Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Diet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: This analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons. RESULTS: Consumption of n-6 γ-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintileQ5-Q1=0.77, 95% CI = 0.64; 0.92, ptrend=0.01, q-value = 0.15). This association was mainly driven by γ-linolenic acid derived from plant sources (HRper unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HRper unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 α-linolenic acid from vegetable sources and endometrial cancer risk (HRper unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk. CONCLUSION: Our results suggest that higher consumption of γ-linolenic acid and α-linoleic acid from plant sources may be associated with lower risk of endometrial cancer.

Milk intake and incident stroke and CHD in populations of European descent: a Mendelian randomisation study.

Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (ß = 13·7 g/d; 95 % CI 8·4, 19·1) and EPIC-NL (36·8 g/d; 95 % CI 20·0, 53·5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1·05; 95 % CI 0·94, 1·16) or CHD (1·02; 95 % CI 0·96, 1·08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1·02; 95 % CI 0·99, 1·05) or CHD (OR 0·99; 95 % CI 0·95, 1·03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.

Dietary intake of advanced glycation end products (AGEs) and changes in body weight in European adults.

PURPOSE: Advanced glycation end products (AGEs) can be formed in foods by the reaction of reducing sugars with proteins, and have been shown to induce insulin resistance and obesity in experimental studies. We examined the association between dietary AGEs intake and changes in body weight in adults over an average of 5 years of follow-up. METHODS: A total of 255,170 participants aged 25-70 years were recruited in ten European countries (1992-2000) in the PANACEA study (Physical Activity, Nutrition, Alcohol, Cessation of smoking, Eating out of home in relation to Anthropometry), a sub-cohort of the EPIC (European Prospective Investigation into Cancer and Nutrition). Body weight was measured at recruitment and self-reported between 2 and 11 years later depending on the study center. A reference database for AGEs was used containing UPLC-MS/MS-measured Nε-(carboxymethyl)-lysine (CML), Nε-(1-carboxyethyl)-lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) in 200 common European foods. This reference database was matched to foods and decomposed recipes obtained from country-specific validated dietary questionnaires in EPIC and intake levels of CEL, CML, and MG-H1 were estimated. Associations between dietary AGEs intake and body weight change were estimated separately for each of the three AGEs using multilevel mixed linear regression models with center as random effect and dietary AGEs intake and relevant confounders as fixed effects. RESULTS: A one-SD increment in CEL intake was associated with 0.111 kg (95% CI 0.087-0.135) additional weight gain over 5 years. The corresponding additional weight gain for CML and MG-H1 was 0.065 kg (0.041-0.089) and 0.034 kg (0.012, 0.057), respectively. The top six food groups contributing to AGEs intake, with varying proportions across the AGEs, were cereals/cereal products, meat/processed meat, cakes/biscuits, dairy, sugar and confectionary, and fish/shellfish. CONCLUSION: In this study of European adults, higher intakes of AGEs were associated with marginally greater weight gain over an average of 5 years of follow-up.

Pattern of mortality after menopausal hormone therapy: long-term follow up in a population-based cohort.

OBJECTIVE: To investigate long-term pattern of mortality in menopausal women according to different modalities of hormone therapy. DESIGN: Population-based prospective cohort study. SETTING: Denmark 1993-2013. POPULATION: A total of 29 243 women aged 50-64 years at entry into the Diet, Cancer and Health Cohort, enrolled 1993-97 and followed through 31 December 2013. METHODS: Cox' proportional hazards models for increasingly longer periods of follow-up time were used to estimate mortality pattern according to baseline hormone use adjusted for relevant potential confounders. MAIN OUTCOME(S): All-cause and cause-specific mortality. Outcome information was obtained from the Danish Register of Causes of Death (linkage 99.6%). RESULTS: A total of 4098 women died during a median follow up of 17.6 years. After adjustment for relevant lifestyle risk factors, hormone use had no impact on all-cause mortality, regardless of modality. Among baseline users, lower cardiovascluar disease mortality was only evident after 5 years [hazard ratio (HR) 0.54; 95% CI 0.32-0.92], but dissipated with additional follow up. Conversely, lower colorectal cancer mortality (HR 0.64; 95% CI 0.46-0.89) and higher breast cancer mortality (HR 1.34; 95% CI 1.05-1.72) only became evident after 15 years of follow up. There were no significant associations for mortality from other types of cancer or from stroke. CONCLUSIONS: In this long-term follow-up study, taking hormones during menopause was not associated with overall mortality among middle-aged women. Investigating cause-specific mortality revealed significant, albeit weak, differential associations according to both causes of death and over time, underlining the importance of carefully considering individual risks and duration of treatment when making decisions on hormone therapy. TWEETABLE ABSTRACT: Long-term follow-up study confirms no association between menopausal hormone therapy and overall mortality.

Alcohol consumption and risk of urothelial cell bladder cancer in the European prospective investigation into cancer and nutrition cohort.

Findings on the association between alcohol consumption and bladder cancer are inconsistent. We investigated that association in the European Prospective Investigation into Cancer and Nutrition cohort. We included 476,160 individuals mostly aged 35-70 years, enrolled in ten countries and followed for 13.9 years on average. Hazard ratios (HR) for developing urothelial cell carcinoma (UCC; 1,802 incident cases) were calculated using Cox proportional hazards models. Alcohol consumption at baseline and over the life course was analyzed, as well as different types of beverages (beer, wine, spirits). Baseline alcohol intake was associated with a statistically nonsignificant increased risk of UCC (HR 1.03; 95% confidence interval (CI) 1.00-1.06 for each additional 12 g/day). HR in smokers was 1.04 (95% CI 1.01-1.07). Men reporting high baseline intakes of alcohol (>96 g/day) had an increased risk of UCC (HR 1.57; 95% CI 1.03-2.40) compared to those reporting moderate intakes (<6 g/day), but no dose-response relationship emerged. In men, an increased risk of aggressive forms of UCC was observed even at lower doses (>6 to 24 g/day). Average lifelong alcohol intake was not associated with the risk of UCC, however intakes of spirits > 24 g/day were associated with an increased risk of UCC in men (1.38; 95% CI 1.01-1.91) and smokers (1.39; 95% CI 1.01-1.92), compared to moderate intakes. We found no association between alcohol and UCC in women and never smokers. In conclusion, we observed some associations between alcohol and UCC in men and in smokers, possibly because of residual confounding by tobacco smoking.

Validity of Peripheral Arterial Disease Diagnoses in the Danish National Patient Registry.

OBJECTIVES/BACKGROUND: The objective was to validate the diagnoses of peripheral arterial disease (PAD) in the legs, obtained from national registers in Denmark. METHODS: In total, 1435 registered cases of PAD were identified in the Danish National Patient Registry among 57,053 middle aged participants from the Danish Diet, Cancer and Health cohort study. Validation was performed by reviewing all medical records using pre-specified criteria for a diagnosis of PAD. RESULTS: The overall positive predictive value (PPV) of PAD diagnoses was 69.4% [95% confidence interval (CI) 67.0-71.7]. The PPV of diagnoses given in departments of vascular surgery was significantly higher than diagnoses given in other departments: 71.9% (95% CI 69.2-74.4) versus 58.3% (95% CI 52.2-64.2), respectively. In a sub-study, 141 potential cases of PAD also registered in the Danish National Vascular Registry were evaluated, and a PPV of 87.9% (95% CI 81.4-92.4) was found for these diagnoses. CONCLUSION: More than 30% of the diagnoses of PAD notified in the Danish National Patient Registry were not valid, stressing the importance of validation when using register information for research purposes. In contrast, diagnoses obtained from the Danish National Vascular Registry had a high validity ready for use without further validation.

Tracking of body mass index from 7 to 69 years of age.

BACKGROUND: Heavy children have an increased risk of being overweight young adults. Whether this risk remains in late adulthood is not well-understood. We investigated body mass index (BMI; kg m(-2)) tracking from childhood to late adulthood. METHODS: From the Copenhagen School Health Records Register, 72 959 men and 25 252 women born between 1930 and 1989 with BMI values at 7 and/or 13 years and as adults were included. Using a meta-regression approach, age- and sex-specific partial correlation analyses and logistic regressions were performed. RESULTS: Correlations between BMI at 7 years and young adult ages (18-19 years) were r=0.55 for men and r=0.55 for women. At late ages (60-69 years) these were r=0.28 for men and r=0.26 for women. The correlations did not differ by birth years. Compared with normal-weight 7-year-olds, overweight children had a higher odds of overweight at 18-19 years; odds ratio (OR)=14.02 (95% confidence interval (CI): 12.14-16.19) for men and 10.46 (95% CI: 4.82-22.70) for women. At ages 60-69 years ORs were 5.46 (95% CI: 0.95-31.36) for men and 1.61 (95% CI: 0.83-3.15) for women. Correlations and ORs were stronger at age 13 years than age 7 years as expected, but the overall patterns were similar. CONCLUSIONS: BMI tracking was weaker at late adult ages than at young adult ages. Although BMI tracks across the life course, childhood BMI is relatively poor at identifying later adult overweight or obesity at ages when chronic diseases generally emerge.

Healthy lifestyle index and risk of gastric adenocarcinoma in the EPIC cohort study.

Several modifiable lifestyle factors, including smoking, alcohol, certain dietary factors and weight are independently associated with gastric cancer (GC); however, their combined impact on GC risk is unknown. We constructed a healthy lifestyle index to investigate the joint influence of these behaviors on GC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The analysis included 461,550 participants (662 first incident GC cases) with a mean follow-up of 11.4 years. A healthy lifestyle index was constructed, assigning 1 point for each healthy behavior related to smoking status, alcohol consumption and diet quality (represented by the Mediterranean diet) for assessing overall GC and also body mass index for cardia GC and 0 points otherwise. Risk of GC was calculated using Cox proportional hazards regression models while adjusting for relevant confounders. The highest versus lowest score in the healthy lifestyle index was associated with a significant lower risk of GC, by 51% overall (HR 0.49 95% CI 0.35, 0.70), by 77% for cardia GC (HR 0.23 95% CI 0.08, 0.68) and by 47% for noncardia GC (HR 0.53 (95% CI 0.32, 0.87), p-trends<0.001. Population attributable risk calculations showed that 18.8% of all GC and 62.4% of cardia GC cases could have been prevented if participants in this population had followed the healthy lifestyle behaviors of this index. Adopting several healthy lifestyle behaviors including not smoking, limiting alcohol consumption, eating a healthy diet and maintaining a normal weight is associated with a large decreased risk of GC.

Fruit and vegetable consumption in relation to hepatocellular carcinoma in a multi-centre, European cohort study.

BACKGROUND: Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case-control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations. METHODS: In 486,799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d(-1) increments of vegetable/fruit intakes. RESULTS: Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d(-1) increment): 0.83; 95% CI: 0.71-0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d(-1) increment): 1.01; 95% CI: 0.92-1.11. CONCLUSIONS: Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease.

Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort.

BACKGROUND: Prospective studies on insulin-like growth factor I (IGF-I) and epithelial ovarian cancer (EOC) risk are inconclusive. Data suggest risk associations vary by tumour characteristics. METHODS: We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate IGF-I concentrations and EOC risk by tumour characteristics (n=565 cases). Multivariable conditional logistic regression models were used to estimate associations. RESULTS: We observed no association between IGF-I and EOC overall or by tumour characteristics. CONCLUSIONS: In the largest prospective study to date was no association between IGF-I and EOC risk. Pre-diagnostic serum IGF-I concentrations may not influence EOC risk.

Diabetes and onset of natural menopause: results from the European Prospective Investigation into Cancer and Nutrition.

STUDY QUESTION: Do women who have diabetes before menopause have their menopause at an earlier age compared with women without diabetes? SUMMARY ANSWER: Although there was no overall association between diabetes and age at menopause, our study suggests that early-onset diabetes may accelerate menopause. WHAT IS KNOWN ALREADY: Today, more women of childbearing age are being diagnosed with diabetes, but little is known about the impact of diabetes on reproductive health. STUDY DESIGN, SIZE, DURATION: We investigated the impact of diabetes on age at natural menopause (ANM) in 258 898 women from the European Prospective Investigation into Cancer and Nutrition (EPIC), enrolled between 1992 and 2000. PARTICIPANTS/MATERIALS, SETTING, METHODS: Determinant and outcome information was obtained through questionnaires. Time-dependent Cox regression analyses were used to estimate the associations of diabetes and age at diabetes diagnosis with ANM, stratified by center and adjusted for age, smoking, reproductive and diabetes risk factors and with age from birth to menopause or censoring as the underlying time scale. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no association between diabetes and ANM was found (hazard ratio (HR) = 0.94; 95% confidence interval (CI) 0.89-1.01). However, women with diabetes before the age of 20 years had an earlier menopause (10-20 years: HR = 1.43; 95% CI 1.02-2.01, <10 years: HR = 1.59; 95% CI 1.03-2.43) compared with non-diabetic women, whereas women with diabetes at age 50 years and older had a later menopause (HR = 0.81; 95% CI 0.70-0.95). None of the other age groups were associated with ANM. LIMITATIONS, REASONS FOR CAUTION: Strengths of the study include the large sample size and the broad set of potential confounders measured. However, results may have been underestimated due to survival bias. We cannot be sure about the sequence of the events in women with a late age at diabetes, as both events then occur in a short period. We could not distinguish between type 1 and type 2 diabetes. WIDER IMPLICATIONS OF THE FINDINGS: Based on the literature, an accelerating effect of early-onset diabetes on ANM might be plausible. A delaying effect of late-onset diabetes on ANM has not been reported before, and is not in agreement with recent studies suggesting the opposite association. STUDY FUNDING/COMPETING INTERESTS: The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ) and Federal Ministry of Education and Research (BMMF) (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skåne and Västerbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Wellcome Trust (UK). None of the authors reported a conflict of interest.

Adherence to the Mediterranean diet and risk of bladder cancer in the EPIC cohort study.

There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers.

Dietary intake of acrylamide and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Three prospective studies have evaluated the association between dietary acrylamide intake and endometrial cancer (EC) risk with inconsistent results. The objective of this study was to evaluate the association between acrylamide intake and EC risk: for overall EC, for type-I EC, and in never smokers and never users of oral contraceptives (OCs). Smoking is a source of acrylamide, and OC use is a protective factor for EC risk. METHODS: Cox regression was used to estimate hazard ratios (HRs) for the association between acrylamide intake and EC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Acrylamide intake was estimated from the EU acrylamide monitoring database, which was matched with EPIC questionnaire-based food consumption data. Acrylamide intake was energy adjusted using the residual method. RESULTS: No associations were observed between acrylamide intake and overall EC (n=1382) or type-I EC risk (n=627). We observed increasing relative risks for type-I EC with increasing acrylamide intake among women who both never smoked and were non-users of OCs (HRQ5vsQ1: 1.97, 95% CI: 1.08-3.62; likelihood ratio test (LRT) P-value: 0.01, n=203). CONCLUSIONS: Dietary intake of acrylamide was not associated with overall or type-I EC risk; however, positive associations with type I were observed in women who were both non-users of OCs and never smokers.

Flavonoid and lignan intake in relation to bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

BACKGROUND: There is growing evidence of the protective role of dietary intake of flavonoids and lignans on cancer, but the association with bladder cancer has not been thoroughly investigated in epidemiological studies. We evaluated the association between dietary intakes of total and subclasses of flavonoids and lignans and risk of bladder cancer and its main morphological type, urothelial cell carcinoma (UCC), within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: A cohort of 477 312 men and women mostly aged 35-70 years, were recruited in 10 European countries. At baseline, dietary flavonoid and lignan intakes were estimated using centre-specific validated questionnaires and a food composition database based on the Phenol-Explorer, the UK Food Standards Agency and the US Department of Agriculture databases. RESULTS: During an average of 11 years of follow-up, 1575 new cases of primary bladder cancer were identified, of which 1425 were UCC (classified into aggressive (n=430) and non-aggressive (n=413) UCC). No association was found between total flavonoid intake and bladder cancer risk. Among flavonoid subclasses, significant inverse associations with bladder cancer risk were found for intakes of flavonol (hazard ratio comparing fifth with first quintile (HRQ5-Q1) 0.74, 95% confidence interval (CI): 0.61-0.91; P-trend=0.009) and lignans (HRQ5-Q1 0.78, 95% CI: 0.62-0.96; P-trend=0.046). Similar results were observed for overall UCC and aggressive UCC, but not for non-aggressive UCC. CONCLUSIONS: Our study suggests an inverse association between the dietary intakes of flavonols and lignans and risk of bladder cancer, particularly aggressive UCC.

Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort.

BACKGROUND: Experimental and epidemiological evidence suggests that prolactin might play a role in the etiology of breast cancer. We analyzed the relationship of prediagnostic circulating prolactin levels with the risk of breast cancer by menopausal status, use of postmenopausal hormone replacement therapy (HRT) at blood donation, and by estrogen and progesterone receptor status of the breast tumors. PATIENTS AND METHODS: Conditional logistic regression was used to analyze the data from a case-control study nested within the prospective European EPIC cohort, including 2250 invasive breast cancer and their matched control subjects. RESULTS: Statistically significant heterogeneity in the association of prolactin levels with breast cancer risk between women who were either pre- or postmenopausal at the time of blood donation was observed (Phet = 0.04). Higher serum levels of prolactin were associated with significant increase in the risk of breast cancer among postmenopausal women [odds ratio (OR)Q4-Q1 = 1.29 (95% confidence interval, CI, 1.05-1.58), Ptrend = 0.09]; however, this increase in risk seemed to be confined to women who used postmenopausal HRT at blood donation [ORQ4-Q1 = 1.45 (95% CI 1.08-1.95), Ptrend = 0.01], whereas no statistically significant association was found for the non-users of HRT [ORQ4-Q1 = 1.11 (95%CI 0.83-1.49), Ptrend = 0.80] (Phet = 0.08). Among premenopausal women, a statistically non-significant inverse association was observed [ORQ4-Q1 = 0.70 (95% CI 0.48-1.03), Ptrend = 0.16]. There was no heterogeneity in the prolactin-breast cancer association by hormone receptor status of the tumor. CONCLUSION: Our study indicates that higher circulating levels of prolactin among the postmenopausal HRT users at baseline may be associated with increased breast cancer risk.

Physical activity, sex steroid, and growth factor concentrations in pre- and post-menopausal women: a cross-sectional study within the EPIC cohort.

PURPOSE: Increased physical activity (PA) is associated with a reduced risk of several cancers. PA may reduce cancer risk by changing endogenous hormones levels, but relatively little research has focused on this topic. The purpose of this study was to elucidate the relation between PA and endogenous hormone concentrations. METHODS: A cross-sectional analysis of 798 pre- and 1,360 post-menopausal women included as controls in case-control studies on endogenous hormones (steroids, progesterone, sex-hormone-binding globulin (SHBG), and growth factors) levels, and cancer risk nested within European Prospective Investigation into Cancer and Nutrition cohort was performed. Multivariate regression analyses were performed to compare geometric mean levels of hormones and SHBG by categories of PA. RESULTS: In pre-menopausal women, active women had 19 % significantly lower concentrations of androstenedione, 14 % lower testosterone, and 20 % lower free testosterone than inactive women, while no differences were observed for estrogens, progesterone, SHBG, and growth factors. In post-menopausal women, active women had 18 % significantly lower estradiol and 20 % lower free estradiol concentrations than inactive women, while no differences were observed for the other hormones and SHBG. More vigorous forms of physical activity were associated with higher insulin-like growth factor-I concentrations. Adjustment for body mass index did not alter the associations. Overall, the percentage of variance in hormone concentrations explained by PA levels was <2 %. CONCLUSIONS: Our results support the hypothesis of an influence, although small in magnitude, of PA on sex hormone levels in blood, independent of body size.

Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.

BACKGROUND: Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies. METHODS: Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided. FINDINGS: We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06-1·35), calculated free oestradiol (1·17, 1·03-1·33), oestrone (1·27, 1·05-1·54), androstenedione (1·30, 1·10-1·55), dehydroepiandrosterone sulphate (1·17, 1·04-1·32), testosterone (1·18, 1·03-1·35), and calculated free testosterone (1·08, 0·97-1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92-1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. INTERPRETATION: Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.

Long-term exposure to traffic-related air pollution and diabetes-associated mortality: a cohort study.

AIMS/HYPOTHESIS: The aim of this study was to investigate whether air pollution from traffic at a residence is associated with mortality related to type 1 or type 2 diabetes. METHODS: We followed up 52,061 participants in the Danish Diet, Cancer and Health cohort for diabetes-related mortality in the nationwide Register of Causes of Death, from baseline in 1993-1997 up to the end of 2009, and traced their residential addresses since 1971 in the Central Population Registry. We used dispersion-modelled concentration of nitrogen dioxide (NO2) since 1971 and amount of traffic at the baseline residence as indicators of traffic-related air pollution and used Cox regression models to estimate mortality-rate ratios (MRRs) with adjustment for potential confounders. RESULTS: Mean levels of NO2 at the residence since 1971 were significantly associated with mortality from diabetes. Exposure above 19.4 µg/m³ (upper quartile) was associated with a MRR of 2.15 (95% CI 1.21, 3.83) when compared with below 13.6 µg/m³ (lower quartile), corresponding to an MRR of 1.31 (95% CI 0.98, 1.76) per 10 µg/m³ NO2 after adjustment for potential confounders. CONCLUSIONS/INTERPRETATION: This study suggests that traffic-related air pollution is associated with mortality from diabetes. If confirmed, reduction in population exposure to traffic-related air pollution could be an additional strategy against the global public health burden of diabetes.

Association between dietary meat consumption and incident type 2 diabetes: the EPIC-InterAct study.

AIMS/HYPOTHESIS: A diet rich in meat has been reported to contribute to the risk of type 2 diabetes. The present study aims to investigate the association between meat consumption and incident type 2 diabetes in the EPIC-InterAct study, a large prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: During 11.7 years of follow-up, 12,403 incident cases of type 2 diabetes were identified among 340,234 adults from eight European countries. A centre-stratified random subsample of 16,835 individuals was selected in order to perform a case-cohort design. Prentice-weighted Cox regression analyses were used to estimate HR and 95% CI for incident diabetes according to meat consumption. RESULTS: Overall, multivariate analyses showed significant positive associations with incident type 2 diabetes for increasing consumption of total meat (50 g increments: HR 1.08; 95% CI 1.05, 1.12), red meat (HR 1.08; 95% CI 1.03, 1.13) and processed meat (HR 1.12; 95% CI 1.05, 1.19), and a borderline positive association with meat iron intake. Effect modifications by sex and class of BMI were observed. In men, the results of the overall analyses were confirmed. In women, the association with total and red meat persisted, although attenuated, while an association with poultry consumption also emerged (HR 1.20; 95% CI 1.07, 1.34). These associations were not evident among obese participants. CONCLUSIONS/INTERPRETATION: This prospective study confirms a positive association between high consumption of total and red meat and incident type 2 diabetes in a large cohort of European adults.

The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the EPIC-InterAct study.

AIMS/HYPOTHESIS: Although a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association. METHODS: A total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created. RESULTS: A family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50 years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history. CONCLUSIONS/INTERPRETATION: Prominent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.