Use of dietary supplements containing soy isoflavones and breast cancer risk among women aged >50 y: a prospective study.

BACKGROUND: Soy-based dietary supplements have been promoted as natural alternatives to menopausal hormone therapy, but their potential effect on breast cancer development is controversial. OBJECTIVES: We examined the relation between the consumption of soy supplements and the risk of breast cancer, overall and by tumor hormone receptor status, among women aged >50 y. METHODS: In total, 76,442 women from the Etude Epidemiologique aupres de Femmes de la Mutuelle Generale de l'Education Nationale (E3N) cohort, born between 1925 and 1950, were followed from 2000 to 2011 (11.2 y on average, starting at a mean age of 59.5 y; 3608 incident breast cancers), with soy supplement use assessed every 2-3 y. HRs of breast cancer were estimated with the use of multivariable Cox models. RESULTS: Compared with never using soy supplements, the HRs associated with current use of soy supplements were 0.92 (95% CI: 0.76, 1.11) for all, 0.78 (95% CI: 0.60, 0.99) for estrogen receptor (ER)-positive, and 2.01 (95% CI: 1.41, 2.86) for ER-negative breast cancers. There was no association between past use of soy supplements and breast cancer. HRs for current use were 1.36 (95% CI: 0.95, 1.93) and 0.82 (95% CI: 0.65, 1.02) among women with and without a family history of breast cancer, respectively (P-interaction = 0.03) and 1.06 (95% CI: 0.87, 1.30) ≥5 y after menopause compared with 0.50 (95% CI: 0.31, 0.81) in premenopause or ≤5 y postmenopause (P-interaction = 0.04). CONCLUSIONS: In this cohort of women aged >50 y, we report opposing associations of soy supplements with ER-positive and ER-negative breast cancer risk. Our results also caution against the use of these supplements in women with a family history of breast cancer. Whether the risk profile of soy supplements could be more favorable among premenopausal or recently postmenopausal women deserves further investigation.

Association of menopausal characteristics and risk of coronary heart disease: a pan-European case-cohort analysis.

BACKGROUND: Earlier age at menopause has been associated with increased risk of coronary heart disease (CHD), but the shape of association and role of established cardiovascular risk factors remain unclear. Therefore, we examined the associations between menopausal characteristics and CHD risk; the shape of the association between age at menopause and CHD risk; and the extent to which these associations are explained by established cardiovascular risk factors. METHODS: We used data from EPIC-CVD, a case-cohort study, which includes data from 23 centres from 10 European countries. We included only women, of whom 10 880 comprise the randomly selected sub-cohort, supplemented with 4522 cases outside the sub-cohort. We conducted Prentice-weighted Cox proportional hazards regressions with age as the underlying time scale, stratified by country and adjusted for relevant confounders. RESULTS: After confounder and intermediate adjustment, post-menopausal women were not at higher CHD risk compared with pre-menopausal women. Among post-menopausal women, earlier menopause was linearly associated with higher CHD risk [HRconfounder and intermediate adjusted per-year decrease = 1.02, 95% confidence interval (CI) = 1.01-1.03, p = 0.001]. Women with a surgical menopause were at higher risk of CHD compared with those with natural menopause (HRconfounder-adjusted = 1.25, 95% CI = 1.10-1.42, p < 0.001), but this attenuated after additional adjustment for age at menopause and intermediates (HR = 1.12, 95% CI = 0.96-1.29, p = 0.15). A proportion of the association was explained by cardiovascular risk factors. CONCLUSIONS: Earlier and surgical menopause were associated with higher CHD risk. These associations could partially be explained by differences in conventional cardiovascular risk factors. These women might benefit from close monitoring of cardiovascular risk factors and disease.

Relation between hysterectomy, oophorectomy and the risk of incident differentiated thyroid cancer: The E3N cohort.

BACKGROUND: Thyroid cancers are threefold more frequent in women than in men. A role of reproductive or hormonal factors has been suggested but with contradictory results. We investigated potential associations between history of hysterectomy, with or without oophorectomy, and history of benign gynaecological disease (uterine fibroids, endometriosis) and the incidence of differentiated thyroid cancer, in a large French prospective cohort. METHODS: A total of 89 340 women from the E3N cohort were followed up between 1990 and 2012. Gynaecological diseases treated by surgery were self-reported. Thyroid cancers were validated by histological reports. Time-dependent covariates included smoking status, BMI and history of benign thyroid disease. Cox proportional hazard models with age as timescale were used to estimate Hazard Ratios (HR) and 95% confidence intervals (CI). RESULTS: A total of 412 cases of thyroid cancer were diagnosed during follow-up. A history of hysterectomy was associated with an increased risk of differentiated thyroid cancer (adjusted HR=2.05; 95%CI: 1.65-2.55). The association was not altered after further adjustment for reproductive factors. Endometriosis, uterine polyps, ovarian cysts and oophorectomy without hysterectomy were not associated with the risk of thyroid cancer. A history of fibroids was also significantly related to the risk of thyroid cancer over the follow-up period (adjusted HR=1.91; 95%CI: 1.50-2.44) and the increased risk persisted after adjustment for history of hysterectomy. CONCLUSIONS: Women who had either a history of fibroids or hysterectomy had an increased risk of differentiated thyroid cancer. These findings suggest shared biological mechanisms between fibroids and thyroid cancer, which deserve to be further dissected.

Use of benzodiazepines and cardiovascular mortality in a cohort of women aged over 50 years.

PURPOSE: To assess the association between use of benzodiazepines (including the Z-drugs zopiclone and zolpidem) and cardiovascular mortality in women aged over 50 years. METHODS: We used data from the E3N cohort. Data self-reported in biennial questionnaires was matched with drug reimbursement and vital status/causes of death data. In Cox models, exposure to benzodiazepines was fitted using time-varying variables, the reference category being women with no benzodiazepine delivery since January 2004. RESULTS: Among 85,353 women born 1925-1950 and followed between 2004 and 2011, 506 cardiovascular deaths occurred. Exposure to benzodiazepines was associated with increased cardiovascular mortality when hazard ratios (HRs) were adjusted only for age (HRever use 1.65; 95% CI 1.39, 1.97), but not when further adjusted for antidepressant use (HRever use 1.15; 95% CI 0.94, 1.40), nor in the multivariable model (HRever use 0.93; 95% CI 0.75, 1.16). Exposure to hypnotic benzodiazepines remained associated with increased cardiovascular mortality (HRever use 1.23; 95% CI 1.01, 1.51), but with no consistent trend across duration/dose or time since last use, while exposure to anxiolytic benzodiazepines was not (HRever use 0.83; 95% CI 0.67, 1.02). CONCLUSION: In our study, adjustment for antidepressant use strongly attenuated any benzodiazepine-cardiovascular mortality association. Whether the modest association observed with hypnotic benzodiazepines is due to residual confounding deserves further investigation.

Influence of a cancer diagnosis on changes in fruit and vegetable consumption according to cancer site, stage at diagnosis and socioeconomic factors: Results from the large E3N-EPIC study.

Many studies have demonstrated that lifestyle factors, including diet, may influence cancer survival. The number of cancer survivors is increasing worldwide and little is known about long-term diet changes in people who had cancer. We studied 53,981 women from the prospective E3N-EPIC cohort study with available dietary data in 1993 and 2005, among whom 4,619 had a cancer diagnosis inbetween (including n = 2,699 breast cancers). We evaluated the potential impact of a cancer diagnosis (comparing women with cancer to women with no cancer) on changes in FV consumption using multivariable linear regression models considering cancer site, stage at diagnosis and socioeconomic factors. Compared to women with no cancer, a statistically significant increase in FV consumption (ß=+2.65%, [1.22-4.09]) was observed in women who had cancer, and this association appeared to be driven by breast cancer exclusively. The increase in FV consumption was larger in women who had an advanced stage of breast cancer (stages II-IV) (ß=+7.23%, [3.92-10.5]) than in women with stages 0-I (ß=+2.03%, [-0.20 to 4.26]). Women with no partner and no children were those having the highest increase in FV consumption (ß=+18.71%, [6.51-30.91]). These changes were only observed in specific SE groups. When considering adherence to guidelines, the proportion of women who consumed less than 7.5 portions a day in 1993 and more in 2005 was greater in women with advanced breast cancer. More research is now needed to understand how the inequities we observed impact the long-term health after cancer.

High dietary phosphorus intake is associated with an increased risk of type 2 diabetes in the large prospective E3N cohort study.

Phosphorus is an essential nutrient; the adult recommended daily intake ranges from 550 to 700 mg/day, with a tolerated upper limit of 4000 mg/day. Phosphorus intake has increased in the general population in recent years, and simultaneously an alarming rise of type 2 diabetes incidences has been observed. No study has investigated the relationship between phosphorus intake and the risk of type 2 diabetes. To evaluate the association between phosphorus intake and incidence of type 2 diabetes. Among 71,270 women from the French E3N-EPIC cohort, 1845 cases of incident type 2 diabetes were validated during follow-up (1993-2011). Adjusted Cox proportional hazards regression models were used to calculate hazard ratios and 95% confidence intervals (95% CI) for the associations between phosphorus intake and type 2 diabetes risk, adjusted on potential confounders. The overall mean (±SD) phosphorus intake was 1477 mg/day (±391 mg/day). High phosphorus intake was associated with risk of type 2 diabetes. In multivariate models, compared with women in the 1st quartile of phosphorus intake (<1203 mg/day), those included in the 2nd (1203-1434.0 mg/day), 3rd (1434-1700 mg/day), and 4th (>1700 mg/day) were at a higher risk of type 2 diabetes, with a hazards ratios (95% CI) of 1.18 (1.00-1.38), 1.41 (1.20-1.66) and 1.54 (1.25-1.90), respectively. Our results may have important public health implications for dietary recommendations in the prevention of type 2 diabetes. More studies are warranted to better understand the biological mechanisms underlying this positive association.

Determinants of folate and vitamin B12 plasma levels in the French E3N-EPIC cohort.

PURPOSE: Impaired B vitamin status has been identified as a risk factor for major chronic diseases. This study aims at examining the determinants of plasma folate and vitamin B12 concentrations, considering lifestyle factors and MTHFR polymorphisms. METHODS: A total of 988 women aged 40-65 years from the French E3N cohort were investigated. Intakes of folate and vitamin B12 were assessed using food frequency questionnaires, and plasma concentrations were measured by microbiological assay. Dietary scores were computed to summarize folate and vitamin B12 dietary sources. MTHFR-C677T and MTHFR-A1298C were determined by Kaspar assay. Pearson's partial correlation coefficients and multivariable linear regression models were used to assess correlations between main determinants and plasma folate and vitamin B12 levels. RESULTS: The partial correlation coefficient between dietary intakes and plasma folate was 0.19 (p value <0.001) and 0.08 (p value = 0.008) for vitamin B12. Dietary scores were the main determinant of B vitamin plasma concentrations with a percent change per unit increase of 12.64% (p value <0.001) for folate and 7.6% (p value <0.001) for vitamin B12. Homozygous (T/T) or heterozygous (C/T) women for MTHFR-C677T had lower plasma folate concentrations [C/T: -6.48% (p value = 0.038) and T/T: -15.89% (p value <0.001)] compared to women carrying the C/C genotype. Other determinants of B vitamin plasma concentration include: smoking status for folate, and age and hormone replacement therapy for vitamin B12. CONCLUSIONS: We confirmed previous findings on the role of diet as main determinant of folate and vitamin B12 plasma concentrations. However, the impact of genetic polymorphisms and lifestyle factors on plasma B vitamin concentrations should not be neglected.

Patterns of Ultraviolet Radiation Exposure and Skin Cancer Risk: the E3N-SunExp Study.

BACKGROUND: While ultraviolet (UV) radiation exposure is a recognized risk factor for skin cancer, associations are complex and few studies have allowed a direct comparison of exposure profiles associated with cutaneous melanoma, basal-cell carcinoma (BCC), and squamous-cell carcinoma (SCC) within a single population. METHODS: We examined associations between UV exposures and skin cancer risk in a nested case-control study within E3N, a prospective cohort of 98,995 French women born in 1925-1950. In 2008, a lifetime UV exposure questionnaire was sent to all reported skin cancer cases and three controls per case, which were matched on age, county of birth, and education. Analyses were performed using conditional logistic regression and included 366 melanoma cases, 1,027 BCC cases, 165 SCC cases, and 3,647 controls. RESULTS: A history of severe sunburns <25 years was associated with increased risks of all skin cancers (melanoma: OR 2.7; BCC: OR 1.7; SCC: OR 2.0 for ≥6 sunburns vs. none), while sunburns ≥25 years were associated with BCC and SCC only. While high-sun protection factor sunscreen use before age 25 was associated with lower BCC risk (Ptrend = 0.02), use since age 25 and reapplication of sunscreen were associated with higher risks of all three types of skin cancer. There were positive linear associations between total UV score and risks of BCC (Ptrend = 0.01) and SCC (Ptrend = 0.09), but not melanoma. While recreational UV score was strongly associated with BCC, total and residential UV scores were more strongly associated with SCC. CONCLUSIONS: Melanoma, BCC, and SCC are associated with different sun exposure profiles in women.

Life course evolution of body size and breast cancer survival in the E3N cohort.

Although adult obesity has been associated with poor breast cancer survival, data on adiposity at different periods in life and its lifelong evolution are scarce. Our aims were to assess the associations between breast cancer survival and body size during childhood, puberty and early adulthood and body size trajectories from childhood to adulthood. Self-assessed body size at age 8, at puberty, at age 20-25 and at age 35-40 and trajectories of body size of 4,662 breast cancer survivors from the prospective E3N cohort were studied in relation to risk of death from any cause, death from breast cancer and second invasive cancer event using multivariate Cox regression models. Four trajectories of body size were identified (T1 "moderate increase," T2 "stable/low increase," T3 "increase at puberty" and T4 "constantly high"). Compared with stable body size, an increase in body size during adult life was associated with an increased risk of death from any cause (HR T1 vs. T2 = 1.27; 95% CI = 1.01-1.60) and an increased risk of second invasive cancer event (HR T1 vs. T2 = 1.25; 95% CI = 1.06-1.47). Silhouettes at various ages were not associated with survival. Our results suggest that the evolution of body size from childhood to adulthood has a long-term influence on breast cancer survival. Although these results need to be confirmed, this work sheds light on the need to combine lifelong approaches to current BMI to better identify breast cancer survivors who are at higher risk of recurrence or second primary cancer, or of death.

Socio-economic factors associated with an increase in fruit and vegetable consumption: a 12-year study in women from the E3N-EPIC study.

OBJECTIVE: To identify individual and contextual socio-economic factors associated with an increase in fruit and vegetable (F&V) consumption over a 12-year period and evaluate if some socio-economic factors were differentially associated with the change in consumption of some types of F&V. DESIGN: Associations between increased F&V consumption and socio-economic factors were studied with multivariate logistic regression. SETTING: E3N, a French prospective cohort study of 98 995 women. SUBJECTS: E3N participants (n 58 193) with information on diet in 1993 and 2005, and numerous individual and contextual socio-economic factors available. RESULTS: Associations between some individual socio-economic factors and changes in F&V consumption were observed. For instance, women who lived in a large household (>3 children v. no child) had higher probability of increasing their vegetable consumption (OR=1·33; 95 % CI 1·24, 1·42). This association was driven by higher consumption of courgette and raw cucumber. Living with a partner was associated with higher odds of increasing consumption of fruits (OR=1·07; 95 % CI 1·02, 1·13) such as pear, peach and grape. CONCLUSIONS: Certain individual socio-economic factors, but none of the contextual socio-economic factors examined, were associated with an increase in F&V consumption. Factors associated with an increase in total F&V consumption were not necessarily associated with an increase in fruit or vegetable consumption separately, or with an increase in each subtype of fruit or vegetable. Magnitudes of the different associations observed also differed when F&V were considered together, separately or by subtype. Increases in F&V consumption were mostly observed in women with high socio-economic position. To develop effective nutritional interventions and policies that take the socio-economic environment of individuals into account, we recommend future research to further focus on (i) pathways through which population characteristics might influence changes in F&V consumption and (ii) existing interactions between individual and contextual socio-economic factors.

Ability of ecological deprivation indices to measure social inequalities in a French cohort.

BACKGROUND: Despite the increasing interest in place effect to explain health inequalities, there is currently no consensus on which kind of area-based socioeconomic measures researchers should use to assess neighborhood socioeconomic position (SEP). The study aimed to evaluate the reliability of different area-based deprivation indices (DIs) in capturing socioeconomic residential conditions of French elderly women cohort. METHODS: We assessed area-based SEP using 3 DIs: Townsend Index, French European Deprivation Index (FEDI) and French Deprivation index (FDep), among women from E3N (Etude épidémiologique auprès des femmes de la Mutuelle Générale de l'Education Nationale). DIs were derived from the 2009 French census at IRIS level (smallest geographical units in France). Educational level was used to evaluate individual-SEP. To evaluate external validity of the 3 DIs, associations between two well-established socially patterned outcomes among French elderly women (smoking and overweight) and SEP, were compared. Odd ratios were computed with generalized estimating equations to control for clustering effects from participants within the same IRIS. RESULTS: The analysis was performed among 63,888 women (aged 64, 47% ever smokers and 30% overweight). Substantial agreement was observed between the two French DIs (Kappa coefficient = 0.61) and between Townsend and FEDI (0.74) and fair agreement between Townsend and FDep (0.21). As expected among French elderly women, those with lower educational level were significantly less prone to be ever smoker (Low vs. High; OR [95% CI] = 0.43 [0.40-0.46]) and more prone to being overweight (1.89 [1.77-2.01]) than women higher educated. FDep showed expected associations at area-level for both smoking (most deprived vs. least deprived quintile; 0.77 [0.73-0.81]) and overweight (1.52 [1.44-1.62]). For FEDI opposite associations with smoking (1.13 [1.07-1.19]) and expected association with overweight (1.20 [1.13-1.28]) were observed. Townsend showed opposite associations to those expected for both smoking and overweight (1.51 [1.43-1.59]; 0.93 [0.88-0.99], respectively). CONCLUSION: FDep seemed reliable to capture socioeconomic residential conditions of the E3N women, more educated in average than general French population. Results varied strongly according to the DI with unexpected results for some of them, which suggested the importance to test external validity before studying social disparities in health in specific populations.

Validity and reproducibility of a short food frequency questionnaire among patients with chronic kidney disease.

BACKGROUND: A balanced diet is essential to slowing the progression of chronic kidney disease (CKD) and managing the symptoms. Currently, no tool is available to easily and quickly assess energy and macronutrient intake in patients with non end-stage CKD. We aimed to develop and evaluate the validity and reproducibility of a new short 49-item food frequency questionnaire (SFFQ) adapted to patients with CKD. METHODS: The CKD-REIN study is a prospective cohort that enrolled 3033 patients with moderate or advanced CKD from a national sample of nephrology clinics. A sub-sample of 201 patients completed the SFFQ twice, at a one-year interval and were included in the reproducibility study. During this interval, 127 patients also completed six 24-h recalls and were included in the validity study. Main nutrient and dietary intakes were computed. Validity was evaluated by calculating crude, energy-adjusted and de-attenuated correlation coefficients (CC) between FFQ and the mean of the 24-h recall results. Bland-Altman plots were performed and cross-classification into quintiles of consumption of each nutrient and food group was computed. Reproducibility between the two SFFQs was evaluated by intraclass CC (ICC). RESULTS: Regarding validity, CC ranged from 0.05 to 0.79 (unadjusted CC, median: 0.40) and 0.10 to 0.59 (de-attenuated CC, median: 0.35) for food group and nutrient intakes, respectively. Five of the most important nutrients of interest in CKD, i.e. protein, calcium, phosphorus, potassium, and sodium had de-attenuated CC of 0.46, 0.43, 0.39, 0.32, and 0.12, respectively. The median of classification into the same or adjacent quintiles was 68% and 65% for food and nutrient intakes, respectively, and ranged from 63% to 69% for the five nutrients mentioned before. Bland-Altman plots showed good agreement across the range of intakes. ICC ranged from 0.18 to 0.66 (median: 0.46). CONCLUSIONS: The CKD-REIN SFFQ showed acceptable validity and reproducibility in a sample of patients with CKD, notably for CKD nutrients of importance. It can now be used in large-scale epidemiological studies to easily assess the relations between diet and CKD outcomes as well as in clinical routine. It may also serve as a basis for the development of FFQs in international CKD cohort networks.

Educational level and family structure influence the dietary changes after the diagnosis of type 2 diabetes: evidence from the E3N study.

Type 2 diabetes (T2D) has no cure but can be controlled by medication, diet, and lifestyle changes. It has been suggested that diabetes dietary self-management is more difficult for people with socioeconomic difficulties. The objective of our study was to test the hypothesis that socioeconomic factors impact the change of diet after T2D diagnosis. The 57 304 French women included in the present study answered food frequency questionnaires in 1993 and 2005 and questionnaires on socioeconomic factors, and were free from T2D in 1993. Between 1993 and 2005, 1249 women developed T2D. Linear regression models evaluated whether having T2D diagnosed had an impact on energy and nutrient intakes and whether socioeconomic factors were implicated. T2D was associated with a reduction of energy (ß=-312.54 kJ/d, P<.001), carbohydrate (ß=-9.29 g/d, P<.001), lipid (ß=-2.01g/d, P<.001), and alcohol (ß=-2.74g/d, P=.002) intakes, whereas there was no association with changes in protein or fiber intakes. The main socioeconomic factors that had an impact on dietary change were the level of education of T2D patients and whether or not they had a family (having a partner and/or children). The present study provides evidence that socioeconomic factors impact the way people with T2D change their dietary habits after diagnosis. Furthermore, the family plays a crucial role in dietary self-management, probably encouraging T2D patients to follow dietary recommendations.

Use of Bisphosphonates and Risk of Breast Cancer in a French Cohort of Postmenopausal Women.

Purpose To assess whether bisphosphonate (BP) use is associated with decreased breast cancer incidence in a cohort of postmenopausal women. Methods The study population included 64,438 postmenopausal women participating in the French E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) prospective cohort, with data self-reported in biennial questionnaires matched with data from a drug reimbursement database. Exposure to BPs and the use of other osteoporosis treatments during follow-up were determined using reimbursement data. Other covariates (breast cancer risk factors, clinical risk factors for osteoporotic fractures, and bone mineral density surveillance) originated from the questionnaires. Hazard ratios (HRs) of breast cancer were estimated using Cox proportional hazards models, considering exposure as a time-varying variable. Results Over an average of 7.2 years of follow-up (2004 to 2011), 2,407 first primary breast cancer cases were identified. The HR of breast cancer associated with exposure to BPs was 0.98 (95% CI, 0.85 to 1.12). We found no effect modification by age, body mass index, time since menopause, use of hormone replacement therapy, use of calcium supplements, or use of vitamin D supplements. There was no heterogeneity across BP molecules and no trend according to cumulative dose, duration of use, or time since last use. We observed a decrease in breast cancer risk restricted to the year after treatment initiation (HR, 0.56; 95% CI, 0.36 to 0.87), which was likely explained by healthy screenee bias. Finally, we did not find any variation in HRs across breast carcinomas defined by their estrogen receptor or invasive or in situ status. Conclusion In our observational cohort of postmenopausal women observed from 2004 to 2011, BP use, likely prescribed for the management of osteoporosis, was not associated with decreased breast cancer incidence.

Tumor characteristics and family history in relation to mammographic density and breast cancer: The French E3N cohort.

BACKGROUND: Mammographic density is a known heritable risk factor for breast cancer, but reports how tumor characteristics and family history may modify this association are inconsistent. METHODS: Dense and total breast areas were assessed using Cumulus™ from pre-diagnostic mammograms for 820 invasive breast cancer cases and 820 matched controls nested within the French E3N cohort study. To allow comparisons across models, percent mammographic density (PMD) was standardized to the distribution of the controls. Odds ratios (OR) and 95% confidence intervals (CI) of breast cancer risk for mammographic density were estimated by conditional logistic regression while adjusting for age and body mass index. Heterogeneity according to tumor characteristic and family history was assessed using stratified analyses. RESULTS: Overall, the OR per 1 SD for PMD was 1.50 (95% CI, 1.33-1.69). No evidence for significant heterogeneity by tumor size, lymph node status, grade, and hormone receptor status (estrogen, progesterone, and HER2) was detected. However, the association of PMD was stronger for women reporting a family history of breast cancer (OR1SD=2.25; 95% CI, 1.67-3.04) than in women reporting none (OR1SD=1.41; 95% CI, 1.24-1.60; pheterogeneity=0.002). Similarly, effect modification by FHBC was observed using categories of PMD (pheterogeneity=0.02) with respective ORs of 15.16 (95% CI, 4.23-54.28) vs. 3.14 (95% CI, 1.89-5.22) for ≥50% vs. <10% PMD. CONCLUSIONS: The stronger association between mammographic density and breast cancer risk with a family history supports the hypothesis of shared genetic factors responsible for familial aggregation of breast cancer and the heritable component of mammographic density.

Nevi, Ambient Ultraviolet Radiation, and Thyroid Cancer Risk: A French Prospective Study.

BACKGROUND: Incidence rates have increased considerably worldwide for both differentiated thyroid cancer and cutaneous melanoma, and two-way associations between these neoplasms have been described. Whether melanoma risk factors are associated with thyroid cancer risk remains unknown. METHODS: Using Cox regression modeling, we prospectively analyzed the relationship between self-reported pigmentary traits, baseline residential ultraviolet (UV) exposure, and thyroid cancer risk in 86,960 women from the E3N cohort, followed-up over 1990-2008 through biennial questionnaires. We assessed associations of pigmentary traits and UV exposure with personal history of benign thyroid diseases using logistic regression modeling. All statistical tests were two sided. RESULTS: In models adjusted for age and thyroid cancer risk factors, number of nevi was positively associated with thyroid cancer risk ("very many" vs. "none": hazards ratio [HR] = 1.7, 95% confidence interval [CI] = 1.0, 2.8; Ptrend = 0.01), independently of residential UV exposure or iodine intake. Risk was inversely associated with latitude and positively associated with mean daily UV level at baseline (HRs for the fourth vs. first quartile of latitude and spring/summer UVB level = 0.7, 95% CI = 0.5, 0.9; Ptrend = 0.03, and HR = 1.9, 95% CI = 1.4, 2.7; Ptrend = 0.02, respectively); associations were restricted to women with dietary iodine below the median intake. Number of nevi and UV level were also associated with personal histories of dysthyroidism and of goiter/nodules, although more weakly so. CONCLUSIONS: Our results suggest that number of nevi and residential UV exposure are associated with the risks of thyroid cancer and benign conditions. They point to novel pathways in thyroid cancer or melanoma etiologies and warrant replication.

Time-Dependent Associations Between Body Composition, Physical Activity, and Current Asthma in Women: A Marginal Structural Modeling Analysis.

The role of obesity in adult asthma is well-known and has been partly attributed to a confounding role of physical inactivity. However, the interrelationships between obesity, physical activity, and asthma have been incompletely addressed, probably because their time-dependent and bidirectional nature represents a methodologically challenging research question. We aimed to estimate the independent causal effects of body mass index (BMI; weight (kg)/height (m)2) and physical activity on current asthma using marginal structural models (MSMs). MSMs were applied to 15,353 adult women from a 2011 case-control study of asthma (Asthma-E3N) nested within the French E3N study (Etude Epidémiologique auprès de Femmes de la Mutuelle Générale de l'Education Nationale). Three time periods (1997-2000-2002, 2000-2002-2005, and 2002-2005-2011) were defined, where exposures (BMI and physical activity) were measured at time t, outcome (current asthma) was measured at time t + 1, and covariates were measured at time t - 1 or at baseline. A strong significant and positive dose-response relationship between BMI and current asthma was observed (odds ratios were 0.90 (95% confidence interval (CI): 0.79, 1.03), 1.29 (95% CI: 1.17, 1.42), and 1.87 (95% CI: 1.60, 2.18) for the BMI groups <20.0, 25.0-29.9, and ≥30.0, respectively, versus the normal-weight group (BMI 20.0-24.9)). We found no association between physical activity and current asthma. Our results suggest an independent causal deleterious effect of overweight and obesity on current asthma, whereas no independent causal effect of physical activity was found.

Socio-economic factors associated with a healthy diet: results from the E3N study.

OBJECTIVE: To identify individual and contextual socio-economic factors associated with a healthy diet. DESIGN: Dietary data from a large cohort study were used to derive two mutually exclusive dietary patterns through a latent class analysis. Associations between dietary patterns and socio-economic factors were studied with logistic regression. SETTING: E3N, a French prospective cohort study composed of women recruited from a national health insurance plan covering people working in the national education system. SUBJECTS: E3N participants (n 73 031) with dietary and socio-economic data available. RESULTS: The 'Healthy' pattern was characterized by a large consumption of fruits and vegetables and the 'Less Healthy' pattern by a large consumption of pizza and processed meat. When all socio-economic factors were analysed together, all of the individual factors considered were associated with a healthy diet (e.g. women with three or more children were less likely to follow a healthy diet v. women with no children, OR (95 % CI): 0·70 (0·66, 0·75)) while the contextual factors associated with a healthy diet included the size of the agglomeration of residence and the area of birth and residence (e.g. women living in the West of France were less likely to follow a healthy diet v. those living in the South of France: 0·78 (0·72, 0·83)). CONCLUSIONS: We demonstrated that individual and contextual factors are both associated with diet. Rather than focusing only on individual factors, we recommend future studies or public health and nutritional strategies on diet to consider both types of factors.

DNA methylome analysis identifies accelerated epigenetic ageing associated with postmenopausal breast cancer susceptibility.

AIM OF THE STUDY: A vast majority of human malignancies are associated with ageing, and age is a strong predictor of cancer risk. Recently, DNA methylation-based marker of ageing, known as 'epigenetic clock', has been linked with cancer risk factors. This study aimed to evaluate whether the epigenetic clock is associated with breast cancer risk susceptibility and to identify potential epigenetics-based biomarkers for risk stratification. METHODS: Here, we profiled DNA methylation changes in a nested case-control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (n = 960) using the Illumina HumanMethylation 450K BeadChip arrays and used the Horvath age estimation method to calculate epigenetic age for these samples. Intrinsic epigenetic age acceleration (IEAA) was estimated as the residuals by regressing epigenetic age on chronological age. RESULTS: We observed an association between IEAA and breast cancer risk (OR, 1.04; 95% CI, 1.007-1.076, P = 0.016). One unit increase in IEAA was associated with a 4% increased odds of developing breast cancer (OR, 1.04; 95% CI, 1.007-1.076). Stratified analysis based on menopausal status revealed that IEAA was associated with development of postmenopausal breast cancers (OR, 1.07; 95% CI, 1.020-1.11, P = 0.003). In addition, methylome-wide analyses revealed that a higher mean DNA methylation at cytosine-phosphate-guanine (CpG) islands was associated with increased risk of breast cancer development (OR per 1 SD = 1.20; 95 %CI: 1.03-1.40, P = 0.02) whereas mean methylation levels at non-island CpGs were indistinguishable between cancer cases and controls. CONCLUSION: Epigenetic age acceleration and CpG island methylation have a weak, but statistically significant, association with breast cancer susceptibility.

Accuracy of two geocoding methods for geographic information system-based exposure assessment in epidemiological studies.

BACKGROUND: Environmental exposure assessment based on Geographic Information Systems (GIS) and study participants' residential proximity to environmental exposure sources relies on the positional accuracy of subjects' residences to avoid misclassification bias. Our study compared the positional accuracy of two automatic geocoding methods to a manual reference method. METHODS: We geocoded 4,247 address records representing the residential history (1990-2008) of 1,685 women from the French national E3N cohort living in the Rhône-Alpes region. We compared two automatic geocoding methods, a free-online geocoding service (method A) and an in-house geocoder (method B), to a reference layer created by manually relocating addresses from method A (method R). For each automatic geocoding method, positional accuracy levels were compared according to the urban/rural status of addresses and time-periods (1990-2000, 2001-2008), using Chi Square tests. Kappa statistics were performed to assess agreement of positional accuracy of both methods A and B with the reference method, overall, by time-periods and by urban/rural status of addresses. RESULTS: Respectively 81.4% and 84.4% of addresses were geocoded to the exact address (65.1% and 61.4%) or to the street segment (16.3% and 23.0%) with methods A and B. In the reference layer, geocoding accuracy was higher in urban areas compared to rural areas (74.4% vs. 10.5% addresses geocoded to the address or interpolated address level, p < 0.0001); no difference was observed according to the period of residence. Compared to the reference method, median positional errors were 0.0 m (IQR = 0.0-37.2 m) and 26.5 m (8.0-134.8 m), with positional errors <100 m for 82.5% and 71.3% of addresses, for method A and method B respectively. Positional agreement of method A and method B with method R was 'substantial' for both methods, with kappa coefficients of 0.60 and 0.61 for methods A and B, respectively. CONCLUSION: Our study demonstrates the feasibility of geocoding residential addresses in epidemiological studies not initially recorded for environmental exposure assessment, for both recent addresses and residence locations more than 20 years ago. Accuracy of the two automatic geocoding methods was comparable. The in-house method (B) allowed a better control of the geocoding process and was less time consuming.