week; HR, 0.90; 95% CI, 0.85 to 0.96) were independently associated with higher rates of AF after multivariate adjustment. Higher levels of physical activity reduced the AF risk conferred by obesity (interaction P=0.033).
Greater physical activity is associated with lower rates of incident AF and modifies the association between obesity and incident AF.
PMCID: PMC4310412  PMID: 25142057
atrial fibrillation; electrophysiology; epidemiology; exercise; obesity
21.  The Relationship of Sedentary Behavior and Physical Activity to Incident Cardiovascular Disease: Results from the Women’s Health Initiative 
The aim was to examine the independent and joint associations of sitting time and physical activity with risk of incident cardiovascular disease (CVD).
Sedentary behavior is recognized as a distinct construct beyond lack of leisure-time physical activity, but limited data exists on the interrelationship between these two components of energy balance.
Participants in the prospective Women’s Health Initiative Observational Study (N = 71,018), aged 50–79 and free of CVD at baseline (1993–1998), provided information on sedentary behavior, defined as hours of sitting per day, and usual physical activity at baseline and during follow-up through September 2010. First CVD (coronary heart disease or stroke) events were centrally adjudicated.
Sitting ≥ 10 hours/day compared to ≤ 5 hours/day was associated with increased CVD risk (HR=1.18, 95% CI 1.09, 1.29) in multivariable models including physical activity. Low physical activity was also associated with higher CVD risk (P, trend <0.001). When women were cross-classified by sitting time and physical activity (P, interaction = 0.94), CVD risk was highest in inactive women (≤1.7 MET-hrs/week) who also reported ≥10 hrs/day of sitting. Results were similar for CHD and stroke when examined separately. Associations between prolonged sitting and risk of CVD were stronger in overweight versus normal weight women and women aged 70 years and older compared to younger women.
Prolonged sitting time was associated with increased CVD risk, independent of leisure-time physical activity, in postmenopausal women without a history of CVD. A combination of low physical activity and prolonged sitting augments CVD risk.
PMCID: PMC3676694  PMID: 23583242
cardiovascular disease; women; physical activity; sedentary behavior
22.  Statins, Angiotensin-Converting Enzyme Inhibitors and Physical Performance in Older Women 
Angiotensin-converting enzyme (ACE) inhibitor and statin medications may preserve skeletal muscle. We examined associations between each medication class and baseline and mean annual change in physical performance measures and muscle strength in older women.
Prospective cohort study
Participants from the Women’s Health Initiative Clinical Trials who were aged 65–79 at baseline and had physical performance measures, self-report of health insurance and no prior history of stroke or congestive heart failure were included (n=5777). Women were recruited between 1993 and 1998.
Medication use was ascertained through a baseline inventory. Physical performance measures (timed 6-meter walk, repeated chair stands in 15 seconds) and grip strength were assessed at baseline and follow-up years 1, 3 and 6. Multivariable adjusted linear repeated- measures models adjusted for demographic and health characteristics.
ACE inhibitor use was negatively associated with mean grip strength at baseline (22.40 kg, 95% confidence interval [CI] 21.89, 22.91 versus 23.18 kg, 95% CI 23.02, 23.34; P = .005) and a greater mean annual change in number of chair stands (−.182, 95% CI −.217, −.147 versus −.145, 95% CI −.156, −.133; P = .05) compared to non-use. Statin use was not significantly associated with baseline or mean annual change for any outcome. A subgroup analysis suggested that statin use was associated with less mean annual change in chair stands (P = .006) in the oldest women.
These results do not support an association of statin or ACE inhibitor use with slower decline in physical performance or muscle strength, and thus do not support the use of these medications for preserving functional status in older adults.
PMCID: PMC3521070  PMID: 23176078
ACE inhibitors; statins; physical performance; grip strength
23.  Associations between smoking and tooth loss according to reason for tooth loss 
Smoking is associated with tooth loss. However, smoking's relationship to the specific reason for tooth loss in postmenopausal women is unknown.
Postmenopausal women (n = 1,106) who joined a Women's Health Initiative ancillary study (The Buffalo OsteoPerio Study) underwent oral examinations for assessment of the number of missing teeth, as well as the self-reported reasons for tooth loss. The authors obtained information about smoking status via a self-administered questionnaire. The authors calculated odds ratios (ORs) and 95 percent confidence intervals (CIs) by means of logistic regression to assess smoking's association with overall tooth loss, as well as with tooth loss due to periodontal disease (PD) and with tooth loss due to caries.
After adjusting for age, education, income, body mass index (BMI), history of diabetes diagnosis, calcium supplement use and dental visit frequency, the authors found that heavy smokers (≥ 26 pack-years) were significantly more likely to report having experienced tooth loss compared with never smokers (OR = 1.82; 95 percent CI, 1.10-3.00). Smoking status, packs smoked per day, years of smoking, pack-years and years since quitting smoking were significantly associated with tooth loss due to PD. For pack-years, the association for heavy smokers compared with that for never smokers was OR = 6.83 (95 percent CI, 3.40-13.72). The study results showed no significant associations between smoking and tooth loss due to caries.
Conclusions and Practical Implications
Smoking may be a major factor in tooth loss due to PD. However, smoking appears to be a less important factor in tooth loss due to caries. Further study is needed to explore the etiologies by which smoking is associated with different types of tooth loss. Dentists should counsel their patients about the impact of smoking on oral health, including the risk of tooth loss due to PD.
PMCID: PMC3842224  PMID: 23449901
Tooth loss; periodontal diseases; caries; smoking; menopause; women's health
24.  Determinants of Racial/Ethnic Disparities in Incidence of Diabetes in Postmenopausal Women in the U.S. 
Diabetes Care  2012;35(11):2226-2234.
To examine determinants of racial/ethnic differences in diabetes incidence among postmenopausal women participating in the Women’s Health Initiative.
Data on race/ethnicity, baseline diabetes prevalence, and incident diabetes were obtained from 158,833 women recruited from 1993–1998 and followed through August 2009. The relationship between race/ethnicity, other potential risk factors, and the risk of incident diabetes was estimated using Cox proportional hazards models from which hazard ratios (HRs) and 95% CIs were computed.
Participants were aged 63 years on average at baseline. The racial/ethnic distribution was 84.1% non-Hispanic white, 9.2% non-Hispanic black, 4.1% Hispanic, and 2.6% Asian. After an average of 10.4 years of follow-up, compared with whites and adjusting for potential confounders, the HRs for incident diabetes were 1.55 for blacks (95% CI 1.47–1.63), 1.67 for Hispanics (1.54–1.81), and 1.86 for Asians (1.68–2.06). Whites, blacks, and Hispanics with all factors (i.e., weight, physical activity, dietary quality, and smoking) in the low-risk category had 60, 69, and 63% lower risk for incident diabetes. Although contributions of different risk factors varied slightly by race/ethnicity, most findings were similar across groups, and women who had both a healthy weight and were in the highest tertile of physical activity had less than one-third the risk of diabetes compared with obese and inactive women.
Despite large racial/ethnic differences in diabetes incidence, most variability could be attributed to lifestyle factors. Our findings show that the majority of diabetes cases are preventable, and risk reduction strategies can be effectively applied to all racial/ethnic groups.
PMCID: PMC3476929  PMID: 22833490
25.  Association between Annual Visit-to-Visit Blood Pressure Variability and Stroke in Postmenopausal Women: Data from the Women's Health Initiative 
Hypertension  2012;60(3):625-630.
Accumulating evidence suggests that increased visit-to-visit variability (VVV) of blood pressure is associated with stroke. No study has examined the association between VVV of blood pressure and stroke in postmenopausal women, and scarce data exists as to whether this relation is independent of the temporal trend of blood pressure. We examined the association of VVV of blood pressure with stroke in 58,228 postmenopausal women enrolled in the Women's Health Initiative. Duplicate blood pressure readings, which were averaged, were taken at baseline and at each annual visit. VVV was defined as the standard deviation about the participant's mean systolic blood pressure (SBP) across visits (SD), and about the participant's regression line with SBP regressed across visits (SDreg). Over a median follow-up of 5.4 years, 997 strokes occurred. In an adjusted model including mean SBP over time, the hazard ratios (95% CI) of stroke for higher quartiles of SD of SBP compared to the lowest quartile (referent) were 1.39 (1.03-1.89) for quartile 2, 1.52 (1.13-2.03) for quartile 3, and 1.72 (1.28-2.32) for quartile 4 (P trend<0.001). The relation was similar for SDreg of SBP quartiles in a model that additionally adjusted for the temporal trend in SBP (P trend<0.001). The associations did not differ by stroke type (ischemic vs. hemorrhagic). There was a significant interaction between mean SBP and SDreg on stroke with the strongest association seen below 120 mmHg. In postmenopausal women, greater VVV of SBP was associated with increased risk of stroke, particularly in the lowest range of mean SBP.
PMCID: PMC3427141  PMID: 22753206
hypertension; blood pressure; stroke; postmenopause; women

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