Neighborhood Socioeconomic Status, Green Space, and Walkability and Risk for Falls Among Postmenopausal Women: The Women's Health Initiative.

PURPOSE: This study estimated associations between neighborhood socioeconomic status (NSES), walkability, green space, and incident falls among postmenopausal women and evaluated modifiers of these associations, including study arm, race and ethnicity, baseline household income, baseline walking, age at enrollment, baseline low physical functioning, baseline fall history, climate region, and urban-rural residence. METHODS: The Women's Health Initiative recruited a national sample of postmenopausal women (50-79 years) across 40 U.S. clinical centers and conducted yearly assessments from 1993 to 2005 (n = 161,808). Women reporting a history of hip fracture or walking limitations were excluded, yielding a final sample of 157,583 participants. Falling was reported annually. NSES (income/wealth, education, occupation), walkability (population density, diversity of land cover, nearby high-traffic roadways), and green space (exposure to vegetation) were calculated annually and categorized into tertiles (low, intermediate, high). Generalized estimating equations assessed longitudinal relationships. RESULTS: NSES was associated with falling before adjustment (high vs. low, odds ratio, 1.01; 95% confidence interval, 1.00-1.01). Walkability was significantly associated with falls after adjustment (high vs. low, odds ratio, 0.99; 95% confidence interval, 0.98-0.99). Green space was not associated with falling before or after adjustment. Study arm, race and ethnicity, household income, age, low physical functioning, fall history, and climate region modified the relationship between NSES and falling. Race and ethnicity, age, fall history, and climate region modified relationships between walkability and green space and falling. CONCLUSIONS: Our results did not show strong associations of NSES, walkability, or green space with falling. Future research should incorporate granular environmental measures that may directly relate to physical activity and outdoor engagement.

Role of dietary patterns and acculturation in cancer risk and mortality among postmenopausal Hispanic women: results from the Women's Health Initiative (WHI).

Aim: To investigate the association between dietary patterns and total and obesity-related cancers risk. Additionally, to examine if acculturation modifies this relationship. Subject and Methods: Dietary intake of postmenopausal Hispanic women (N=5,482) enrolled in the Women's Health Initiative was estimated from a Food Frequency Questionnaire and used to calculate dietary pattern scores; Healthy Eating Index-2015 (HEI-2015), Mexican Diet (MexD) score, alternate Mediterranean Diet Score (aMED), and the energy adjusted-Dietary Inflammatory Index (E-DII™). Associations were evaluated using Cox proportional hazards regression models. Results: 631 cancers and 396 obesity-related cancers were diagnosed over a mean-follow up of 12 years. Across dietary scores, there were no significant associations with cancer risk or mortality. Trend analysis suggest a potentially lower risk for total cancer related to the highest MexD score (HR 0.68, 95% CI 0.45-1.04, P-trend=0.03), and lower risk for obesity-related cancer mortality related to the highest score category for MexD (HR 0.65, 95% CI 0.37-1.16, P-trend=0.02), and aMED (HR 0.87, 95% CI 0.45-1.67, P-trend=0.04). Further analysis suggests less acculturated women with higher MexD scores had 56% lower risk for any cancer (HR 0.44, 95% CI 0.22-0.88, P-trend=0.03) and 83% lower risk for cancer mortality (HR 0.17, 95% CI 0.04-0.76, P-trend=0.01) compared to more acculturated Hispanic women. Conclusions: Dietary patterns were not associated with cancer risk and mortality in postmenopausal Hispanic women. Less-acculturated, Spanish-preferred speakers, who reported consuming a more traditional Mexican diet may experience a lower risk for cancer and cancer mortality.

Long-Term Exposures to Air Pollution and the Risk of Atrial Fibrillation in the Women's Health Initiative Cohort.

BACKGROUND: Atrial fibrillation (AF) is associated with substantial morbidity and mortality. Short-term exposures to air pollution have been associated with AF triggering; less is known regarding associations between long-term air pollution exposures and AF incidence. OBJECTIVES: Our objective was to assess the association between long-term exposures to air pollution and distance to road on incidence of AF in a cohort of U.S. women. METHODS: We assessed the association of high resolution spatiotemporal model predictions of long-term exposures to particulate matter (PM10 and PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and distance to major roads with incidence of AF diagnosis, identified through Medicare linkage, among 83,117 women in the prospective Women's Health Initiative cohort, followed from enrollment in Medicare through December 2012, incidence of AF, or death. Using time-varying Cox proportional hazards models adjusted for age, race/ethnicity, study component, body mass index, physical activity, menopausal hormone therapy, smoking, diet quality, alcohol consumption, educational attainment, and neighborhood socioeconomic status, we estimated the relative risk of incident AF in association with each pollutant. RESULTS: A total of 16,348 incident AF cases were observed over 660,236 person-years of follow-up. Most exposure-response associations were nonlinear. NO2 was associated with risk of AF in multivariable adjusted models [Hazard Ratio (HR)=1.18; 95% confidence interval (CI): 1.13, 1.24, comparing the top to bottom quartile, p-for-trend=<0.0001]. Women living closer to roadways were at higher risk of AF (e.g., HR=1.07; 95% CI: 1.01, 1.13 for living within 50m of A3 roads, compared with ≥1,000 m, p-for-trend=0.02), but we did not observe adverse associations with exposures to PM10, PM2.5, or SO2. There were adverse associations with PM10 (top quartile HR=1.10; 95% CI: 1.05, 1.16, p-for-trend=<0.0001) and PM2.5 (top quartile HR=1.09; 95% CI: 1.03, 1.14, p-for-trend=0.002) in sensitivity models adjusting for census region. DISCUSSION: In this study of postmenopausal women, NO2 and distance to road were consistently associated with higher risk of AF. https://doi.org/10.1289/EHP7683.

Short Sleep Is Associated With Low Bone Mineral Density and Osteoporosis in the Women's Health Initiative.

Short sleep duration, recognized as a public health epidemic, is associated with adverse health conditions, yet little is known about the association between sleep and bone health. We tested the associations of usual sleep behavior and bone mineral density (BMD) and osteoporosis. In a sample of 11,084 postmenopausal women from the Women's Health Initiative (WHI; mean age 63.3 years, SD = 7.4), we performed a cross-sectional study of the association of self-reported usual hours of sleep and sleep quality (WHI Insomnia Rating Score) with whole body, total hip, femoral neck, and spine BMD using linear regression models. We also studied the association of sleep duration and quality with dual-energy X-ray absorptiometry (DXA)-defined low bone mass (T-score < -2.5 to <-1) and osteoporosis (T-score ≤ -2.5) using multinomial regression models. We adjusted for age, DXA machine, race, menopausal symptoms, education, smoking, physical activity, body mass index, alcohol use, physical function, and sleep medication use. In adjusted linear regression models, women who reported sleeping 5 hours or less per night had on average 0.012 to 0.018 g/cm2 significantly lower BMD at all four sites compared with women who reported sleeping 7 hours per night (reference). In adjusted multinomial models, women reporting 5 hours or less per night had higher odds of low bone mass and osteoporosis of the hip (odds ratio [OR] = 1.22; 95% confidence interval [CI] 1.03-1.45, and 1.63; 1.15-2.31, respectively). We observed a similar pattern for spine BMD, where women with 5 hours or less per night had higher odds of osteoporosis (adjusted OR = 1.28; 95% CI 1.02-1.60). Associations of sleep quality and DXA BMD failed to reach statistical significance. Short sleep duration was associated with lower BMD and higher risk of osteoporosis. Longitudinal studies are needed to confirm the cross-sectional effects of sleep duration on bone health and explore associated mechanisms. © 2019 American Society for Bone and Mineral Research.

Relation of Pregnancy Loss to Risk of Cardiovascular Disease in Parous Postmenopausal Women (From the Women's Health Initiative).

Women with history of pregnancy loss (PL) have higher burden of cardiovascular disease (CVD) later in life, yet it is unclear whether this is attributable to an association with established CVD risk factors (RFs). We examined whether PL is associated with CVD RFs and biomarkers in parous postmenopausal women in the Women's Health Initiative, and whether the association between PL and CVD RFs accounted for the association between PL and incident CVD. Linear and logistic regressions were used to estimate associations between baseline history of PL and CVD RFs. Cox proportional hazards regression models were used to estimate the associations between baseline history of PL and incident CVD after adjustment for baseline RFs. Of 79,121 women, 27,272 (35%) had experienced PL. History of PL was associated with higher body mass index (p < 0.0001), hypertension (p < 0.0001), diabetes (p = 0.003), depression (p < 0.0001), and lower income (p < 0.0001), physical activity (p = 0.01), poorer diet (p < 0.0001), smoking (p < 0.0001), and alcohol use (p < 0.0001). After adjustment for CVD RFs, PL was significantly associated with incident CVD over mean follow up of 16 years (hazard ratio 1.11, 95% confidence interval 1.06 to 1.16). In conclusion, several CVD RFs are associated with PL, but they do not entirely account for the association between PL and incident CVD.

Estrogen metabolism in menopausal hormone users in the women's health initiative observational study: Does it differ between estrogen plus progestin and estrogen alone?

The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. One thousand eight hundred and sixty-four women in a WHIOS case-control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E + P users (351 used CEE + MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses were conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway) and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E + P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p = 0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E + P users. Similar but not significant patterns were observed in CEE-alone and CEE + MPA users. Our data suggest that compared to E + P users, women using E alone have more extensive metabolism via the 2- vs. the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI.

Risk of cardiovascular disease among women with endometrial cancer compared to cancer-free women in the Women's Health Initiative.

BACKGROUND: The majority of women diagnosed with endometrial cancer (EC) have low cancer-specific mortality; however, a high prevalence of cardiovascular disease (CVD) risk factors places EC patients at high risk of developing CVD. In the Women's Health Initiative (WHI), we assessed the hypothesis that CVD risk was higher among women who developed EC compared with women who did not develop EC. METHODS: We compared the incidence of fatal and non-fatal CVD events among 1,179 women who developed Type I EC, 211 women who developed Type II EC, and 92,217 women who did not develop EC. We first estimated univariable cause-specific hazard ratios (CHRs) and 95% confidence intervals (CIs) for the association between an EC diagnosis (overall and by EC type) with CVD risk using Cox proportional hazards regression. Potential confounders were examined using a risk factor modeling approach; final multivariable-adjusted models included covariates that changed univariable CHRs for EC diagnosis by≥5%. RESULTS: In multivariable-adjusted models, CVD risk did not significantly differ between women who developed EC compared to women who did not develop EC (CHR=1.01, 95% CI=0.87-1.16), particularly for the subgroup of women who developed Type I EC (CHR=0.98, 95% CI=0.84-1.14); however, there was a positive but statistically nonsignificant association for Type II EC (CHR=1.32, 95% CI=0.88-1.97). CONCLUSION: Despite our null findings, women with EC should still receive counseling and support to make lifestyle changes aimed at reducing weight as appropriate, given the high prevalence of CVD risk factors at diagnosis.

Reproductive Factors and Incidence of Heart Failure Hospitalization in the Women's Health Initiative.

BACKGROUND: Reproductive factors reflective of endogenous sex hormone exposure might have an effect on cardiac remodeling and the development of heart failure (HF). OBJECTIVES: This study examined the association between key reproductive factors and the incidence of HF. METHODS: Women from a cohort of the Women's Health Initiative were systematically evaluated for the incidence of HF hospitalization from study enrollment through 2014. Reproductive factors (number of live births, age at first pregnancy, and total reproductive duration [time from menarche to menopause]) were self-reported at study baseline in 1993 to 1998. We employed Cox proportional hazards regression analysis in age- and multivariable-adjusted models. RESULTS: Among 28,516 women, with an average age of 62.7 ± 7.1 years at baseline, 1,494 (5.2%) had an adjudicated incident HF hospitalization during an average follow-up of 13.1 years. After adjusting for covariates, total reproductive duration in years was inversely associated with incident HF: hazard ratios (HRs) of 0.99 per year (95% confidence interval [CI]: 0.98 to 0.99 per year) and 0.95 per 5 years (95% CI: 0.91 to 0.99 per 5 years). Conversely, early age at first pregnancy and nulliparity were significantly associated with incident HF in age-adjusted models, but not after multivariable adjustment. Notably, nulliparity was associated with incident HF with preserved ejection fraction in the fully adjusted model (HR: 2.75; 95% CI: 1.16 to 6.52). CONCLUSIONS: In post-menopausal women, shorter total reproductive duration was associated with higher risk of incident HF, and nulliparity was associated with higher risk for incident HF with preserved ejection fraction. Whether exposure to endogenous sex hormones underlies this relationship should be investigated in future studies.

Osteoporosis in the Women's Health Initiative: Another Treatment Gap?

BACKGROUND: Osteoporotic fractures are associated with high morbidity, mortality, and cost. METHODS: We performed a post hoc analysis of the Women's Health Initiative (WHI) clinical trials data to assess osteoporosis treatment and identify participant characteristics associated with utilization of osteoporosis medication(s) after new diagnoses of osteoporosis or fracture. Information from visits prior to and immediately subsequent to the first fracture event or osteoporosis diagnosis were evaluated for medication use. A full logistic regression model was used to identify factors predictive of osteoporosis medication use after a fracture or a diagnosis of osteoporosis. RESULTS: The median length of follow-up from enrollment to the last WHI clinic visit for the study cohort was 13.9 years. Among the 13,990 women who reported new diagnoses of osteoporosis or fracture between enrollment and their final WHI visit, and also had medication data available, 21.6% reported taking an osteoporosis medication other than estrogen. Higher daily calcium intake, diagnosis of osteoporosis alone or both osteoporosis and fracture (compared with diagnosis of fracture alone), Asian or Pacific Islander race/ethnicity (compared with White/Caucasian), higher income, and hormone therapy use (past or present) were associated with significantly higher likelihood of osteoporosis pharmacotherapy. Women with Black/African American race/ethnicity (compared with White/Caucasian), body mass index ≥30 (compared with body mass index of 18.5-24.9), current tobacco use (compared with past use or lifetime nonusers), and history of arthritis were less likely to use osteoporosis treatment. CONCLUSION: Despite well-established treatment guidelines in postmenopausal women with osteoporosis or history of fractures, pharmacotherapy use was suboptimal in this study. Initiation of osteoporosis treatment after fragility fracture may represent an opportunity to improve later outcomes in these high-risk women. Specific attention needs to be paid to increasing treatment among women with fragility fractures, obesity, current tobacco use, history of arthritis, or of Black race/ethnicity.

Post-diagnosis body mass index and mortality among women diagnosed with endometrial cancer: Results from the Women's Health Initiative.

Higher body mass index (BMI) measured before endometrial cancer diagnosis has been associated with greater risk of developing endometrial cancer and higher mortality, but the association between BMI measured after diagnosis and mortality risk is unclear. We identified 467 women (91 deaths) in the Women's Health Initiative (WHI) with information on BMI measured after diagnosis and used Cox proportional hazards regression to generate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality. Comparing BMI 35+ with <25 kg/m2, we observed no association with all-cause mortality (HR = 1.02, 95% CI 0.55-1.91). Our study does not support the hypothesis that higher BMI after endometrial cancer diagnosis is associated with poorer survival.

Low Birth Weight and Risk of Later-Life Physical Disability in Women.

BACKGROUND: There is strong evidence that low and high birth weight due to in-utero programming results in elevated risk for adult diseases, though less research has been performed examining the influence of birth weight and physical disability later in life. METHODS: Baseline data from 76,055 postmenopausal women in the Women's Health Initiative, a large multi-ethnic cohort, were used to examine the association between self-reported birth weight category (<6 lbs, 6-7 lbs 15 oz, 8-9 lbs 15 oz, and ≥10 lbs) and the self-reported physical functioning score on the RAND 36-item Health Survey. Linear regression models were adjusted for age, education, race/ethnicity, body mass index, and a comorbidity score. RESULTS: Unadjusted models indicate that women born in the lowest and highest birth weight categories have significantly lower physical functioning scores as compared to women born in the normal weight category (ß = -2.22, p < .0001 and ß = -3.56, p < .0001, respectively). After adjustments, the relationship between the lowest birth weight category and physical functioning score remained significant (ß = -1.52, p < .0001); however, the association with the highest birth weight category dissipated. CONCLUSIONS: Preconception and prenatal interventions aimed at reducing the incidence of low birth weight infants may subsequently reduce the burden of later-life physical disability.

Physical impairment and body weight history in postmenopausal women: the Women's Health Initiative.

OBJECTIVE: To examine whether weight history and weight transitions over adult lifespan contribute to physical impairment among postmenopausal women. DESIGN: BMI categories were calculated among postmenopausal women who reported their weight and height at age 18 years. Multiple-variable logistic regression was used to determine the association between BMI at age 18 years and BMI transitions over adulthood on severe physical impairment (SPI), defined as scoring <60 on the Physical Functioning subscale of the Rand thirty-six-item Short-Form Health Survey. SETTING: Participants were part of the Women's Health Initiative Observational Study (WHI OS), where participants' health was followed over time via questionnaires and clinical assessments. SUBJECTS: Postmenopausal women (n 76 016; mean age 63·5 (sd 7·3) years). RESULTS: Women with overweight (BMI=25·0-29·9 kg/m2) or obesity (BMI≥30·0 kg/m2) at 18 years had greater odds (OR (95 % CI)) of SPI (1·51 (1·35, 1·69) and 2·14 (1·72, 2·65), respectively) than normal-weight (BMI=18·5-24·9 kg/m2) counterparts. Transitions from normal weight to overweight/obese or to underweight (BMI<18·5 kg/m2) were associated with greater odds of SPI (1·97 (1·84, 2·11) and 1·35 (1·06, 1·71), respectively) compared with 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)). CONCLUSIONS: Higher weight history and transitions into higher weight classes were associated with higher likelihood of SPI, while transitioning into lower weight classes for those with overweight/obesity was protective among postmenopausal women.

GENOME-WIDE ASSOCIATION STUDY (GWAS) AND GENOME-WIDE BY ENVIRONMENT INTERACTION STUDY (GWEIS) OF DEPRESSIVE SYMPTOMS IN AFRICAN AMERICAN AND HISPANIC/LATINA WOMEN.

BACKGROUND: Genome-wide association studies (GWAS) have made little progress in identifying variants linked to depression. We hypothesized that examining depressive symptoms and considering gene-environment interaction (GxE) might improve efficiency for gene discovery. We therefore conducted a GWAS and genome-wide by environment interaction study (GWEIS) of depressive symptoms. METHODS: Using data from the SHARe cohort of the Women's Health Initiative, comprising African Americans (n = 7,179) and Hispanics/Latinas (n = 3,138), we examined genetic main effects and GxE with stressful life events and social support. We also conducted a heritability analysis using genome-wide complex trait analysis (GCTA). Replication was attempted in four independent cohorts. RESULTS: No SNPs achieved genome-wide significance for main effects in either discovery sample. The top signals in African Americans were rs73531535 (located 20 kb from GPR139, P = 5.75 × 10(-8) ) and rs75407252 (intronic to CACNA2D3, P = 6.99 × 10(-7) ). In Hispanics/Latinas, the top signals were rs2532087 (located 27 kb from CD38, P = 2.44 × 10(-7) ) and rs4542757 (intronic to DCC, P = 7.31 × 10(-7) ). In the GEWIS with stressful life events, one interaction signal was genome-wide significant in African Americans (rs4652467; P = 4.10 × 10(-10) ; located 14 kb from CEP350). This interaction was not observed in a smaller replication cohort. Although heritability estimates for depressive symptoms and stressful life events were each less than 10%, they were strongly genetically correlated (rG = 0.95), suggesting that common variation underlying self-reported depressive symptoms and stressful life event exposure, though modest on their own, were highly overlapping in this sample. CONCLUSIONS: Our results underscore the need for larger samples, more GEWIS, and greater investigation into genetic and environmental determinants of depressive symptoms in minorities.

Sleep duration, cognitive decline, and dementia risk in older women.

INTRODUCTION: Consistent evidence linking habitual sleep duration with risks of mild cognitive impairment (MCI) and dementia is lacking. METHODS: We conducted a prospective study on 7444 community-dwelling women (aged 65-80 y) with self-reported sleep duration, within the Women's Health Initiative Memory Study in 1995-2008. Incident MCI/dementia cases were ascertained by validated protocols. Cox models were used to adjust for multiple sociodemographic and lifestyle factors, depression, cardiovascular disease (CVD), and other clinical characteristics. RESULTS: We found a statistically significant (P = .03) V-shaped association with a higher MCI/dementia risk in women with either short (≤6 hours/night) or long (≥8 hours/night) sleep duration (vs. 7 hours/night). The multicovariate-adjusted hazard for MCI/dementia was increased by 36% in short sleepers irrespective of CVD, and by 35% in long sleepers without CVD. A similar V-shaped association was found with cognitive decline. DISCUSSION: In older women, habitual sleep duration predicts the future risk for cognitive impairments including dementia, independent of vascular risk factors.

Prospective Analysis of Health and Mortality Risk in Veteran and Non-Veteran Participants in the Women's Health Initiative.

BACKGROUND: The health of postmenopausal 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). METHODS: 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. RESULTS: 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 variables, and health risk factors, veteran status was associated with significantly increased risk of all-cause mortality (hazard ratio [HR], 1.13; 95% CI, 1.03-1.23), but not with risk of CVD (HR, 1.00; 95% CI, 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). CONCLUSIONS: Women veterans' postmenopausal 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.

Joint Associations of Diet, Lifestyle, and Genes with Age-Related Macular Degeneration.

PURPOSE: Unhealthy lifestyles have been associated with increased odds for age-related macular degeneration (AMD). Whether this association is modified by genetic risk for AMD is unknown and was investigated. DESIGN: Interactions between healthy lifestyles AMD risk genotypes were studied in relation to the prevalence of AMD, assessed 6 years later. PARTICIPANTS: Women 50 to 79 years of age in the Carotenoids in Age-Related Eye Disease Study with exposure and AMD data (n=1663). METHODS: Healthy lifestyle scores (0-6 points) were assigned based on Healthy Eating Index scores, physical activity (metabolic equivalent of task hours/week), and smoking pack years assessed in 1994 and 1998. Genetic risk was based on Y402H in complement factor H (CFH) and A69S in age-related maculopathy susceptibility locus 2 (ARMS2). Additive and multiplicative interactions in odds ratios were assessed using the synergy index and a multiplicative interaction term, respectively. MAIN OUTCOME MEASURES: AMD presence and severity were assessed from grading of stereoscopic fundus photographs taken in 2001-2004. AMD was present in 337 women, 91% of whom had early AMD. RESULTS: The odds of AMD were 3.3 times greater (95% confidence interval [CI], 1.8-6.1) in women with both low healthy lifestyle score (0-2) and high-risk CFH genotype (CC), relative to those who had low genetic risk (TT) and high healthy lifestyle scores (4-6). There were no significant additive (synergy index [SI], 1.08; 95% CI, 0.70-1.67) or multiplicative (Pinteraction=0.94) interactions in the full sample. However, when limiting the sample to women with stable diets before AMD assessment (n=728) the odds for AMD associated with low healthy lifestyle scores and high-risk CFH genotype were strengthened (odds ratio, 4.6; 95% CI, 1.8-11.6) and the synergy index was significant (SI, 1.34; 95% CI, 1.05-1.70). Adjusting for dietary lutein and zeaxanthin attenuated, and therefore partially explained, the joint association. There were no significant additive or multiplicative interactions for ARMS2 and lifestyle score. CONCLUSIONS: Having unhealthy lifestyles and 2 CFH risk alleles increased AMD risk (primarily in the early stages), in an or additive or greater (synergistic) manner. However, unhealthy lifestyles increased AMD risk regardless of AMD risk genotype.

Association between vitamin D status and age-related macular degeneration by genetic risk.

IMPORTANCE: Deficient 25-hydroxyvitamin D (25[OH]D) concentrations have been associated with increased odds of age-related macular degeneration (AMD). OBJECTIVE: To examine whether this association is modified by genetic risk for AMD and whether there is an association between AMD and single-nucleotide polymorphisms of genes involved in vitamin D transport, metabolism, and genomic function. DESIGN, SETTING, AND PARTICIPANTS: Postmenopausal women (N = 913) who were participants of the Carotenoids in Age-Related Eye Disease Study (CAREDS) (aged 54 to <75 years) with available serum 25(OH)D concentrations (assessed October 1, 1993, to December 31, 1998), genetic data, and measures of AMD (n = 142) assessed at CAREDS baseline from May 14, 2001, through January 31, 2004, were studied. MAIN OUTCOMES AND MEASURES: Prevalent early or late AMD was determined from graded, stereoscopic fundus photographs. Logistic regression was used to estimate odds ratios (ORs) and 95% CIs for AMD by the joint effects of 25(OH)D (<12, ≥12 to <20, ≥20 to <30, and ≥30 ng/mL) and risk genotype (noncarrier, 1 risk allele, or 2 risk alleles). The referent group was noncarriers with adequate vitamin D status (≥30 ng/mL). Joint effect ORs were adjusted for age, smoking, iris pigmentation, self-reported cardiovascular disease, self-reported diabetes status, and hormone use. Additive and multiplicative interactions were assessed using the synergy index (SI) and an interaction term, respectively. To examine the association between AMD and variants in vitamin D-related genes, age-adjusted ORs and 95% CIs were estimated using logistic regression. RESULTS: Among the 913 women, 550 had adequate levels of vitamin D (≥20 ng/mL), 275 had inadequate levels (≥12 to <20 mg/mL), and 88 had deficient levels (<12 ng/mL). A 6.7-fold increased odds of AMD (95% CI, 1.6-28.2) was observed among women with deficient vitamin D status (25[OH]D <12 ng/mL) and 2 risk alleles for CFH Y402H (SI for additive interaction, 1.4; 95% CI, 1.1-1.7; P for multiplicative interaction = .25). Significant additive (SI, 1.4; 95% CI, 1.1-1.7) and multiplicative interactions (P = .02) were observed for deficient women with 2 high-risk CFI (rs10033900) alleles (OR, 6.3; 95% CI, 1.6-24.2). The odds of AMD did not differ by genotype of candidate vitamin D genes. CONCLUSIONS AND RELEVANCE: In this study, the odds of AMD were highest in those with deficient vitamin D status and 2 risk alleles for the CFH and CFI genotypes, suggesting a synergistic effect between vitamin D status and complement cascade protein function. Limited sample size led to wide CIs. Findings may be due to chance or explained by residual confounding.

Statins and breast cancer stage and mortality in the Women's Health Initiative.

PURPOSE: To evaluate the association between statins and breast cancer stage and mortality in the Women's Health Initiative. METHODS: The study population included 128,675 postmenopausal women aged 50-79 years, out of which there were 7,883 newly diagnosed cases of in situ (19%), local (61%)-, regional (19%)- and distant (1%)-stage breast cancer and 401 deaths due to breast cancer after an average of 11.5 (SD = 3.7) years of follow-up. Stage was coded using SEER criteria and was stratified into early (in situ and local)- versus late (regional and distant)-stage disease. Information on statins and other risk factors were collected by self- and interviewer-administered questionnaires. Cause of death was based on medical record review. Multivariable-adjusted hazards ratios (HR) and 95% confidence intervals (CIs) evaluating the relationship between statin use (at baseline only and in a time-dependent manner) and diagnosis of late-stage breast cancer and breast cancer-specific mortality were computed from Cox proportional hazards analyses after adjusting for appropriate confounders. RESULTS: Statins were used by 10,474 women (8%) at baseline. In the multivariable-adjusted time-dependent model, use of lipophilic statins was associated with a reduction in diagnosis of late-stage breast cancer (HR 0.80, 95% CI 0.64-0.98, p = 0.035) which was also significant among women with estrogen receptor-positive disease (HR 0.72, 95% CI 0.56-0.93, p = 0.012). Breast cancer mortality was marginally lower in statin users compared with nonusers (HR 0.59, 95 % CI 0.32-1.06, p = 0.075). CONCLUSIONS: Prior statin use is associated with lower breast cancer stage at diagnosis.

Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans.

IMPORTANCE: The association between sickle cell trait (SCT) and chronic kidney disease (CKD) is uncertain. OBJECTIVE: To describe the relationship between SCT and CKD and albuminuria in self-identified African Americans. DESIGN, SETTING, AND PARTICIPANTS: Using 5 large, prospective, US population-based studies (the Atherosclerosis Risk in Communities Study [ARIC, 1987-2013; n = 3402], Jackson Heart Study [JHS, 2000-2012; n = 2105], Coronary Artery Risk Development in Young Adults [CARDIA, 1985-2006; n = 848], Multi-Ethnic Study of Atherosclerosis [MESA, 2000-2012; n = 1620], and Women's Health Initiative [WHI, 1993-2012; n = 8000]), we evaluated 15,975 self-identified African Americans (1248 participants with SCT [SCT carriers] and 14,727 participants without SCT [noncarriers]). MAIN OUTCOMES AND MEASURES: Primary outcomes were CKD (defined as an estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73 m2 at baseline or follow-up), incident CKD, albuminuria (defined as a spot urine albumin:creatinine ratio of >30 mg/g or albumin excretion rate >30 mg/24 hours), and decline in eGFR (defined as a decrease of >3 mL/min/1.73 m2 per year). Effect sizes were calculated separately for each cohort and were subsequently meta-analyzed using a random-effects model. RESULTS: A total of 2233 individuals (239 of 1247 SCT carriers [19.2%] vs 1994 of 14,722 noncarriers [13.5%]) had CKD, 1298 (140 of 675 SCT carriers [20.7%] vs 1158 of 8481 noncarriers [13.7%]) experienced incident CKD, 1719 (150 of 665 SCT carriers [22.6%] vs 1569 of 8249 noncarriers [19.0%]) experienced decline in eGFR, and 1322 (154 of 485 SCT carriers [31.8%] vs 1168 of 5947 noncarriers [19.6%]) had albuminuria during the study period. Individuals with SCT had an increased risk of CKD (odds ratio [OR], 1.57 [95% CI, 1.34-1.84]; absolute risk difference [ARD], 7.6% [95% CI, 4.7%-10.8%]), incident CKD (OR, 1.79 [95% CI, 1.45-2.20]; ARD, 8.5% [95% CI, 5.1%-12.3%]), and decline in eGFR (OR, 1.32 [95% CI, 1.07-1.61]; ARD, 6.1% [95% CI, 1.4%-13.0%]) compared with noncarriers. Sickle cell trait was also associated with albuminuria (OR, 1.86 [95% CI, 1.49-2.31]; ARD, 12.6% [95% CI, 7.7%-17.7%]). CONCLUSIONS AND RELEVANCE: Among African Americans in these cohorts, the presence of SCT was associated with an increased risk of CKD, decline in eGFR, and albuminuria, compared with noncarriers. These findings suggest that SCT may be associated with the higher risk of kidney disease in African Americans.

Quality of life in MAP.3 (Mammary Prevention 3): a randomized, placebo-controlled trial evaluating exemestane for prevention of breast cancer.

PURPOSE: Exemestane, a steroidal aromatase inhibitor, reduced invasive breast cancer incidence by 65% among 4,560 postmenopausal women randomly assigned to exemestane (25 mg per day) compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MAP.3 (Mammary Prevention 3) trial, but effects on quality of life (QOL) were not fully described. PATIENTS AND METHODS: Menopause-specific and health-related QOL were assessed by using the four Menopause-Specific Quality of Life Questionnaire (MENQOL) domains and the eight Medical Outcomes Study Short Form Health Survey (SF-36) scales at baseline, 6 months, and yearly thereafter. MENQOL questionnaire completion was high (88% to 98%) in both groups at each follow-up visit. Change scores for each MENQOL and SF-36 scale, calculated at each assessment time relative to baseline, were compared by using the Wilcoxon rank-sum test. Clinically important worsened QOL was defined as a MENQOL change score increase of more than 0.5 (of 8) points and an SF-36 change score decrease of more than 5 (of 100) points from baseline. RESULTS: Exemestane had small negative effects on women's self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of QOL at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed. Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment. CONCLUSION: Exemestane given for prevention has limited negative impact on menopause-specific and health-related QOL in healthy postmenopausal women at risk for breast cancer.