BACKGROUND Age is one of the strongest predictors of cancer, chronic disease, and mortality, but biological responses to aging differ among people. Epigenetic DNA modifications have been used to estimate "biological age," which may be a useful predictor of disease risk. We tested this hypothesis for breast cancer. METHODS Using a case-cohort approach, we measured baseline blood DNA methylation of 2764 women enrolled in the Sister Study, 1566 of whom subsequently developed breast cancer after an average of 6 years. Using three previously established methylation-based "clocks" (Hannum, Horvath, and Levine), we defined biological age acceleration for each woman by comparing her estimated biological age with her chronological age. Hazard ratios and 95% confidence intervals for breast cancer risk were estimated using Cox regression models. All statistical tests were two-sided. RESULTS Each of the three clocks showed that biological age acceleration was statistically significantly associated with increased risk of developing breast cancer (5-year age acceleration, Hannum's clock: hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.00 to 1.21, P = .04; Horvath's clock: HR = 1.08, 95% CI = 1.00 to 1.17, P = .04; Levine's clock: HR = 1.15, 95% CI = 1.07 to 1.23, P < .001). For Levine's clock, each 5-year acceleration in biological age corresponded with a 15% increase in breast cancer risk. Although biological age may accelerate with menopausal transition, age acceleration in premenopausal women independently predicted breast cancer. Case-only analysis suggested that, among women who develop breast cancer, increased age acceleration is associated with invasive cancer (odds ratio for invasive = 1.09, 95% CI = 0.98 to 1.22, P = .10). CONCLUSIONS DNA methylation-based measures of biological age may be important predictors of breast cancer risk.

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Methylation-Based Biological Age and Breast Cancer Risk.

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family histor ...

Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies

Importance Short sleep has been associated with obesity, but to date the association between exposure to artificial light at night (ALAN) while sleeping and obesity is unknown. Objective To determine whether ALAN exposure while sleeping is associated with the prevalence and risk of obesity. Design, Setting, and Participants This baseline and prospective analysis included women aged 35 to 74 years enrolled in the Sister Study in all 50 US states and Puerto Rico from July 2003 through March 2009. Follow-up was completed on August 14, 2015. A total of 43 722 women with no history of cancer or cardiovascular disease who were not shift workers, daytime sleepers, or pregnant at baseline were included in the analysis. Data were analyzed from September 1, 2017, through December 31, 2018. Exposures Artificial light at night while sleeping reported at enrollment, categorized as no light, small nightlight in the room, light outside the room, and light or television in the room. Main Outcomes and Measures Prevalent obesity at baseline was based on measured general obesity (body mass index [BMI] ≥30.0) and central obesity (waist circumference [WC] ≥88 cm, waist-to-hip ratio [WHR] ≥0.85, or waist-to-height ratio [WHtR]≥0.5). To evaluate incident overweight and obesity, self-reported BMI at enrollment was compared with self-reported BMI at follow-up (mean [SD] follow-up, 5.7 [1.0] years). Generalized log-linear models with robust error variance were used to estimate multivariable-adjusted prevalence ratios (PRs) and relative risks (RRs) with 95% CIs for prevalent and incident obesity. Results Among the population of 43 722 women (mean [SD] age, 55.4 [8.9] years), having any ALAN exposure while sleeping was positively associated with a higher prevalence of obesity at baseline, as measured using BMI (PR, 1.03; 95% CI, 1.02-1.03), WC (PR, 1.12; 95% CI, 1.09-1.16), WHR (PR, 1.04; 95% CI, 1.00-1.08), and WHtR (PR, 1.07; 95% CI, 1.04-1.09), after adjusting for confounding factors, with P P P  = .04 for trend), incident overweight (RR, 1.22; 95% CI,1.06-1.40;  P  = .03 for trend), and incident obesity (RR, 1.33; 95% CI, 1.13-1.57; P Conclusions and Relevance These results suggest that exposure to ALAN while sleeping may be a risk factor for weight gain and development of overweight or obesity. Further prospective and interventional studies could help elucidate this association and clarify whether lowering exposure to ALAN while sleeping can promote obesity prevention.

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Association of Exposure to Artificial Light at Night While Sleeping With Risk of Obesity in Women.

BACKGROUND Peripheral blood DNA methylation may be associated with breast cancer, but studies of candidate genes and global and genome-wide DNA methylation have been inconsistent. METHODS We performed an epigenome-wide study using Infinium HumanMethylation450 BeadChips with prospectively collected blood DNA samples from the Sister Study (1552 cases, 1224 subcohort). Differentially methylated cytosine-phosphate-guanine sites (dmCpGs) were identified using case-cohort proportional hazard models and replicated using deposited data from European Prospective Investigation into Cancer and Nutrition in Italy (EPIC-Italy) (n = 329). The correlation between methylation and time to diagnosis was examined using robust linear regression. Causal or consequential relationships of methylation to breast cancer were examined by Mendelian randomization using OncoArray 500 K single-nucleotide polymorphism data. All statistical tests were two-sided. RESULTS We identified 9601 CpG markers associated with invasive breast cancer (false discovery rate = q < 0.01), with 510 meeting a strict Bonferroni correction threshold (10-7). A total of 2095 of these CpGs replicated in the independent EPIC-Italy dataset, including 144 meeting the Bonferroni threshold. Sister Study women who developed ductal carcinoma in situ had methylation similar to noncases. Most (1501, 71.6%) dmCpGs showed lower methylation in invasive cases. In case-only analysis, methylation was statistically significantly associated (false discovery rate = q < 0.05) with time to diagnosis for 892 (42.6%) of the dmCpGs. Analyses based on genetic association suggest that methylation differences are likely a consequence rather than a cause of breast cancer. Pathway analysis shows enrichment of breast cancer-related gene pathways, and dmCpGs are overrepresented in known breast cancer susceptibility genes. CONCLUSIONS Our findings suggest that the DNA methylation profile of blood starts to change in response to invasive breast cancer years before the tumor is clinically detected.

Blood DNA Methylation and Breast Cancer: A Prospective Case-Cohort Analysis in the Sister Study

Background:Toxic metals show evidence of carcinogenic and estrogenic properties. However, little is known about the relationship between airborne metals and breast cancer. We evaluated the risk of breast cancer in relation to exposure to toxic metallic substances in air, individually and combined, i

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Metallic Air Pollutants and Breast Cancer Risk in a Nationwide Cohort Study.

Background: The Sister Study was designed to address gaps in the study of environment and breast cancer by taking advantage of more frequent breast cancer diagnoses among women with a sister histor...

The Sister Study Cohort: Baseline Methods and Participant Characteristics

Importance
Poor olfaction is common in older adults and signifies multiple adverse health outcomes, but it often goes unrecognized.


Objective
To characterize the self-awareness of poor olfaction in women, including its prevalence, associated factors, reporting reliability, validity against an objective test, and factors associated with validity.


Design, Setting, and Participants
These cross-sectional survey data and a case-control subsample were taken from the National Institute of Environmental Health Sciences' Sister Study. Of 41 118 participants (aged 41-85 years) who reported olfaction in 2014 through 2016, 3406 (aged 50-79 years) reported olfaction again in 2018 through 2019 and completed the 12-item Brief Smell Identification Test, version A, including 2353 women who self-reported poor olfaction in 2014 through 2016 and 1053 women who reported normal olfaction. Data analyses were performed between May 28, 2021, and December 23, 2021.


Main Outcomes and Measures
Self-reported (yes/no) and objectively tested poor olfaction defined as a Brief Smell Identification Test score of 9 or lower. Multivariable logistic regressions were used to assess factors that might be associated with the prevalence and reporting accuracy of self-reported olfaction. In subsample analyses, the sampling strategy was accounted for to extrapolate data to eligible cohort samples.


Results
Of the 41 118 women (mean [SD] age, 64.3 [8.7] years) included in the analysis, 3322 (8.1%) self-reported poor olfaction. Higher prevalence was associated with older age, not being married, current smoking status, frequent coffee drinking, overweight or obesity, less than optimal health, Parkinson disease, cognitive impairment, depression, anxiety, and seasonal allergy, whereas a lower prevalence was associated with non-Hispanic Black race and physical activity. In the subsample analyses, olfaction status reported 3 years apart showed a modest agreement (κ, 0.56; 95% CI, 0.51-0.61). The prevalence of objectively tested poor olfaction was 13.3% (95% CI, 11.5%-15.0%), and in contrast with self-reports, it was twice as high in non-Hispanic Black women as in non-Hispanic White women (24.5% vs 12.5%). Compared with objective tests, self-reports showed a low sensitivity (22.6%; 95% CI, 19.6%-25.6%), especially in non-Hispanic Black women (12.4%; 95% CI, 7.0%-17.8%). The specificity was uniformly high (>90%). Among participants who reported poor olfaction, higher odds of true vs false positives were associated with age older than 60 years (60-64 years old, 1.68; 95% CI, 1.51-1.87; 65-69 years old, 2.26; 95% CI, 2.03-2.51; 70-74 years old, 3.34; 95% CI, 3.00-3.73; ≥75 years old, 5.17; 95% CI, 4.43-6.03), non-Hispanic Black race (2.00; 95% CI, 1.70-2.36), no college education (1.34; 95% CI, 1.22-1.48), underweight (1.40; 95% CI, 1.04-1.88), fair or poor health (1.37; 95% CI, 1.22-1.54), and Parkinson disease (7.60; 95% CI, 5.60-10.32). Among those with objectively tested poor olfaction, lower odds of true positives vs false negatives were associated with Black race (0.46; 95% CI, 0.25-0.86).


Conclusions and Relevance
In this case-control study, the self-awareness and reporting accuracy of poor olfaction in middle-aged and older women were low, particularly in non-Hispanic Black women. Given its potential health implications, awareness of this common sensory deficit should be raised.

Assessment of Self-reported Sense of Smell, Objective Testing, and Associated Factors in Middle-aged and Older Women.

BACKGROUND
Large prospective studies are essential for investigating the environmental causes of Parkinson's disease (PD), but diagnosis via clinical exams is often infeasible.


OBJECTIVE
To present case ascertainment strategy and data collection in a US cohort of women.


METHODS
In the Sister Study (n = 50,884, baseline ages 55.6±9.0), physician-made PD diagnoses were first reported by participants or their proxies. Cohort-wide follow-up surveys collected data on subsequent diagnoses, medication usage and PD-relevant motor and nonmotor symptoms. We contacted self-reported PD cases and their treating physicians to obtain relevant diagnostic and treatment history. Diagnostic adjudication was made via expert review of all available data, except nonmotor symptoms. We examined associations of nonmotor symptoms with incident PD, using multivariable logistic regression models and reported odds ratio (OR) and 95% confidence intervals (CI).


RESULTS
Of the 371 potential PD cases identified, 242 diagnoses were confirmed. Compared with unconfirmed cases, confirmed cases were more likely to report PD diagnosis from multiple sources, medication usage, and motor and nonmotor feature consistently during the follow-up. PD polygenic risk score was associated with confirmed PD (ORinter-quartile range = 1.74, 95% CI: 1.45-2.10), but not with unconfirmed cases (corresponding OR = 1.05). Hyposmia, dream-enacting behaviors, constipation, depression, unexplained weight loss, dry eyes, dry mouth, and fatigue were significantly related to PD risk, with ORs from 1.71 to 4.88. Only one of the eight negative control symptoms was associated with incident PD.


CONCLUSION
Findings support our PD case ascertainment approach in this large cohort of women. PD prodromal presentation is likely beyond its well-documented profile.

Lourdes M Suarez

Papers

The Sister Study Cohort: Baseline Methods and Participant Characteristics

Assessment of Self-reported Sense of Smell, Objective Testing, and Associated Factors in Middle-aged and Older Women.

Parkinson's Disease Case Ascertainment in the Sister Study: A Cohort for Environmental Health Research.