Ultra-processed Food Intake and Risk of Type 2 Diabetes in Korean Adults.

BACKGROUND: Several studies from the United States and European countries reported a positive association between ultra-processed food intake and diabetes risk. However, little is known about the association in Asian populations. It is also unknown about the individual ultra-processed food items that are most unfavorably associated with diabetes risk. OBJECTIVE: We examined the associations of ultra-processed food intake (combined, as well as individual ultra-processed food items) with the risk of type 2 diabetes. METHODS: This prospective analysis included 7438 participants aged 40-69 y from the Korean Genome and Epidemiology Study Ansan-Ansung cohort. Dietary intake was assessed at baseline using a 103-item semiquantitative food-frequency questionnaire. Ultra-processed foods were classified using the Nova definition. Incident type 2 diabetes cases were identified via follow-up interviews and health examination. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: During the follow-up (2001-2019; median: 15 y), a total of 1187 type 2 diabetes cases were identified. Compared with the lowest quartile of ultra-processed food intake, the highest quartile was positively associated with diabetes risk [HR (95% CI) = 1.34 (1.13, 1.59), P-trend = 0.002]. The association did not change after additional adjustment for diet quality or BMI. Among individual ultra-processed food items, a higher consumption of ham/sausage [per 1% increase in the weight ratio: HR (95% CI) = 1.40 (1.05, 1.86)], instant noodles [1.07 (1.02, 1.11)], ice cream [1.08 (1.03, 1.13)], and carbonated beverages [1.02 (1.00, 1.04)] were associated with an increased risk of type 2 diabetes, whereas a higher intake of candy/chocolate was associated with a decreased risk [0.78 (0.62, 0.99)]. CONCLUSIONS: Our data suggest that the high intake of ultra-processed foods, particularly ham/sausage, instant noodles, ice cream, and carbonated beverages, is associated with an increased risk of type 2 diabetes in Korean adults.

Aerobic, muscle-strengthening, and flexibility physical activity and risks of all-cause and cause-specific mortality: a population-based prospective cohort of Korean adults.

BACKGROUND: Studies have shown that aerobic and muscle-strengthening physical activities reduce mortality risk. However, little is known about the joint associations of the two activity types and whether other type of physical activity, such as flexibility activity, can provide similar mortality risk reduction. OBJECTIVES: We examined the independent associations of aerobic, muscle-strengthening, and flexibility physical activities with all-cause and cause-specific mortality in a population-based prospective cohort of Korean men and women. We also examined the joint associations of aerobic and muscle-strengthening activities, the two physical activity types that are recommended by the current World Health Organization physical activity guidelines. DESIGN: This analysis included 34,379 Korea National Health and Nutrition Examination Survey 2007-2013 participants (aged 20-79 years) with mortality data linkage through December 31, 2019. Engagement in walking, aerobic, muscle-strengthening, and flexibility physical activities was self-reported at baseline. Cox proportional hazards model was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: Flexibility physical activity (≥ 5 vs. 0 d/wk) was inversely associated with all-cause (HR [95% CI] = 0.80 [0.70-0.92]; P-trend < 0.001) and cardiovascular mortality (0.75 [0.55-1.03], P-trend = 0.02). Moderate- to vigorous-intensity aerobic physical activity (≥ 50.0 vs. 0 MET-h/wk) was also associated with lower all-cause (HR [95% CI] = 0.82 [0.70-0.95]; P-trend < 0.001) and cardiovascular mortality (0.55 [0.37-0.80]; P-trend < 0.001). Similar inverse associations were observed with total aerobic physical activity, including walking. Muscle-strengthening activity (≥ 5 vs. 0 d/wk) was inversely associated with all-cause mortality (HR [95% CI] = 0.83 [0.68-1.02]; P-trend = 0.01) but was not associated with cancer or cardiovascular mortality. Compared to participants meeting the highest guidelines for both moderate- to vigorous-intensity aerobic and muscle-strengthening physical activities, those not meeting in any guideline were associated with higher all-cause (1.34 [1.09-1.64]) and cardiovascular mortality (1.68 [1.00-2.82]). CONCLUSIONS: Our data suggest that aerobic, muscle-strengthening, and flexibility activities are associated with lower risk of mortality.

Early-life body mass index and risks of breast, endometrial, and ovarian cancers: a dose-response meta-analysis of prospective studies.

BACKGROUND: The evidence for the associations between early-life adiposity and female cancer risks is mixed. Little is known about the exact shape of the relationships and whether the associations are independent of adult adiposity. METHODS: We conducted dose-response meta-analyses of prospective studies to summarise the relationships of early-life body mass index (BMI) with breast, endometrial, and ovarian cancer risks. Pubmed and Embase were searched through June 2020 to identify relevant studies. Using random-effects models, the summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated per 5-kg/m2 increase in BMI at ages ≤ 25 years. A nonlinear dose-response meta-analysis was conducted using restricted cubic spline analysis. RESULTS: After screening 33,948 publications, 37 prospective studies were included in this analysis. The summary RRs associated with every 5-kg/m2 increase in early-life BMI were 0.84 (95% CI = 0.81-0.87) for breast, 1.40 (95% CI = 1.25-1.57) for endometrial, and 1.15 (95% CI = 1.07-1.23) for ovarian cancers. For breast cancer, the association remained statistically significant after adjustment for adult BMI (RR = 0.80, 95% CI = 0.73-0.87). For premenopausal breast, endometrial, and ovarian cancers, the dose-response curves suggested evidence of nonlinearity. CONCLUSIONS: With early-life adiposity, our data support an inverse association with breast cancer and positive associations with ovarian and endometrial cancer risks.

Smartphone Usage Patterns and Dietary Risk Factors in Adolescents.

BACKGROUND: Whereas earlier studies have shown that traditional screen time such as TV watching influences dietary behaviors in adolescents, little is known about the effects of modern screen time such as smartphone use. OBJECTIVES: We examined the associations of smartphone usage duration and content type with dietary risk factors among adolescents. METHODS: We conducted a cross-sectional analysis using a nationally representative sample of 54,601 middle- and high-school students (aged 12-18 y; 26,928 boys and 27,673 girls) in the Korea Youth Risk Behavior Web-Based Survey 2017. Smartphone use (average duration and most frequently used content type) and dietary intakes [frequent breakfast skipping; less frequent intakes of fruits and vegetables; more frequent intakes of instant noodles, fast food, chips/crackers, and sugar-sweetened beverages (SSBs)] were self-reported via an online-based questionnaire. Multivariable logistic regression was performed to estimate ORs and 95% CIs for the associations of smartphone usage duration and content type with prevalence of dietary risk factors, adjusting for potential confounders. All analyses accounted for complex survey sampling. RESULTS: Prolonged smartphone use (≥300 compared with 1-59 min/d) was associated with (OR; 95% CI) higher prevalence of frequent breakfast skipping (1.60; 1.45, 1.76); frequent intakes of instant noodles (1.65; 1.47, 1.84), fast food (1.36; 1.20, 1.53), and SSBs (1.92; 1.75, 2.11); and less frequent intakes of fruits (1.44; 1.30, 1.59) and vegetables (1.32; 1.18, 1.47). Adjusting for usage duration, using smartphones mainly for messenger/e-mail, social networking service (SNS)/forum, and games were associated with less frequent intakes of fruits (OR: 1.21; 95% CI: 1.12, 1.31; OR: 1.28; 95% CI: 1.17, 1.40; and OR: 1.20; 95% CI: 1.10, 1.32, respectively) and vegetables (OR: 1.24; 95% CI: 1.12, 1.37; OR: 1.26; 95% CI: 1.13, 1.40; and OR: 1.25; 95% CI: 1.12, 1.40, respectively) than was using smartphones for education/information search. Using smartphones mainly for messenger/e-mail (OR: 1.24; 95% CI: 1.14, 1.35) and SNS/forum (OR: 1.18; 95% CI: 1.08, 1.29) were also associated with more frequent intake of SSBs. CONCLUSIONS: Our data suggest that both duration and content type of smartphone use are independently associated with dietary risk factors among adolescents.

Validity evaluation of indirect adjustment method for multiple unmeasured confounders: A simulation and empirical study.

BACKGROUND: An indirect adjustment method was developed to control for unmeasured confounders in a large administrative cohort study. A previous study that proposed the indirect adjustment method assessed the validity of the method by simulations but did not consider the direction of bias and scenarios with multiple missing confounders. In this study, we evaluated the direction and the magnitude of bias of the indirect adjustment method with multiple correlated unmeasured confounders using simulation and empirical datasets. METHODS: A simulation study was conducted to compare the bias of the indirect adjustment by varying the number of confounders, magnitude of correlation between confounders, and the number of adjustment variables. An empirical study was conducted by applying the indirect adjustment method to the association between PM10 and mortality using the Korea National Health and Nutrition Examination Survey linked Cause of Death data for 2007-2016. RESULTS: The simulations of the present study demonstrated that 1) when a confounder is positively associated with both exposure and outcome, indirect adjustment might bias the effect size downward; 2) the magnitude of bias might depend on the correlation between unmeasured confounders; and 3) indirect adjustment for multiple missing confounders at once could result in a higher bias than that for some of the missing confounders. Empirical analyses also showed consistent results, but the bias of indirectly adjusted effect estimates was sometimes larger than that of unadjusted effect estimates. CONCLUSIONS: The indirect adjustment method is a promising technique to reduce the bias from unmeasured confounding; however, it should be implemented carefully, particularly when there are multiple correlated unmeasured confounders of the same direction.

Associations of reproductive breast cancer risk factors with breast tissue composition.

BACKGROUND: We investigated the associations of reproductive factors with the percentage of epithelium, stroma, and fat tissue in benign breast biopsy samples. METHODS: This study included 983 cancer-free women with biopsy-confirmed benign breast disease (BBD) within the Nurses' Health Study and Nurses' Health Study II cohorts. The percentage of each tissue type (epithelium, stroma, and fat) was measured on whole-section images with a deep-learning technique. All tissue measures were log-transformed in all the analyses to improve normality. The data on reproductive variables and other breast cancer risk factors were obtained from biennial questionnaires. Generalized linear regression was used to examine the associations of reproductive factors with the percentage of tissue types, while adjusting for known breast cancer risk factors. RESULTS: As compared to parous women, nulliparous women had a smaller percentage of epithelium (ß = - 0.26, 95% confidence interval [CI] - 0.41, - 0.11) and fat (ß = - 0.34, 95% CI - 0.54, - 0.13) and a greater percentage of stroma (ß = 0.04, 95% CI 0.01, 0.08). Among parous women, the number of children was inversely associated with the percentage of stroma (ß per child = - 0.01, 95% CI - 0.02, - 0.00). The duration of breastfeeding of ≥ 24 months was associated with a reduced proportion of fat (ß = - 0.30, 95% CI - 0.54, - 0.06; p-trend = 0.04). In a separate analysis restricted to premenopausal women, older age at first birth was associated with a greater proportion of epithelium and a smaller proportion of stroma. CONCLUSIONS: Our findings suggest that being nulliparous as well as having a fewer number of children (both positively associated with breast cancer risk) is associated with a smaller proportion of epithelium and a greater proportion of stroma, potentially suggesting the importance of epithelial-stromal interactions. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.

Gastric and duodenal ulcers, periodontal disease, and risk of bladder cancer in the Health Professionals Follow-up Study.

PURPOSE: Studies suggest that peptic ulcer and periodontal disease are positively associated with bladder cancer risk. These two factors are likely to share common biologic mechanisms such as inflammation and dysbiosis. We examined the joint association of peptic ulcer (gastric/duodenal) and periodontal disease on bladder cancer risk. METHODS: We conducted a prospective analysis among 45,185 men (563 invasive bladder cancer cases) in the Health Professionals Follow-Up Study (follow-up 1986-2016). History of ulcer and periodontal disease was self-reported at baseline and updated during the follow-up. Cox proportional hazards models estimated hazard ratio (HR) and 95% confidence interval (CI) for the joint associations of ulcers (gastric, duodenal) and periodontal disease, adjusting for age and other potential confounders. We tested for interaction using the Wald test for product terms. RESULTS: Compared with men having no history of ulcer and periodontal disease, men with a history of peptic ulcer only (HR 1.22, 95% CI 0.90-1.66) and men with a history of periodontal disease only (HR 1.19, 95% CI 0.98-1.46) were associated with higher risk of invasive bladder cancer. The highest bladder cancer risk was observed in men with a history of both peptic ulcer and periodontal disease (HR 1.52, 95% CI 1.05-2.20). Similar results were found when we stratified by ulcer types. The interactions between ulcer and periodontal disease were not statistically significant for all ulcer types (p-interaction ≥ 0.59). CONCLUSION: We did not find sufficient evidence for interaction between gastric/duodenal ulcers and periodontal disease on bladder cancer risk.

Sleep duration and mortality in Korean adults: a population-based prospective cohort study.

BACKGROUND: Increasing evidence suggests that sleep duration is associated with risks of various diseases including type 2 diabetes, cardiovascular disease (CVD), and certain types of cancer. However, the relationship with mortality is not clear, particularly in non-European populations. In this study, we investigated the association between sleep duration and mortality in a population-based prospective cohort of Korean adults. METHODS: This analysis included 34,264 participants (14,704 men and 19,560 women) of the Korea National Health and Nutrition Examination Survey (KNHANES) 2007-2013 who agreed to mortality follow-up through December 31, 2016. Sleep duration was self-reported at baseline and was categorized into four groups: ≤4, 5-6, 7-8, and ≥ 9 h/day. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations with mortality (all-cause as well as CVD- and cancer-specific), adjusting for potential confounders. RESULTS: During up to 9.5 years of follow-up, we identified a total of 1028 deaths. We observed the lowest mortality at 5-6 h/day sleep. Compared with 7-8 h/day of sleep, short (≤4 h/day) and long (≥9 h/day) sleep were associated with a 1.05-fold (95% CI = 0.79-1.39) and 1.47-fold (95% CI = 1.15-1.87) higher all-cause mortality, respectively. After additional adjustment for self-rated health, the positive association with short sleep disappeared (HR = 0.99, 95% CI = 0.75-1.32) and the association with long sleep was slightly attenuated (HR = 1.38, 95% CI = 1.08-1.76). Long sleep was also nonsignificantly positively associated with both cancer-mortality (HR = 1.30, 95% CI = 0.86-1.98) and CVD-mortality (HR = 1.27, 95% CI = 0.73-2.21). There was no statistically significant evidence for nonlinearity in the relationships between sleep duration and mortality (all-cause as well as CVD- and cancer-specific). Effect modification by age, sex, education, and occupation were not statistically significant. CONCLUSIONS: Our findings suggest that long sleep duration is associated with an increased all-cause mortality in Korean adults.

Relationship of circulating insulin-like growth factor-I and binding proteins 1-7 with mammographic density among women undergoing image-guided diagnostic breast biopsy.

BACKGROUND: Mammographic density (MD) is a strong breast cancer risk factor that reflects fibroglandular and adipose tissue composition, but its biologic underpinnings are poorly understood. Insulin-like growth factor binding proteins (IGFBPs) are markers that may be associated with MD given their hypothesized role in breast carcinogenesis. IGFBPs sequester IGF-I, limiting its bioavailability. Prior studies have found positive associations between circulating IGF-I and the IGF-I:IGFBP-3 ratio and breast cancer risk. We evaluated the associations of IGF-I, IGFBP-3, and six other IGFBPs with MD. METHODS: Serum IGF measures were quantified in 296 women, ages 40-65, undergoing diagnostic image-guided breast biopsy. Volumetric density measures (MD-V) were assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Area density measures (MD-A) were estimated by computer-assisted thresholding software. Age, body mass index (BMI), and BMI2-adjusted linear regression models were used to examine associations of serum IGF measures with MD. Effect modification by BMI was also assessed. RESULTS: IGF-I and IGFBP-3 were not strongly associated with MD after BMI adjustment. In multivariable analyses among premenopausal women, IGFBP-2 was positively associated with both percent MD-V (ß = 1.49, p value = 0.02) and MD-A (ß = 1.55, p value = 0.05). Among postmenopausal women, positive relationships between IGFBP-2 and percent MD-V (ß = 2.04, p = 0.003) were observed; the positive associations between IGFBP-2 and percent MD-V were stronger among lean women (BMI < 25 kg/m2) (ß = 5.32, p = 0.0002; p interaction = 0.0003). CONCLUSIONS: In this comprehensive study of IGFBPs and MD, we observed a novel positive association between IGFBP-2 and MD, particularly among women with lower BMI. In concert with in vitro studies suggesting a dual role of IGFBP-2 on breast tissue, promoting cell proliferation as well as inhibiting tumorigenesis, our findings suggest that further studies assessing the role of IGFBP-2 in breast tissue composition, in addition to IGF-1 and IGFBP-3, are warranted.

Different dietary fibre sources and risks of colorectal cancer and adenoma: a dose-response meta-analysis of prospective studies.

Dietary fibre is believed to provide important health benefits including protection from colorectal cancer. However, the evidence on the relationships with different dietary fibre sources is mixed and little is known about which fibre source provides the greatest benefits. We conducted a dose-response meta-analysis of prospective cohorts to summarise the relationships of different fibre sources with colorectal cancer and adenoma risks. Analyses were restricted to publications that reported all fibre sources (cereals, vegetables, fruits, legumes) to increase comparability between results. PubMed and Embase were searched through August 2018 to identify relevant studies. The summary relative risks (RR) and 95 % CI were estimated using a random-effects model. This analysis included a total of ten prospective studies. The summary RR of colorectal cancer associated with each 10 g/d increase in fibre intake were 0·91 (95 % CI 0·82, 1·00; I2 = 0 %) for cereal fibre, 0·95 (95 % CI 0·87, 1·03, I2 = 0 %) for vegetable fibre, 0·91 (95 % CI 0·78, 1·06, I2 = 43 %) for fruit fibre and 0·84 (95 % CI 0·63, 1·13, I2 = 45 %) for legume fibre. For cereal fibre, the association with colorectal cancer risk remained statistically significant after adjustment for folate intake (RR 0·89, 95 % CI 0·80, 0·99, I2 = 2 %). For vegetable and fruit fibres, the dose-response curve suggested evidence of non-linearity. All fibre sources were inversely associated with incident adenoma (per 10 g/d increase: RR 0·81 (95 % CI 0·54, 1·21) cereals, 0·84 (95 % CI 0·71, 0·98) for vegetables, 0·78 (95 % CI 0·65, 0·93) for fruits) but not associated with recurrent adenoma. Our data suggest that, although all fibre sources may provide some benefits, the evidence for colorectal cancer prevention is strongest for fibre from cereals/grains.

Impact of Pharmacy Student-Driven Postdischarge Telephone Calls on Heart Failure Hospital Readmission Rates: A Pilot Program.

Background: Heart failure (HF) hospitalization rates have remained high in the past 10 years. Numerous studies have shown significant improvement in HF readmission rates when pharmacists or pharmacy residents conduct postdischarge telephone calls. Objective: The purpose of this retrospective review of a pilot program was to evaluate the impact of pharmacy student-driven postdischarge phone calls on 30- and 90-day hospital readmission rates in patients recently discharged with HF. Methods: A retrospective manual chart review was conducted for all patients who received a telephone call from the pharmacy students. The primary endpoint compared historical readmissions, 30 and 90 days prior to hospital discharge, with 30 and 90 days post discharge readmissions. For the secondary endpoints, historical and postdischarge 30-day and 90-day readmission rates were compared for patients with a primary diagnosis of HF and for patients with a secondary diagnosis of HF. Descriptive statistics were calculated in the form of means and standard deviations for continuous variables and frequencies and percentages for categorical variables. Results: Statistically significant decrease was observed for both the 30-day (P = .006) and 90-day (P = .007) readmission periods. Prior to the pharmacy students' phone calls, the overall group of 131 patients had historical readmission rates of 24.43% within 30 days and 38.17% within 90 days after hospital discharge. After the postdischarge phone calls, the readmission rates decreased to 11.45%, for 30 days, and 22.90%, for 90 days. Conclusion: Postdischarge phone calls, specifically made by pharmacy students, demonstrated a positive impact on reducing HF-associated hospital readmissions, adding to the growing body of evidence of different methods of pharmacy interventions and highlighting the clinical impact pharmacy students may have in transition of care services.

Serum insulin-like growth factor (IGF)-I and IGF binding protein-3 in relation to terminal duct lobular unit involution of the normal breast in Caucasian and African American women: The Susan G. Komen Tissue Bank.

Lesser degrees of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini/TDLU, are associated with elevated breast cancer risk. In rodent models, the insulin-like growth factor (IGF) system regulates involution of the mammary gland. We examined associations of circulating IGF measures with TDLU involution in normal breast tissues among women without precancerous lesions. Among 715 Caucasian and 283 African American (AA) women who donated normal breast tissue samples to the Komen Tissue Bank between 2009 and 2012 (75% premenopausal), serum concentrations of IGF-I and binding protein (IGFBP)-3 were quantified using enzyme-linked immunosorbent assay. Hematoxilyn and eosin-stained tissue sections were assessed for numbers of TDLUs ("TDLU count"). Zero-inflated Poisson regression models with a robust variance estimator were used to estimate relative risks (RRs) for association of IGF measures (tertiles) with TDLU count by race and menopausal status, adjusting for potential confounders. AA (vs. Caucasian) women had higher age-adjusted mean levels of serum IGF-I (137 vs. 131 ng/mL, p = 0.07) and lower levels of IGFBP-3 (4165 vs. 4684 ng/mL, p < 0.0001). Postmenopausal IGFBP-3 was inversely associated with TDLU count among AA (RRT3vs.T1 = 0.49, 95% CI = 0.28-0.84, p-trend = 0.04) and Caucasian (RRT3vs.T1 =0.64, 95% CI = 0.42-0.98, p-trend = 0.04) women. In premenopausal women, higher IGF-I:IGFBP-3 ratios were associated with higher TDLU count in Caucasian (RRT3vs.T1 =1.33, 95% CI = 1.02-1.75, p-trend = 0.04), but not in AA (RRT3vs.T1 =0.65, 95% CI = 0.42-1.00, p-trend = 0.05), women. Our data suggest a role of the IGF system, particularly IGFBP-3, in TDLU involution of the normal breast, a breast cancer risk factor, among Caucasian and AA women.

Anthropometric measures and serum estrogen metabolism in postmenopausal women: the Women's Health Initiative Observational Study.

BACKGROUND: Several anthropometric measures have been associated with hormone-related cancers. However, it is unknown whether estrogen metabolism plays an important role in these relationships. We examined whether measured current body mass index (BMI), waist-to-hip ratio (WHR), height, and self-reported BMI at age 18 years were associated with serum estrogens/estrogen metabolites using baseline, cross-sectional data from 1835 postmenopausal women enrolled in the Women's Health Initiative Observational Study. METHODS: Fifteen estrogens/estrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Geometric means (GMs) of estrogens/estrogen metabolites (in picomoles per liter) were estimated using inverse probability weighted linear regression, adjusting for potential confounders and stratified on menopausal hormone therapy (MHT) use. RESULTS: Among never or former MHT users, current BMI (≥30 vs. <25 kg/m2) was positively associated with parent estrogens (multivariable adjusted GM 432 vs. 239 pmol/L for estrone, 74 vs. 46 pmol/L for estradiol; p-trend < 0.001 for both) and all of the 2-, 4-, and 16-pathway estrogen metabolites evaluated (all p-trend ≤ 0.02). After additional adjustment for estradiol, unconjugated methylated 2-catechols were inversely associated (e.g., 2-methoxyestrone multivariable GM 9.3 vs. 12.0 pmol/L; p-trend < 0.001). Among current MHT users, current BMI was not associated with parent estrogens but was inversely associated with methylated catechols (e.g., 2-methoxyestrone multivariable GM 216 vs. 280 pmol/L; p-trend = 0.008). Similar patterns of association were found with WHR; however, the associations were not independent of BMI. Height and BMI at age 18 years were not associated with postmenopausal estrogens/estrogen metabolite levels. CONCLUSIONS: Our data suggest that postmenopausal BMI is associated with increased circulating levels of parent estrogens and reduced methylation of catechol estrogen metabolites, the estrogen metabolism patterns that have previously been associated with higher breast cancer risk.

Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast.

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per-allele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.

Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women's Health Initiative Observational Study.

BACKGROUND: Prolonged sitting and lower levels of physical activity have been associated with increased levels of parent oestrogens (oestrone and oestradiol), the key hormones in female cancers, in postmenopausal women. However, it is unknown whether sitting and physical activity are associated with circulating oestrogen metabolite levels. METHODS: Among 1804 postmenopausal women enrolled in the Women's Health Initiative Observational Study, 15 serum oestrogens/oestrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting were self-reported via questionnaire. Using baseline, cross-sectional data, geometric means (GM) of oestrogens/oestrogen metabolites (pmol l-1) were estimated using inverse probability weighted linear regression, adjusting for potential confounders and stratified on menopausal hormone therapy (MHT) use. RESULTS: Longer time spent sitting (⩾10 vs ⩽5h per day) was associated with higher levels of unconjugated oestrone, independent of moderate- to vigorous-intensity physical activity and body mass index, among both never/former (GM=70.6 vs 57.7) and current MHT users (GM=242 vs 179) (P-trend ⩽0.03). Among never/former MHT users, sitting (⩾10 vs ⩽5h per day) was positively associated with 2-methoxyestradiol (GM=16.4 vs 14.4) and 4-methoxyestradiol (GM=2.36 vs 1.98) (P-trend ⩽0.04), independent of parent oestrogens. Inverse associations between moderate- to vigorous-intensity physical activity (⩾15 vs 0 metabolic equivalent task-hours per week) and parent oestrogens were found as expected. After adjustment for parent oestrogens, physical activity was not associated with oestrogen metabolites. CONCLUSIONS: Our data suggest that prolonged sitting and lower moderate- to vigorous-intensity physical activity are associated with higher levels of postmenopausal oestrogens/oestrogen metabolites, the oestrogen metabolism patterns that have previously been associated with higher endometrial and breast cancer risk.

Sedentary behaviors and light-intensity activities in relation to colorectal cancer risk.

A recent meta-analysis found that sedentary behaviors are associated with an increased colorectal cancer (CRC) risk. Yet, the finding on TV viewing time, the most widely used surrogate of sedentary behaviors, was based on only two studies. Furthermore, light-intensity activities (e.g., standing and slow walking), non-sedentary by posture but close to sedentary behaviors by Metabolic Equivalent Task values, have not been investigated in relation to CRC risk. Thus, we prospectively analyzed the relationships based on 69,715 women from Nurses' Health Study (1992-2010) and 36,806 men from Health Professionals Follow-Up Study (1988 - 2010). Throughout follow-up, time spent on sedentary behaviors including sitting watching TV and on light-intensity activities were assessed repeatedly; incidence of CRC was ascertained. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models from each cohort. A total of 1,119 and 913 incident cases were documented from women and men, respectively. The multivariable HR comparing ≥ 21 versus < 7 hr/week of sitting watching TV was 1.21 (95% CI = 1.02 to 1.43, ptrend =.01) in women and 1.06 (95% CI = 0.84 to 1.34, ptrend =.93) in men. In women, those highly sedentary and physically less active had an approximately 41% elevated risk of CRC (95% CI = 1.03 to 1.92) compared with those less sedentary and physically more active. The other sedentary behaviors and light-intensity activities were not related to CRC risk in women or men. In conclusion, we found that prolonged sitting time watching TV was associated with an increased CRC risk in women but not in men.

Ages at menarche- and menopause-related genetic variants in relation to terminal duct lobular unit involution in normal breast tissue.

Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single-nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. Fourteen percent of evaluated SNPs (eight SNPs) were associated with TDLU counts at p < 0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50 % that were either significantly or nonsignificantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among ten SNPs that were statistically significantly associated with at least one TDLU involution measure (p < 0.05), seven SNPs (rs466639: RXRG; rs2243803: SLC14A2; rs2292573: GAB2; rs6438424: 3q13.32; rs7606918: METAP1D; rs11668344: TMEM150B; rs1635501: EXO1) were associated in the consistent directions. Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results.

The interaction between early-life body size and physical activity on risk of breast cancer.

While early-life body leanness is associated with increased breast cancer risk, early-life physical activity may protect against breast cancer. We examined whether the excess risk among lean girls is modified by their levels of prior, concurrent, or future physical activity. We conducted an analysis among 74,723 women in the Nurses' Health Study II (follow-up 1997-2011). Participants recalled their body size at ages 5, 10 and 20 years in 1989 using a 9-level pictogram (Level 1 most lean). In 1997, they reported adolescent levels of physical activity (ages 12-13 and 14-17 years). Cox proportional hazards models estimated the overall association of body size with breast cancer risk and assessed interactions of adolescent physical activity with body size at three different age periods (5-10, 10-20 and 20 years), adjusting for early-life and adult risk factors for breast cancer. Regardless of levels of adolescent physical activity, early-life body leanness (level 1-2 vs. 4.5+) was significantly associated with higher breast cancer risk. The association was slightly attenuated among those who were active (60+ MET-hr/wk) during adolescence compared to those who were inactive (<30 MET-hr/wk) (body size at ages 5-10 years: hazard ratio = 1.37, 95% confidence interval = 1.04-1.81 vs. 1.66, 1.29-2.12), but the interaction was not significant (p = 0.72). The results were similar for body size at three different age periods. Being lean during early life is a risk factor for breast cancer among both inactive and active girls. Adolescent physical activity did not significantly modify the association, although some interaction cannot be excluded.

Dietary Fat and Fiber Intakes Are Not Associated with Patterns of Urinary Estrogen Metabolites in Premenopausal Women.

BACKGROUND: Interindividual differences in the bioavailability of potentially carcinogenic estrogen and estrogen metabolites (EMs) may play a role in the risk of breast cancer. OBJECTIVE: We examined whether dietary intakes of fiber and fat influence premenopausal EM profiles through effects on estrogen synthesis, metabolism, or excretion. METHODS: We conducted a cross-sectional analysis of 598 premenopausal women who participated in a reproducibility study (n = 109) or served as controls in a nested case-control study of breast cancer (n = 489) within the Nurses' Health Study II. Dietary intakes of fiber and fat were assessed via semiquantitative food frequency questionnaires in 1995 and 1999. Midluteal urine samples were collected between 1996 and 1999 and EMs were quantified with the use of HPLC-tandem mass spectrometry. Linear mixed models were used to estimate creatinine-adjusted geometric means for individual EMs and their pathway groups across categories of dietary intake while controlling for total energy intake and potential confounders. RESULTS: Higher total dietary fiber intake (>25 g/d vs. ≤15 g/d) was associated with significantly higher concentrations of 4-methoxyestradiol (50% difference, P-difference = 0.01, P-trend = 0.004) and lower concentrations of 17-epiestriol (-27% difference, P-difference = 0.03, P-trend = 0.03), but was not associated with any other EMs. The associations did not vary by fiber intake from different sources. Total fat intake (>35% energy vs. ≤25% energy) was suggestively positively associated with 17-epiestriol (22.6% difference, P-difference = 0.14, P-trend = 0.06); the association was significant for polyunsaturated fatty acid (37% difference, P-difference = 0.01, P-trend = 0.01) and trans fat (36.1% difference, P-difference = 0.01, P-trend = 0.01) intakes. CONCLUSION: Fiber and fat intakes were not strongly associated with patterns of estrogen metabolism in premenopausal women. Our data suggest estrogen metabolism is not a major mechanism through which dietary fiber and fat may affect breast or other hormone-related cancer risks.

Adolescent physical activity in relation to breast cancer risk.

Adolescent physical activity may protect against premenopausal breast cancer. Whether it also prevents postmenopausal breast cancer, and whether associations are independent of adult activity, is unclear. We evaluated this association among 75,669 women in the Nurses' Health Study II. In 1997, participants reported strenuous, moderate, and walking activity (hours/week) at ages 12-13, 14-17, 18-22, and 23-29 years. We estimated metabolic equivalent task hours (MET-h)/week. Participants also reported current physical activity over follow-up. Breast cancer diagnoses (n = 2,697; premenopausal = 1,351; postmenopausal = 965) through 2011 were reported by participants and confirmed with medical records. We additionally stratified analyses by median age at diagnosis. In Cox proportional hazards models adjusted for adolescent characteristics, physical activity from ages 14-22 was modestly inversely associated with premenopausal breast cancer [e.g., hazard ratio (HR) comparing 72+ to <21 MET-h/week 0.81 (95 % confidence interval (CI) 0.69-0.95; p-trend = 0.10) for ages 14-17 and 0.85 (95 % CI 0.71-1.02; p-trend = 0.06 for ages 18-22]. However, adjustment for adult activity and additional breast cancer risk factors attenuated the associations [ages 14-17: 0.85 (95 % CI 0.73-1.00; p-trend = 0.33)]. Associations were stronger among women diagnosed at younger ages [e.g., ages 18-22, HR 0.77 (95 % CI 0.60-0.99; p-trend = 0.05) for women diagnosed before 46.9 years; HR 1.02 (95 % CI 0.79-1.32; p-trend = 0.94) for those diagnosed at/after 46.9 years]. Early life physical activity was not associated with postmenopausal breast cancer. Overall, adolescent physical activity was not associated with breast cancer risk. However, we observed a suggestive inverse association of physical activity at ages 14-22 years with premenopausal breast cancer.