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Background and purpose Previous literature has demonstrated an association between high serum levels of type-II secretory phospholipase A2 (sPLA2) concentration and an increased risk of coronary artery disease. However, such association has not been established in terms of ischemic stroke risk. We aimed to evaluate the association between both sPLA2 concentration and activity as continuous variables with risk of future ischemic stroke. Methods We conducted a nested case-control study using data from the European Prospective Investigation into Cancer - Norfolk study. Cases (n=145) in the current study were participants who developed ischemic stroke during follow-up, with controls (n=290) matched in a 2:1 ratio based on age and sex. Statistical analyses were performed using SPSS (version 25.0, Chicago, Ill) software. Logistic regression was used to determine odds ratios (OR) and corresponding 95% confidence intervals (95% CIs) for ischemic stroke. Results After adjusting for a wide array of cardiovascular confounders, sPLA2 activity was found to be associated with an increased risk of ischemic stroke using both multiple imputations with chained equations and complete case analysis: OR 1.20 (95% CI: 1.01-1.43) and OR 1.23 (95% CI: 1.01 -1.49), respectively. However, sPLA2 concentration was not found to be associated with increased risk of ischemic stroke. Conclusions The activity of sPLA2, but not sPLA2 concentration, is associated with an increased risk of future ischemic stroke. This finding may be significant in risk group stratification, allowing targeted prophylactic treatment, or the development of novel therapeutic agents.

Aims We aimed to determine the sex differences in longitudinal systolic and diastolic blood pressure (SBP and DBP) trajectories in mid-life and delineate the associations between these and mortality (all-cause, cardiovascular, and non-cardiovascular) and incident cardiovascular disease (CVD) in old age. Methods and results Participants were selected from the European Prospective Investigation into Cancer, Norfolk (EPIC-Norfolk) cohort study. Sex-specific trajectories were determined using group-based trajectory models using three clinic BP measurements acquired between 1993 and 2012 (mean exposure ∼12.9 years). Multivariable Cox regressions determined the associations between trajectories and incident outcomes over the follow-up (median follow-up 9.4 years). A total of 2897 men (M) and 3819 women (F) were included. At baseline, women were younger (F-55.5, M-57.1), had a worse cardiometabolic profile and were less likely to receive primary CVD prevention including antihypertensive treatment (F-36.0%, M-42.0%). Over the exposure period, women had lower SBP trajectories while men exhibited more pronounced SBP decreases over this period. Over the follow-up period, women had lower mortality (F-11.9%, M-20.5%) and CVD incidence (F-19.8%, M-29.6%). Compared to optimal SBP (≤120 mmHg) and DBP (≤70 mmHg) trajectories, hypertensive trajectories were associated with increased mortality and incident CVD in both men and women during follow-up at univariable level. These associations were nevertheless not maintained upon extensive confounder adjustment including antihypertensive therapies. Conclusion We report sex disparities in CVD prevention which may relate to worse cardiometabolic profiles and less pronounced longitudinal SBP decreases in women. Effective anti-hypertensivetherapy may offset the adverse outcomes associated with prolonged exposure to high blood pressure.

Purpose To examine associations between retinal vessel morphometry and cardiometabolic risk factors in older British men and women. Design Retinal imaging examination as part of the European Prospective Investigation into Cancer—Norfolk Eye Study. Participants Retinal imaging and clinical assessments were carried out in 7411 participants. Retinal images were analyzed using a fully automated validated computerized system that provides novel measures of vessel morphometry. Methods Associations between cardiometabolic risk factors, chronic disease, and retinal markers were analyzed using multilevel linear regression, adjusted for age, gender, and within-person clustering, to provide percentage differences in tortuosity and absolute differences in width. Main Outcomes Measures Retinal arteriolar and venular tortuosity and width. Results In all, 279 802 arterioles and 285 791 venules from 5947 participants (mean age, 67.6 years; standard deviation [SD], 7.6 years; 57% female) were analyzed. Increased venular tortuosity was associated with higher body mass index (BMI; 2.5%; 95% confidence interval [CI], 1.7%–3.3% per 5 kg/m 2 ), hemoglobin A1c (HbA1c) level (2.2%; 95% CI, 1.0%–3.5% per 1%), and prevalent type 2 diabetes (6.5%; 95% CI, 2.8%–10.4%); wider venules were associated with older age (2.6 μm; 95% CI, 2.2–2.9 μm per decade), higher triglyceride levels (0.6 μm; 95% CI, 0.3–0.9 μm per 1 mmol/l), BMI (0.7 μm; 95% CI, 0.4–1.0 per 5 kg/m 2 ), HbA1c level (0.4 μm; 95% CI, –0.1 to 0.9 per 1%), and being a current smoker (3.0 μm; 95% CI, 1.7–4.3 μm); smoking also was associated with wider arterioles (2.1 μm; 95% CI, 1.3–2.9 μm). Thinner venules were associated with high-density lipoprotein (HDL) (1.4 μm; 95% CI, 0.7–2.2 per 1 mmol/l). Arteriolar tortuosity increased with age (5.4%; 95% CI, 3.8%–7.1% per decade), higher systolic blood pressure (1.2%; 95% CI, 0.5%–1.9% per 10 mmHg), in females (3.8%; 95% CI, 1.4%–6.4%), and in those with prevalent stroke (8.3%; 95% CI, –0.6% to 18%); no association was observed with prevalent myocardial infarction. Narrower arterioles were associated with age (0.8 μm; 95% CI, 0.6–1.0 μm per decade), higher systolic blood pressure (0.5 μm; 95% CI, 0.4–0.6 μm per 10 mmHg), total cholesterol level (0.2 μm; 95% CI, 0.0–0.3 μm per 1 mmol/l), and HDL (1.2 μm; 95% CI, 0.7–1.6 μm per 1 mmol/l). Conclusions Metabolic risk factors showed a graded association with both tortuosity and width of retinal venules, even among people without clinical diabetes, whereas atherosclerotic risk factors correlated more closely with arteriolar width, even excluding those with hypertension and cardiovascular disease. These noninvasive microvasculature measures should be evaluated further as predictors of future cardiometabolic disease.

Background There is broad consensus that regular physical activity yields major health benefits. However, current guidelines on physical activity are mainly aimed at middle-aged adults. It is unclear whether physical activity also translates into cardiovascular health benefits in older adults. Therefore, we aimed to compare the association between different levels of physical activity and the risk of cardiovascular disease (CVD) in elderly to middle-aged individuals. Methods We analysed data from the EPIC Norfolk prospective population study. Cox proportional hazards models were used to analyse the association between physical activity levels and time to CVD events in three age categories (65 years). Interaction between age categories and physical activity levels was assessed. Results Analyses were based on 24,502 study participants aged 39–79 years. A total of 5240 CVD events occurred during 412,954 person-years follow-up (median follow-up was 18.0 years). Among individuals aged over 65 years, hazard ratios for CVD were 0.86 (95% confidence interval (CI) 0.78–0.96), 0.87 (95% CI 0.77–0.99) and 0.88 (95% CI 0.77–1.02) in moderately inactive, moderately active and active people, respectively, compared to inactive people. Among people aged 55–65 and less than 55 years, the associations were directionally similar, but not statistically significant. The interaction term between physical activity levels and age categories was not significant ( P = 0.38). Conclusion The inverse association between physical activity and the risk of CVD was significant in elderly and comparable with middle-aged individuals. In addition, we observed that modest levels of physical activity confer benefits in terms of CVD risk, compared to being completely inactive.

BACKGROUND: Conflicting data exist about the cardiovascular risk of metabolically healthy obese persons. The prognostic value of C-reactive protein (CRP) in this intriguing group is unknown. We assessed the association between CRP levels and the risk of coronary heart disease (CHD) in metabolically healthy persons with abdominal obesity. METHODS AND RESULTS: In the European Prospective Investigation of Cancer-Norfolk prospective cohort, CRP levels and information on metabolic syndrome criteria were available for 7279 participants, of whom 825 (11%) developed CHD during a follow-up period of 10.9±1.8 years. There was a trend toward a higher multivariable-adjusted hazard ratio for CHD in metabolically healthy obese participants with CRP levels >2 mg/L compared with

Background and aims Lipoprotein(a) (Lp[a]) is a strong genetic risk factor for cardiovascular disease (CVD). The American Heart Association has prioritised seven cardiovascular health metrics to reduce the burden of CVD: body mass index, healthy diet, physical activity, smoking status, blood pressure, diabetes and cholesterol levels (together also known as ideal cardiovascular health). Our objective was to determine if individuals with high Lp(a) levels could derive cardiovascular benefits if characterized by ideal cardiovascular health. Methods A total of 14,051 participants of the EPIC-Norfolk study were stratified according to the cardiovascular health score (based on the number of health metrics with an ideal, intermediate or poor status). Of them, 1732 had a CVD event during a mean follow-up of 11.5 years. Cox proportional hazards models were used to describe the association between the cardiovascular health score and Lp(a) level or genotype (as estimated by the rs10455872 variant) with the risk of CVD. Results We observed little or no differences in serum Lp(a) levels across the seven cardiovascular health metric categories. Among participants with high serum Lp(a) levels ≥50 mg/dl), those in the highest (i.e. healthiest) cardiovascular health score category (10–14) had an adjusted hazard ratio for cardiovascular disease of 0.33 (95% CI = 0.17–0.63, p = 0.001) compared to participants in the lowest (i.e. unhealthiest) cardiovascular health score category(0–4). Similar results were obtained when we replaced Lp(a) with rs10455872. Conclusions Although Lp(a) levels are only slightly influenced by cardiovascular health metrics, an ideal cardiovascular health could substantially reduce CVD risk associated with high Lp(a) levels or genotype., Highlights • Elevated lipoprotein(a) levels is one of the strongest genetic risk factors for CVD. • Few health professionals routinely measure Lp(a) presumably because there are no therapeutic agents available to lower Lp(a). • Clinical and lifestyle-related factors do not appear to influence Lp(a) levels at the population level. • Individuals with high Lp(a) levels who control clinical and lifestyle-related risk factors have a lower risk of CVD. • Targeting clinical and lifestyle-related risk factors could reduce cardiovascular risk in individuals with high Lp(a) levels.

Adequate intake of copper and zinc, two essential micronutrients, are important for antioxidant functions. Their imbalance may have implications for development of diseases like colorectal cancer (CRC), where oxidative stress is thought to be etiologically involved. As evidence from prospective epidemiologic studies is lacking, we conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to investigate the association between circulating levels of copper and zinc, and their calculated ratio, with risk of CRC development. Copper and zinc levels were measured by reflection X-ray fluorescence spectrometer in 966 cases and 966 matched controls. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression and are presented for the fifth versus first quintile. Higher circulating concentration of copper was associated with a raised CRC risk (OR = 1.50; 95% CI: 1.06, 2.13; P-trend = 0.02) whereas an inverse association with cancer risk was observed for higher zinc levels (OR = 0.65; 95% CI: 0.43, 0.97; P-trend = 0.07). Consequently, the ratio of copper/zinc was positively associated with CRC (OR = 1.70; 95% CI: 1.20, 2.40; P-trend = 0.0005). In subgroup analyses by follow-up time, the associations remained statistically significant only in those diagnosed within 2 years of blood collection. In conclusion, these data suggest that copper or copper levels in relation to zinc (copper to zinc ratio) become imbalanced in the process of CRC development. Mechanistic studies into the underlying mechanisms of regulation and action are required to further examine a possible role for higher copper and copper/zinc ratio levels in CRC development and progression.

ObjectiveDietary supplements are commonly consumed but may not be beneficial for everyone. It is known that supplement users have healthy behaviour characteristics but until now concordance between spouses living in the same household has not been investigated and concordance may be an important behavioural determinant.DesignProspective cohort study, cross-sectional data analysis.SettingEuropean Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) in the UK, recruitment between 1993 and 1998.SubjectsMarried (or living as married) participants sharing a household, who attended a health examination and completed a 7 d diet diary were included in the analysis (n 11 060). The age range was 39–79 years.ResultsNearly 75 % of the households in EPIC-Norfolk were concordant in their supplement use, with 46·7 % not using supplements and 27·0 % using supplements. Concordance increased with age; the percentage of concordant couples varied less by other sociodemographic characteristics. Participants who had a spouse who used a supplement were nearly nine times more likely to use a supplement (unadjusted). Depending on participants’ sex and type of supplement used, odds ratios for ‘supplement use by spouse’ in the prediction of participants’ supplement use varied between 6·2 and 11·7 adjusted for participants’ age, smoking status, BMI, social class, education level and physical activity.Conclusions‘Supplement use by spouse’ is an independent and the strongest predictor of participants’ supplement use. This phenomenon can be useful in the design of studies and health interventions; or when assessing risk of excessive intake from dietary supplements.

The aim of the present study was to describe the energy, nutrient and crude v. disaggregated food intake measured using 7 d diet diaries (7dDD) for the full baseline Norfolk cohort recruited for the European Prospective Investigation into Cancer (EPIC-Norfolk) study, with emphasis on methodological issues. The first data collection took place between 1993 and 1998 in Norfolk, East Anglia (UK). Of the 30,445 men and women, aged 40-79 years, registered with a general practitioner invited to participate in the study, 25,639 came for a health examination and were asked to complete a 7dDD. Data from diaries with data recorded for at least 1 d were obtained for 99% members of the cohort; 10,354 (89·8%) of the men and 12,779 (91·5%) of the women completed the diet diaries for all 7 d. Mean energy intake (EI) was 9·44 (SD 2·22) MJ/d and 7·15 (SD 1·66) MJ/d, respectively. EI remained approximately stable across the days, but there was apparent under-reporting among the participants, especially among those with BMI >25 kg/m². Micronutrient density was higher among women than among men. In conclusion, under-reporting is an issue, but not more so than that found in national surveys. How foods were grouped (crude or disaggregated) made a difference to the estimates obtained, and comparison of intakes showed wide limits of agreement. The choice of variables influences estimates obtained from the food group data; while this may not alter the ranking of individuals within studies, this issue may be relevant when comparing absolute food intakes between studies.

BACKGROUND: Dietary oleic acid may prevent pancreatic ductal adenocarcinoma (PDA) by reducing hyperinsulinaemia which can otherwise promote DNA damage and tumour growth. Results from previous epidemiological studies investigating oleic acid are inconsistent. This study aims to clarify the relationship between dietary oleic acid intake and the risk of developing PDA using nutritional information from food diaries plus published serum biomarker data from HbA1c. METHODS: 23,658 participants, aged 40-74 years, were recruited into EPIC-Norfolk and completed 7-day food diaries which recorded; foods, brands and portion sizes to calculate nutrient intakes. Serum HbA1c was measured at recruitment in 11,147 participants (48.7% of cohort). Hazard ratios (HRs) for quintiles of dietary oleic acid intake and serum HbA1c were estimated using Cox regression. Additional analyses were made according to whether body mass index (BMI) was greater or less than 25 kg/m2 as this influences hyperinsulinaemia. RESULTS: 88 participants (55% women) developed PDA after a mean follow-up of 8.4 years (SD = 3.9) (mean age at diagnosis = 72.6 years, SD = 8.8). A decreased risk of PDA was associated with increased dietary oleic acid intake (highest vs lowest quintile, HR = 0.29, 95% CI = 0.10-0.81, P trend across quintiles = 0.011), with statistical significance maintained when BMI>25 kg/m2 but not if BMI

OBJECTIVE: Many patients receiving medical treatment for anxiety relapse or do not improve. Research has therefore been turning to coping mechanisms as a way to decrease anxiety rates. Previously, we showed that living in a deprived area significantly increases the risk of anxiety in women, but not in men. The objective of this study is to assess whether sense of coherence (coping mechanism) buffers the influence of area deprivation on women's risk of generalised anxiety disorder using data from the European Prospective Investigation of Cancer-Norfolk. DESIGN: Large, population study. SETTING: UK population-based cohort. PARTICIPANTS: 30 445 people over the age of 40 years were recruited through general practice registers in England. Of these, 20 919 completed a structured health and lifestyle questionnaire used to assess generalised anxiety disorder and sense of coherence. Area deprivation was measured using 1991 Census data, and sense of coherence and anxiety were examined in 1996-2000. 10 183 women had data on all variables. MAIN OUTCOME MEASURE: Past-year generalised anxiety disorder defined according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. RESULTS: In this study, 2.6% (260/10 183) of women had generalised anxiety disorder. In those with a strong sense of coherence, area deprivation was not significantly associated with anxiety (OR 1.29, 95% CI 0.77 to 2.17). However, among women with a weak sense of coherence, those living in deprived areas were almost twice as likely to have generalised anxiety disorder compared with those living in more affluent areas (OR 1.99, 95% CI 1.37 to 2.91). CONCLUSION: The number of women living in deprived conditions is large worldwide, and significant numbers are affected by generalised anxiety disorder. Sense of coherence moderates the association between area deprivation and anxiety in women; therefore, interventions targeting coping mechanisms may need to be considered for people with anxiety.

BACKGROUND: Stroke is primarily a disease of older age, with a substantial impact on global mortality and morbidity. Medications with anticholinergic effects are widely used, but no studies have been conducted to examine the relationship between anticholinergic burden (ACB) and stroke in a general population. METHOD: The sample was drawn from the EPIC-Norfolk cohort. Baseline assessments were carried out during 1993-97 and participants were followed up until March 2016. Participants were divided into four groups according to their total ACB score at baseline; these groups were those with a total ACB score of 0, 1, 2-3 and >3. After exclusion, Cox proportional hazards models were constructed to determine the associations between the ACB score groups and the risk of incident stroke and stroke mortality. Sensitivity analysis and propensity score matched analyses were performed. RESULTS: In total 25 639 participants attended the first health check; 3917 participants were excluded, leaving 21 722 participants to be included. Participants had a mean age [standard deviation (SD)] of 58.9 (9.2) years (54.4% women). Of these, 2131 suffered incident stroke and 562 died from stroke. Mean follow-up was approximately 18 years for both outcomes. In the fully adjusted model, those with an ACB of >3 had 59% relative risk of incident stroke {hazard ratio [HR] [95% confidence interval (CI) 1.59 [1.34-1.89]} and 86% relative risk of stroke mortality [1.86 (1.37-2.53)] compared with those in ACB 0 category. Sensitivity analyses and propensity score matched analyses showed similar results. CONCLUSIONS: Our results provide an incentive for the cautious use of medications with anticholinergic properties, to help reduce the global burden of stroke.

The dietary approaches to stop hypertension (DASH) diet could be an important population-level strategy to reduce cardiovascular disease (CVD) in the UK, but there is little UK-based evidence on this diet pattern in relation to CVD risk. We tested whether dietary accordance with DASH was associated with risk of CVD in a population-based sample of 23,655 UK adults. This prospective analysis of the EPIC-Norfolk cohort study analysed dietary intake (assessed using a validated food frequency questionnaire) to measure accordance with DASH, based on intakes of eight food groups and nutrients, ranking the sample into quintiles. Cox proportional hazards regression models tested for association between DASH accordance and incident stroke, ischemic heart disease (IHD) and total incident CVD (stroke and IHD only), as well as CVD mortality, non-CVD mortality and total mortality. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated adjusting for age, sex, behavioral and clinical risk factors and socioeconomic status. Over an average of 12.4 years follow-up, we ascertained 4129 incident CVD events, of which stroke accounted for 1011. Compared to participants with the least DASH-accordant diets, those with the most DASH-accordant diets had 20% lower risk of incident stroke (HR, 95% CI 0.80, 0.65-0.99) and 13% lower risk of total incident CVD (0.88, 0.79-0.99) but no lower risk of CHD (0.90, 0.79-1.02). CVD-related mortality also showed strong inverse associations with DASH accordance (0.72, 0.60-0.85). This study provides evidence for the cardioprotective effects of DASH diet in a UK context.

Supplemental digital content is available in the article., Purpose Television (TV) watching is the most prevalent sedentary leisure time activity in the United Kingdom. We examined associations between TV viewing time, measured over 10 yr, and two objective measures of physical capability, usual walking speed (UWS) and grip strength. Methods Community-based participants (n = 8623; 48–92 yr old) enrolled in the European Prospective Investigation of Cancer—Norfolk study attended a third health examination (3HC, 2006–2011) for measurement of maximum grip strength (Smedley dynamometer) and UWS. TV viewing time was estimated using a validated questionnaire (n = 6086) administered during two periods (3HC, 2006–2007; 2HC, 1998–2000). Associations between physical capability and TV viewing time category (

OBJECTIVE: The objective of the present study was to investigate associations between sugar intake and overweight using dietary biomarkers in the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). DESIGN: Prospective cohort study. SETTING: EPIC-Norfolk in the UK, recruitment between 1993 and 1997. SUBJECTS: Men and women (n 1734) aged 39-77 years. Sucrose intake was assessed using 7 d diet diaries. Baseline spot urine samples were analysed for sucrose by GC-MS. Sucrose concentration adjusted by specific gravity was used as a biomarker for intake. Regression analyses were used to investigate associations between sucrose intake and risk of BMI>25·0 kg/m2 after three years of follow-up. RESULTS: After three years of follow-up, mean BMI was 26·8 kg/m2. Self-reported sucrose intake was significantly positively associated with the biomarker. Associations between the biomarker and BMI were positive (β=0·25; 95 % CI 0·08, 0·43), while they were inverse when using self-reported dietary data (β=-1·40; 95 % CI -1·81, -0·99). The age- and sex-adjusted OR for BMI>25·0 kg/m2 in participants in the fifth v. first quintile was 1·54 (95 % CI 1·12, 2·12; P trend=0·003) when using biomarker and 0·56 (95 % CI 0·40, 0·77; P trend

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 Generale de l’Education Nationale; and Institut National de la Sante et de la Recherche Medicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum; and Federal Ministry of Education and Research (Germany); Hellenic Health Foundation; Stavros Niarchos Foundation; and the Hellenic Ministry of Health and Social Solidarity (Greece); Italian Association for Research on Cancer (AIRC); National Research Council; and Associazione Iblea per la Ricerca Epidemiologica (AIRE-ONLUS) Ragusa, Associazione Volontari Italiani Sangu (AVIS) Ragusa, Sicilian Government (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); and Statistics Netherlands (the Netherlands); European Research Council (ERC) (grant number ERC-2009-AdG 232997) and Nordforsk; and Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS); Regional Governments of Andalucia, Asturias, Basque Country, Murcia (No. 6236) and Navarra; and the Centro de Investigacion Biomedica en Red en Epidemiologia y Salud Publica and Instituto de Salud Carlos II (ISCIII RETIC) (RD06/0020) (Spain); Swedish Cancer Society; Swedish Scientific Council; and Regional Government of Skane and Vasterbotten (Sweden); Cancer Research UK; Medical Research Council; Stroke Association; British Heart Foundation; Department of Health; Food Standards Agency; and the Wellcome Trust (UK). Funding for the biomarker measurements in the random sub-cohort was provided by grants to EPIC-InterAct from the European Community Framework Programme 6 and to EPIC-Heart from the Medical Research Council and British Heart Foundation (Joint Award G0800270). We thank Nicola Kerrison (MRC Epidemiology Unit, Cambridge) for managing the data for the InterAct Project. Funding for the InterAct project was provided by the EU FP6 programme (grant number LSHM_CT_2006_037197). The work undertaken by David C Muller was done during the tenure of an IARC, Australia postdoctoral fellowship, supported by the Cancer Council Australia. Domenico Palli was supported by a grant from the Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

AIMS: Lipoprotein(a) (Lp(a)) elevation is a causal risk factor for cardiovascular disease (CVD). It has however been suggested that elevated Lp(a) causes CVD mainly in individuals with high low-density lipoprotein cholesterol (LDL-C) levels. We hypothesized that the risk associated with high Lp(a) levels would largely be attenuated at low LDL-C levels. METHODS AND RESULTS: In 16 654 individuals from the EPIC-Norfolk prospective population study, and in 9448 individuals from the Copenhagen City Heart Study (CCHS) parallel statistical analyses were performed. Individuals were categorized according to their Lp(a) and LDL-C levels. Cut-offs were set at the 80th cohort percentile for Lp(a). Low-density lipoprotein cholesterol cut-offs were set at 2.5, 3.5, 4.5, and 5.5 mmol/L. Low-density lipoprotein cholesterol levels in the primary analyses were corrected for Lp(a)-derived LDL-C (LDL-Ccorr). Multivariable-adjusted hazard ratios were calculated for each category. The category with LDL-Ccorr

Aims/hypothesis Gene–macronutrient interactions may contribute to the development of type 2 diabetes but research evidence to date is inconclusive. We aimed to increase our understanding of the aetiology of type 2 diabetes by investigating potential interactions between genes and macronutrient intake and their association with the incidence of type 2 diabetes. Methods We investigated the influence of interactions between genetic risk scores (GRSs) for type 2 diabetes, insulin resistance and BMI and macronutrient intake on the development of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a prospective case-cohort study across eight European countries (N = 21,900 with 9742 incident type 2 diabetes cases). Macronutrient intake was estimated from diets reported in questionnaires, including proportion of energy derived from total carbohydrate, protein, fat, plant and animal protein, saturated, monounsaturated and polyunsaturated fat and dietary fibre. Using multivariable-adjusted Cox regression, we estimated country-specific interaction results on the multiplicative scale, using random-effects meta-analysis. Secondary analysis used isocaloric macronutrient substitution. Results No interactions were identified between any of the three GRSs and any macronutrient intake, with low-to-moderate heterogeneity between countries (I2 range 0–51.6%). Results were similar using isocaloric macronutrient substitution analyses and when weighted and unweighted GRSs and individual SNPs were examined. Conclusions/interpretation Genetic susceptibility to type 2 diabetes, insulin resistance and BMI did not modify the association between macronutrient intake and incident type 2 diabetes. This suggests that macronutrient intake recommendations to prevent type 2 diabetes do not need to account for differences in genetic predisposition to these three metabolic conditions.

BACKGROUND: Metabolic effects of omega-6 polyunsaturated fatty acids (n-6 PUFA) remain contentious, and evidence is limited regarding their potential role in primary prevention of type 2 diabetes (T2D). METHODS: Global consortium of 20 prospective cohort studies with new, harmonized, individual-level analyses. Each study measured biomarker linoleic acid (LA, the major dietary PUFA) and arachidonic acid (AA, a precursor of metabolic- and inflammation-mediating metabolites) at baseline among adults without prevalent T2D. Associations of n-6 PUFA biomarkers with T2D risk were assessed prospectively using a pre-specified analytic plan for exposures, covariates, and effect modifiers. Findings were pooled using inverse-variance weighted meta-analysis. FINDINGS: This study comprised 39,740 adults from 10 countries, with age (range of cohort means) 49-76yrs and BMI, 23∙3-28∙4kg/m2, including 4,347 incident T2D cases during 366,073 person-years of follow-up. In multivariable-adjusted pooled analyses, higher LA biomarker associated with 35% lower risk of T2D (RR per interquintile range: 0∙65, 95%CI: 0∙60-0∙72, P

Background: High sedentary time is associated with adverse metabolic health outcomes and mortality in older adults. It has been suggested that breaking up sedentary time may be beneficial for metabolic health; however, population prevalence data are lacking on the patterns of sedentary behaviour which would identify opportunities for intervention. Methods: We used data of adults aged ≥ 60 years (n = 3705) from the population-based EPIC-Norfolk cohort, to characterize the patterns of total sedentary time, breaks in sedentary time and sedentary bouts across the day and assess their associations with participant characteristics, using multi-level regression. Sedentary time was measured objectively by a hip-mounted accelerometer (Actigraph™ GT1M) worn for 7 days during waking time. Results: More than 50% of every waking hour was spent sedentary, increasing to a peak of 83% in the evening. On average fewer breaks were accrued in the evenings compared with earlier in the day. Marginally more sedentary time was accrued on weekend days compared with weekdays (difference 7.4 min, 95% confidence interval 5.0–9.7). Large proportions of this sedentary time appear to be accrued in short bouts (bouts of < 10 min for 32% of the time). Older age, being male, being retired, not being in paid employment and having a higher body mass index were associated with greater sedentary time and fewer breaks. Conclusion: Sedentary time is common throughout the day but peaks in the evenings with fewer breaks and longer bouts. We identified a number of characteristics associated with sedentary time and additionally inversely associated with sedentary breaks, which should inform the development and targeting of strategies to reduce sedentary time among older adults.

Objectives: Assess the association between marine omega-3 polyunsaturated fatty acid (n 3 PUFA) intake from supplements, mainly cod liver oil, and coronary heart disease (CHD) mortality. Design: Prospective cohort study, with three exposure measurements over 22 y. Setting: Norfolk-based European Prospective Investigation into Cancer (EPIC-Norfolk, UK). Participants: 22,035 men and women from the general population, 39-79 y at recruitment. Exposure: Supplement use was assessed in three questionnaires (1993-1998; 2002-2004; 2004-2011). Participants were grouped into non-supplement users (NSU), n 3 PUFA supplement users (SU+n3) and non n 3 PUFA supplement users (SU n3). Cox regression adjusted for time-point specific variables: age, smoking, prevalent illnesses, BMI, alcohol consumption, physical activity and season and baseline assessments of sex, social class, education and dietary intake (7-day diet diary). Primary and secondary outcome measures: During a median of 19 y follow-up, 1562 CHD deaths were registered for 22,035 included participants. Results: Baseline supplement use was not associated with CHD mortality, but baseline food and supplement intake of n 3 PUFA was inversely associated with CHD mortality after adjustment for fish consumption. Using time-varying covariate analysis, significant associations were observed for SU+n3 (HR: 0.74, 95%CI: 0.66, 0.84), but not for SU n3 vs. NSU. In further analyses, the association for SU+n3 persisted in those who did not take other supplements (HR: 0.83, 95%CI: 0.71, 0.96) and those who did (HR: 0.74, 95%CI: 0.60, 0.91). Those who became SU+n3 over time or were consistent SU+n3 vs. consistent NSU had a lower hazard of CHD mortality; no association with CHD was observed in those who stopped using n 3 PUFA-containing supplements. Conclusions: Recent use of n 3 PUFA supplements was associated with a lower hazard of CHD mortality in this general population with low fish consumption. Residual confounding cannot be excluded, but the findings observed may be explained by postulated biological mechanisms and the results were specific to SU+n3.

BACKGROUND: Oxidative stress may be involved in the aetiology of inflammatory bowel disease and whether dietary polyphenols, which possess antioxidants properties, prevent its development is unknown.METHODS: A total of 401,326 men and women aged 20 to 80 years from 8 countries were recruited between 1991 and 1998 and at baseline completed validated food frequency questionnaires. Dietary polyphenol intake was measured using Phenol-Explorer, a database with information on the content of 502 polyphenols. Incident cases of Crohn's diseases (CD) and ulcerative colitis (UC) were identified during the follow-up period of up to December 2010. A nested case-control study using conditional logistic regression estimated the odds ratios (ORs), and 95% confidence intervals, for polyphenol intake (categories based on quartiles) and developing CD or UC.RESULTS: In total, 110 CD (73% women) and 244 UC (57% women) cases were identified and matched to 440 and 976 controls, respectively. Total polyphenol intake was not associated with CD (P trend = 0.17) or UC (P trend = 0.16). For flavones and CD, there were reduced odds for all quartiles, which were statistically significant for the third (OR3rd versus 1st quartile = 0.33; 95% confidence interval, 0.15-0.69) and there was an inverse trend across quartiles (P = 0.03). Similarly, for resveratrol, there was an inverse association with CD (OR4th versus 1st quartile = 0.40; 95% confidence interval, 0.20-0.82) with an inverse trend across quartiles (P = 0.02). No significant associations between subtypes of polyphenols and UC were found. Effect modification by smoking in CD was documented with borderline statistical significance.CONCLUSIONS: The data supports a potential role of flavones and resveratrol in the risk of developing CD; future aetiological studies should investigate these dietary components and further examine the potential for residual confounding.

Background: Neoplastic and non-neoplastic events may raise levels of mucins, CA15.3, and CA125, and generate antibodies against them, but their impact on epithelial ovarian cancer (EOC) risk has not been fully defined.Methods: CA15.3, CA125, and IgG1 antibodies against them were measured in 806 women who developed EOC and 1,927 matched controls from the European Prospective Investigation of Nutrition and Cancer. Associations between epidemiologic factors and anti-mucin antibodies were evaluated using generalized linear models; EOC risks associated with anti-mucin antibodies, by themselves or in combination with respective antigens, were evaluated using conditional logistic regression.Results: In controls, lower antibodies against both mucins were associated with current smoking; and, in postmenopausal women, higher levels with longer oral contraceptive use and later-age-at and shorter-interval-since last birth. Lower anti-CA15.3 antibodies were associated with higher body mass and, in premenopausal women, more ovulatory cycles. Higher anti-CA15.3 and anti-CA125 antibodies were associated with higher risk for mucinous EOC occurring ≥ 3 years from enrollment. Long-term risk for serous EOC was reduced in women with low CA125 and high anti-CA125 antibodies relative to women with low concentrations of both.Conclusions: We found general support for the hypothesis that anti-mucin antibody levels correlate with risk factors for EOC. Antibodies alone or in combinations with their antigen may predict longer term risk of specific EOC types.Impact: Anti-CA125 and anti-CA15.3 antibodies alone or in perspective of antigens may be informative in the pathogenesis of EOC subtypes, but less useful for informing risk for all EOC. Cancer Epidemiol Biomarkers Prev; 27(7); 790-804. ©2018 AACR., 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), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy 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, 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), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford; United Kingdom)

Improvements in colorectal cancer (CRC) detection and treatment have led to greater numbers of CRC survivors, for whom there is limited evidence on which to provide dietary guidelines to improve survival outcomes. Higher intake of red and processed meat and lower intake of fibre are associated with greater risk of developing CRC, but there is limited evidence regarding associations with survival after CRC diagnosis. Among 3789 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, pre-diagnostic consumption of red meat, processed meat, poultry and dietary fibre was examined in relation to CRC-specific mortality (n 1008) and all-cause mortality (n 1262) using multivariable Cox regression models, adjusted for CRC risk factors. Pre-diagnostic red meat, processed meat or fibre intakes (defined as quartiles and continuous grams per day) were not associated with CRC-specific or all-cause mortality among CRC survivors; however, a marginal trend across quartiles of processed meat in relation to CRC mortality was detected (P 0·053). Pre-diagnostic poultry intake was inversely associated with all-cause mortality among women (hazard ratio (HR)/20 g/d 0·92; 95 % CI 0·84, 1·00), but not among men (HR 1·00; 95 % CI 0·91, 1·09) (P for heterogeneity=0·10). Pre-diagnostic intake of red meat or fibre is not associated with CRC survival in the EPIC cohort. There is suggestive evidence of an association between poultry intake and all-cause mortality among female CRC survivors and between processed meat intake and CRC-specific mortality; however, further research using post-diagnostic dietary data is required to confirm this relationship., The coordination of EPIC is financially supported by the European Commission (Directorate General for Health and Consumer Affairs; 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 and Institut National de la Santé et de la Recherche Médicale (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro (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 and Statistics Netherlands (The Netherlands); Nordic Center of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra and ISCIII RETIC (Instituto de Salud Carlos III Las Redes temáticas de investigación cooperativa en salud) (RD06/0020) (Spain); World Cancer Research Foundation ref. 2011/428, AGAUR (Agency for Management of University and Research Grants), Generalitat de Catalunya (exp. 2014 SGR 726), Health Research Funds (FIS Exp PI11/1486) and RD12/0036/0018 and Catalan Institute of Oncology (ICO-IDIBELL)(Barcelona); Swedish Cancer Society, Swedish Scientific Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 to EPIC-Oxford) and Medical Research Council (1000143 to EPIC-Norfolk) (UK).

Background The contribution of apolipoprotein A‐I (apoA‐I) to coronary heart disease ( CHD ) risk stratification over and above high‐density lipoprotein cholesterol ( HDL ‐C) is unclear. We studied the associations between plasma levels of HDL ‐C and apoA‐I, either alone or combined, with risk of CHD events and cardiovascular risk factors among apparently healthy men and women. Methods and Results HDL ‐C and apoA‐I levels were measured among 17 661 participants of the EPIC (European Prospective Investigation into Cancer)‐Norfolk prospective population study. Hazard ratios for CHD events and distributions of risk factors were calculated by quartiles of HDL ‐C and apoA‐I. Results were validated using data from the ARIC (Atherosclerosis Risk in Communities) and WHS (Women's Health Study) cohorts, comprising 15 494 and 27 552 individuals, respectively. In EPIC ‐Norfolk, both HDL ‐C and apoA‐I quartiles were strongly and inversely associated with CHD risk. Within HDL ‐C quartiles, higher apoA‐I levels were not associated with lower CHD risk; in fact, CHD risk was higher within some HDL ‐C quartiles. ApoA‐I levels were associated with higher levels of CHD risk factors: higher body mass index, HbA1c, non‐ HDL ‐C, triglycerides, apolipoprotein B, systolic blood pressure, and C‐reactive protein, within fixed HDL ‐C quartiles. In contrast, HDL ‐C levels were consistently inversely associated with overall CHD risk and CHD risk factors within apoA‐I quartiles ( P ARIC and WHS cohorts. Conclusions Our findings demonstrate that apoA‐I levels do not offer predictive information over and above HDL ‐C. In fact, within some HDL ‐C quartiles, higher apoA‐I levels were associated with higher risk of CHD events, possibly because of the unexpected higher prevalence of cardiovascular risk factors in association with higher apoA‐I levels. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00000479.

Objective— Apolipoprotein C-III (apoC-III) is a key regulator of triglyceride metabolism. Elevated triglyceride-rich lipoproteins and apoC-III levels are causally linked to coronary artery disease (CAD) risk. The mechanism(s) through which apoC-III increases CAD risk remains largely unknown. The aim was to confirm the association between apoC-III plasma levels and CAD risk and to explore which lipoprotein subfractions contribute to this relationship between apoC-III and CAD risk. Approach and Results— Plasma apoC-III levels were measured in baseline samples from a nested case–control study in the European Prospective Investigation of Cancer (EPIC)-Norfolk study. The study comprised 2711 apparently healthy study participants, of whom 832 subsequently developed CAD. We studied the association of baseline apoC-III levels with incident CAD risk, lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy and inflammatory biomarkers. ApoC-III levels were significantly associated with CAD risk (odds ratio, 1.91; 95% confidence interval, 1.48–2.48 for highest compared with lowest quintile), retaining significance after adjustment for traditional CAD risk factors (odds ratio, 1.47; 95% confidence interval, 1.11–1.94). ApoC-III levels were positively correlated with triglyceride levels, ( r =0.39), particle numbers of very-low-density lipoprotein ( r =0.25), intermediate-density lipoprotein ( r =0.23), small dense low-density lipoprotein ( r =0.26), and high-sensitivity C-reactive protein ( r =0.15), whereas an inverse correlation was observed with large low-density lipoprotein particle number ( r =−0.11), P Conclusions— ApoC-III levels are significantly associated with incident CAD risk. Elevated levels of remnant lipoproteins, small dense low-density lipoprotein, and low-grade inflammation may explain this association.

Background Little is known about how pre-diagnostic metabolites in blood relate to risk of prostate cancer. We aimed to investigate the prospective association between plasma metabolite concentrations and risk of prostate cancer overall, and by time to diagnosis and tumour characteristics, and risk of death from prostate cancer. Methods In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition, pre-diagnostic plasma concentrations of 122 metabolites (including acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose and sphingolipids) were measured using targeted mass spectrometry (AbsoluteIDQ p180 Kit) and compared between 1077 prostate cancer cases and 1077 matched controls. Risk of prostate cancer associated with metabolite concentrations was estimated by multi-variable conditional logistic regression, and multiple testing was accounted for by using a false discovery rate controlling procedure. Results Seven metabolite concentrations, i.e. acylcarnitine C18:1, amino acids citrulline and trans-4-hydroxyproline, glycerophospholipids PC aa C28:1, PC ae C30:0 and PC ae C30:2, and sphingolipid SM (OH) C14:1, were associated with prostate cancer (p

BACKGROUND: Emerging evidence from cohort studies indicates that adiposity is associated with greater incidence of head and neck cancer (HNC). However, most studies have used self-reported anthropometry which is prone to error. METHODS: Among 363 094 participants in the European Prospective Investigation into Cancer and Nutrition study (EPIC) with measured anthropometry, there were 837 incident cases of HNC. HNC risk was examined in relation to body mass index (BMI) [lean: < 22.5 kg/m², normal weight (reference): 22.5-24.9 kg/m², overweight 25-29.9 kg/m², obese: > 30 kg/m²], waist circumference (WC), hip circumference (HC) and waist to hip ratio (WHR) using Cox proportional hazards models. RESULTS: Among men, a BMI < 22.5 kg/m² was associated with higher HNC risk [hazard ratio (HR) 1.62, 95% confidence interval (CI) 1.23 - 2.12)]; BMI was not associated with HNC among women. WC and WHR were associated with greater risk of HNC among women, (WC per 5 cm: HR 1.08, 95% CI 1.02 - 1.15; WHR per 0.1 unit: HR 1.64, 95% CI 1.38 - 1.93). After stratification by smoking status, the association for WHR was present only among smokers (p interaction 0.004). Among men, WC and WHR were associated with HNC only upon additional adjustment for BMI (WC per 5 cm: HR 1.16, 95% CI 1.07 - 1.26; WHR per 0.1 unit: HR 1.42, 95% CI 1.21 - 1.65). CONCLUSION: Central adiposity, particularly among women, may have a stronger association with HNC risk than previously estimated. IMPACT: Strategies to reduce obesity may beneficially impact HNC incidence., 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), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy 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), PI13/00061 to Granada; , PI13/01162 to EPIC-Murcia), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to K.T. Khaw, N.J. Wareham; C570/A16491 to R.C. Travis and C8221/A19170 to Tim Key (EPIC-Oxford), Medical Research Council (1000143 to K.T. Khaw, N.J. Wareham, MR/M012190/1 to Tim Key (EPIC-Oxford)) (United Kingdom).

All Author: Veronika Fedirko, Hao Quang Tran, Andrew T. Gewirtz, Magdalena Stepien, Antonia Trichopoulou, Krasimira Aleksandrova, Anja Olsen, Anne Tjønneland, Kim Overvad, Franck Carbonnel, Marie-Christine Boutron-Ruault, Gianluca Severi, Tilman Kühn, Rudolf Kaaks, Heiner Boeing, Christina Bamia, Pagona Lagiou, Sara Grioni, Salvatore Panico, Domenico Palli, Rosario Tumino, Alessio Naccarati, Petra H. Peeters, H. B. Bueno-de-Mesquita, Elisabete Weiderpass, José María Huerta Castaño, Aurelio Barricarte, María-José Sánchez, Miren Dorronsoro, J. Ramón Quirós, Antonio Agudo, Klas Sjöberg, Bodil Ohlsson, Oskar Hemmingsson, Mårten Werner, Kathryn E. Bradbury, Kay-Tee Khaw, Nick Wareham, Konstantinos K. Tsilidis, Dagfinn Aune, Augustin Scalbert, Isabelle Romieu, Elio Riboli and Mazda Jenab., Background: Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking. Methods: We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression. Results: Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70–81.40; Ptrend = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses. Conclusions: These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted., This work was supported by the French National Cancer Institute (L’Institut National du Cancer; INCA) (grant number 2009-139; Principal Investigator: M. Jenab). 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 the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); the Sicilian Government, AIRE ONLUS Ragusa, AVIS Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, 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), and Statistics Netherlands (the Netherlands); Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, Regional Government of Asturias (Asturias, Spain), and ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 to EPIC-Oxford) and Medical Research Council (1000143 to EPIC-Norfolk) (United Kingdom); and a Girdlers’ New Zealand Health Research Council Fellowship (to Dr. K.E. Bradbury). The funding sources had no influence on the design of the study; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication.

Background Few studies have assessed the predictors of changes in commuting. This study investigated the associations between physical environmental characteristics and changes in active commuting. Methods Adults from the population-based European Prospective Investigation into Cancer (EPIC)-Norfolk cohort self-reported commuting patterns in 2000 and 2007. Active commuters were defined as those who reported ‘always’ or ‘usually’ walking or cycling to work. Environmental attributes around the home and route were assessed using Geographical Information Systems. Associations between potential environmental predictors and uptake and maintenance of active commuting were modelled using logistic regression, adjusting for age, sex and BMI. Results Of the 2757 participants (62% female, median baseline age: 52, IQR: 50–56 years), most were passive commuters at baseline (76%, n = 2099) and did not change their usual commute mode over 7 years (82%, n = 2277). In multivariable regression models, participants living further from work were less likely to take up active commuting and those living in neighbourhoods with more streetlights were more likely to take up active commuting (both p

BACKGROUND: The consumption of sweet beverages has been associated with greater risk of type 2 diabetes and obesity, which may be involved in the development of pancreatic cancer. Therefore, it has been hypothesized that sweet beverages may increase pancreatic cancer risk as well.OBJECTIVE: We examined the association between sweet-beverage consumption (including total, sugar-sweetened, and artificially sweetened soft drink and juice and nectar consumption) and pancreatic cancer risk.DESIGN: The study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort. A total of 477,199 participants (70.2% women) with a mean age of 51 y at baseline were included, and 865 exocrine pancreatic cancers were diagnosed after a median follow-up of 11.60 y (IQR: 10.10-12.60 y). Sweet-beverage consumption was assessed with the use of validated dietary questionnaires at baseline. HRs and 95% CIs were obtained with the use of multivariable Cox regression models that were stratified by age, sex, and center and adjusted for educational level, physical activity, smoking status, and alcohol consumption. Associations with total soft-drink consumption were adjusted for juice and nectar consumption and vice versa.RESULTS: Total soft-drink consumption (HR per 100 g/d: 1.03; 95% CI: 0.99, 1.07), sugar-sweetened soft-drink consumption (HR per 100 g/d: 1.02; 95% CI: 0.97, 1.08), and artificially sweetened soft-drink consumption (HR per 100 g/d: 1.04; 95% CI: 0.98, 1.10) were not associated with pancreatic cancer risk. Juice and nectar consumption was inversely associated with pancreatic cancer risk (HR per 100 g/d: 0.91; 95% CI: 0.84, 0.99); this association remained statistically significant after adjustment for body size, type 2 diabetes, and energy intake.CONCLUSIONS: Soft-drink consumption does not seem to be associated with pancreatic cancer risk. Juice and nectar consumption might be associated with a modest decreased pancreatic cancer risk. Additional studies with specific information on juice and nectar subtypes are warranted to clarify these results.

In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma, however epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption and risk of melanoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multi-centre prospective study that enrolled over 500,000 participants aged 25-70 years from ten European countries in 1992-2000. Information on coffee and tea drinking was collected at baseline using validated country-specific dietary questionnaires. We used adjusted Cox proportional hazards regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between coffee and tea consumption and melanoma risk. Overall, 2,712 melanoma cases were identified during a median follow-up of 14.9 years among 476,160 study participants. Consumption of caffeinated coffee was inversely associated with melanoma risk among men (HR for highest quartile of consumption vs. non-consumers 0.31, 95% CI 0.14-0.69) but not among women (HR 0.96, 95% CI 0.62-1.47). There were no statistically significant associations between consumption of decaffeinated coffee or tea and the risk of melanoma among both men and women. The consumption of caffeinated coffee was inversely associated with melanoma risk among men in this large cohort study. Further investigations are warranted to confirm our findings and clarify the possible role of caffeine and other coffee compounds in reducing the risk of melanoma., In France, the E3N study was financially supported by the Mutuelle Générale de l'Education Nationale (MGEN), the European Community, the French League Against Cancer (LNCC); Gustave Roussy; and the French Institute of Health and Medical research (INSERM). EPIC-Greece was supported by the Hellenic Health Foundation. Support for EPIC Norfolk is from Medical Research Council UK and Cancer Research UK. EPIC-Italy was supported by the Italian Association for Cancer Research (AIRC).

All Author: Renée T. Fortner, Danja Sarink, Helena Schock, Theron Johnson, Anne Tjønneland, Anja Olsen, Kim Overvad, Aurélie Affret, Mathilde His, Marie-Christine Boutron-Ruault, Heiner Boeing, Antonia Trichopoulou, Androniki Naska, Philippos Orfanos, Domenico Palli, Sabina Sieri, Amalia Mattiello, Rosario Tumino, Fulvio Ricceri, H. Bas Bueno-de-Mesquita, Petra H. M. Peeters, Carla H. Van Gils, Elisabete Weiderpass, Eiliv Lund, J. Ramón Quirós, Antonio Agudo, Maria-José Sánchez, María-Dolores Chirlaque, Eva Ardanaz, Miren Dorronsoro, Tim Key, Kay-Tee Khaw, Sabina Rinaldi, Laure Dossus, Marc Gunter, Melissa A. Merritt, Elio Riboli and Rudolf Kaaks, Background: Circulating osteoprotegerin (OPG), a member of the receptor activator of nuclear factor kappa-B (RANK) axis, may influence breast cancer risk via its role as the decoy receptor for both the RANK ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Circulating OPG and breast cancer risk has been examined in only one prior study. Methods: A case-control study was nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 2008 incident invasive breast cancer cases (estrogen receptor (ER)+, n = 1622; ER–, n = 386), matched 1:1 to controls, were included in the analysis. Women were predominantly postmenopausal at blood collection (77%); postmenopausal women included users and non-users of postmenopausal hormone therapy (HT). Serum OPG was quantified with an electrochemiluminescence assay. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Results: The associations between OPG and ER+ and ER– breast cancer differed significantly. Higher concentrations of OPG were associated with increased risk of ER– breast cancer (top vs. bottom tertile RR = 1.93 [95% CI 1.24–3.02]; ptrend = 0.03). We observed a suggestive inverse association for ER+ disease overall and among women premenopausal at blood collection. Results for ER– disease did not differ by menopausal status at blood collection (phet = 0.97), and we observed no heterogeneity by HT use at blood collection (phet ≥ 0.43) or age at breast cancer diagnosis (phet ≥ 0.30). Conclusions: This study provides the first prospective data on OPG and breast cancer risk by hormone receptor subtype. High circulating OPG may represent a novel risk factor for ER– breast cancer., This project was funded by research grant 111454 from the Deutsche Kresbshilfe. RT Fortner was supported by a Marie Curie International Incoming Fellowship of the European Commission’s Seventh Framework Programme (MC-IIF-623984). 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 the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and the National Research Council (Italy); the 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), and 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), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra, and ISCIII RETIC (RD06/0020) (Spain); the Swedish Cancer Society, Swedish Research Council, and County Councils of Skåne and Västerbotten (Sweden); and Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), and the Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK).

Objective— Carriers of the PCSK9 (proprotein convertase subtilisin/kexin 9) R46L genetic variant (rs11591147) are characterized by low levels of low-density lipoprotein cholesterol and a decreased risk of cardiovascular disease. We studied the impact of the R46L variant on lipoprotein size and composition. Approach and Results— Lipoprotein size and composition were measured by nuclear magnetic resonance spectroscopy in 2373 participants of the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study. After adjusting for age, sex, and cardiovascular disease status, carriers of the R46L variant (n=77) were characterized by lower concentrations of very low–density lipoprotein particles (85.8±26.2 versus 99.0±33.3 nmol/L; P P P P =0.004) and lipoprotein-associated phospholipase A2 activity (47.5±14.1 versus 52.4±16.2 nmol/mL/min; P =0.02) compared with noncarriers. Conclusions— Results of this study suggest that carriers of the PCSK9 R46L genetic variant have lower very low–density lipoprotein and low-density lipoprotein particle concentrations, lower lipoprotein(a) levels, and lower secretory phospholipase A2 and lipoprotein-associated phospholipase A2 activity compared with noncarriers.

Background The relationship between body size and prostate cancer risk, and in particular risk by tumour characteristics, is not clear because most studies have not differentiated between high-grade or advanced stage tumours, but rather have assessed risk with a combined category of aggressive disease. We investigated the association of height and adiposity with incidence of and death from prostate cancer in 141,896 men in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods Multivariable-adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). After an average of 13.9 years of follow-up, there were 7024 incident prostate cancers and 934 prostate cancer deaths. Results Height was not associated with total prostate cancer risk. Subgroup analyses showed heterogeneity in the association with height by tumour grade (P heterogeneity = 0.002), with a positive association with risk for high-grade but not low-intermediate-grade disease (HR for high-grade disease tallest versus shortest fifth of height, 1.54; 95% CI, 1.18–2.03). Greater height was also associated with a higher risk for prostate cancer death (HR = 1.43, 1.14–1.80). Body mass index (BMI) was significantly inversely associated with total prostate cancer, but there was evidence of heterogeneity by tumour grade (P heterogeneity = 0.01; HR = 0.89, 0.79–0.99 for low-intermediate grade and HR = 1.32, 1.01–1.72 for high-grade prostate cancer) and stage (P heterogeneity = 0.01; HR = 0.86, 0.75–0.99 for localised stage and HR = 1.11, 0.92–1.33 for advanced stage). BMI was positively associated with prostate cancer death (HR = 1.35, 1.09–1.68). The results for waist circumference were generally similar to those for BMI, but the associations were slightly stronger for high-grade (HR = 1.43, 1.07–1.92) and fatal prostate cancer (HR = 1.55, 1.23–1.96). Conclusions The findings from this large prospective study show that men who are taller and who have greater adiposity have an elevated risk of high-grade prostate cancer and prostate cancer death. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0876-7) contains supplementary material, which is available to authorized users.

This work was supported by the French National Cancer Institute (L'Institut National du Cancer; INCA; grant number 2009-139; PI: M Jenab) and the Health Research Board of Ireland (award number HRA_PHS/2013/397; PI: DJ Hughes). 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 Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy 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); Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada), Regional Governments of Andalucia, Asturias, Basque Country, Murcia (No. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk and MR/M012190/1 to EPIC- Oxford) (UK); Medical Research Council (1000143 to EPIC- Norfolk) (UK). For information on how to submit an application for gaining access to EPIC data and/or bio-specimens, please follow the instructions at http://epic.iarc.fr/access/index.php, Stepien, M., Hughes, D.J., Hybsier, S., Bamia, C., Tjønneland, A., Overvad, K., Affret, A., His, M., Boutron-Ruault, M.-C., Katzke, V., Kühn, T., Aleksandrova, K., Trichopoulou, A., Lagiou, P., Orfanos, P., Palli, D., Sieri, S., Tumino, R., Ricceri, F., Panico, S., Bueno-De-Mesquita, H.B., Peeters, P.H., Weiderpass, E., Lasheras, C., Bonet Bonet, C., Molina-Portillo, E., Dorronsoro, M., Huerta, J.M., Barricarte, A., Ohlsson, B., Sjöberg, K., Werner, M., Shungin, D., Wareham, N., Khaw, K.-T., Travis, R.C., Freisling, H., Cross, A.J., Schomburg, L., Jenab, M.

Background Higher circulating levels of the branched-chain amino acids (BCAAs; i.e., isoleucine, leucine, and valine) are strongly associated with higher type 2 diabetes risk, but it is not known whether this association is causal. We undertook large-scale human genetic analyses to address this question. Methods and Findings Genome-wide studies of BCAA levels in 16,596 individuals revealed five genomic regions associated at genome-wide levels of significance (p < 5 × 10−8). The strongest signal was 21 kb upstream of the PPM1K gene (beta in standard deviations [SDs] of leucine per allele = 0.08, p = 3.9 × 10−25), encoding an activator of the mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) responsible for the rate-limiting step in BCAA catabolism. In another analysis, in up to 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of 1 SD in amino acid level was associated with an odds ratio for type 2 diabetes of 1.44 (95% CI 1.26–1.65, p = 9.5 × 10−8) for isoleucine, 1.85 (95% CI 1.41–2.42, p = 7.3 × 10−6) for leucine, and 1.54 (95% CI 1.28–1.84, p = 4.2 × 10−6) for valine. Estimates were highly consistent with those from prospective observational studies of the association between BCAA levels and incident type 2 diabetes in a meta-analysis of 1,992 cases and 4,319 non-cases. Metabolome-wide association analyses of BCAA-raising alleles revealed high specificity to the BCAA pathway and an accumulation of metabolites upstream of branched-chain alpha-ketoacid oxidation, consistent with reduced BCKD activity. Limitations of this study are that, while the association of genetic variants appeared highly specific, the possibility of pleiotropic associations cannot be entirely excluded. Similar to other complex phenotypes, genetic scores used in the study captured a limited proportion of the heritability in BCAA levels. Therefore, it is possible that only some of the mechanisms that increase BCAA levels or affect BCAA metabolism are implicated in type 2 diabetes. Conclusions Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes., Claudia Langenberg and colleagues show that high circulating branched chain amino acids associate with future risk of type 2 diabetes., Author Summary Why Was This Study Done? Higher circulating levels of isoleucine, leucine, and valine, i.e., the branched-chain amino acids (BCAAs), are strongly associated with the risk of future type 2 diabetes. It is not known if this association reflects a causal relationship. It is important to assess the aetiologic nature of this relationship. If it is causal, then intervening on BCAA levels or metabolism may reduce the risk of diabetes. What Did the Researchers Do and Find? We used a human genetics framework known as “Mendelian randomisation” to study this question. Mendelian randomisation postulates that if a biomarker is causally implicated in a disease, then genetic variants specifically associated with that biomarker should also be associated with the disease. In a meta-analysis of 1,992 incident cases of type 2 diabetes and 4,319 non-cases, we found strong associations between higher levels of each of the BCAAs and a higher risk of type 2 diabetes. In a genome-wide meta-analysis of 16,596 individuals, we identified five genomic regions where common genetic variants were associated with BCAA levels. In a meta-analysis of genetic association studies including 47,877 cases of type 2 diabetes and 267,694 controls, a genetically predicted difference of one standard deviation in amino acid level was associated with an odds ratio of type 2 diabetes of 1.44 (95% confidence interval 1.26–1.65) for isoleucine, 1.85 (1.41–2.42) for leucine, and 1.54 (1.28–1.84) for valine. What Do These Findings Mean? Evidence from this large-scale human genetic and metabolomic study is consistent with a causal role of BCAA metabolism in the aetiology of type 2 diabetes. Possible limitations of the study included the possibility of non-specific associations of the genetic variants included in the study (i.e., “pleiotropy”) and the relatively low proportion of heritability in BCAA levels explained by the identified genetic variants.

BACKGROUND: Much of the current literature on diet-colorectal cancer (CRC) associations focused on studies of single foods/nutrients, whereas less is known about nutrient patterns. We investigated the association between major nutrient patterns and CRC risk in participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) study.METHODS: Among 477 312 participants, intakes of 23 nutrients were estimated from validated dietary questionnaires. Using results from a previous principal component (PC) analysis, four major nutrient patterns were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed for the association of each of the four patterns and CRC incidence using multivariate Cox proportional hazards models with adjustment for established CRC risk factors.RESULTS: During an average of 11 years of follow-up, 4517 incident cases of CRC were documented. A nutrient pattern characterised by high intakes of vitamins and minerals was inversely associated with CRC (HR per 1 s.d.=0.94, 95% CI: 0.92-0.98) as was a pattern characterised by total protein, riboflavin, phosphorus and calcium (HR (1 s.d.)=0.96, 95% CI: 0.93-0.99). The remaining two patterns were not significantly associated with CRC risk.CONCLUSIONS: Analysing nutrient patterns may improve our understanding of how groups of nutrients relate to CRC.British Journal of Cancer advance online publication 20 October 2016; doi:10.1038/bjc.2016.334 www.bjcancer.com.

PURPOSE: To determine if topical beta-blocker use is associated with increased cardiovascular mortality, particularly among people with self-reported glaucoma. METHODS: All participants who participated in the first health check (N = 25,639) of the European Prospective Investigation into Cancer (EPIC) Norfolk cohort (1993-2013) were included in this prospective cohort study, with a median follow-up of 17.0 years. We determined use of topical beta-blockers at baseline through a self-reported questionnaire and prescription check at the first clinical visit. Cardiovascular mortality was ascertained through data linkage with the Office for National Statistics mortality database. Hazard ratios (HRs) were estimated using multivariable Cox regression models. Meta-analysis of the present study's results together with other identified literature was performed using a random effects model. RESULTS: We did not find an association between the use of topical beta-blockers and cardiovascular mortality (HR 0.93, 95% confidence interval, CI, 0.67-1.30). In the 514 participants with self-reported glaucoma, no association was found between the use of topical beta-blockers and cardiovascular mortality (HR 0.89, 95% CI 0.56-1.40). In the primary meta-analysis of four publications, there was no evidence of an association between the use of topical beta-blockers and cardiovascular mortality (pooled HR estimate 1.10, 95% CI 0.84-1.36). CONCLUSION: Topical beta-blockers do not appear to be associated with excess cardiovascular mortality. This evidence does not indicate that a change in current practice is warranted, although clinicians should continue to assess individual patients and their cardiovascular risk prior to commencing topical beta-blockers.

Background/Objectives: The influence of dietary factors remains controversial for screen-detected prostate cancer and inconclusive for clinically detected disease. We aimed to examine these associations using prospectively collected food diaries. Subjects/Methods: A total of 1,717 prostate cancer cases in middle-aged and older UK men were pooled from four prospective cohorts with clinically detected disease (n=663), with routine data follow-up (means 6.6–13.3 years) and a case-control study with screen-detected disease (n=1054), nested in a randomised trial of prostate cancer treatments (ISCTRN 20141297). Multiple-day food diaries (records) completed by men prior to diagnosis were used to estimate intakes of 37 selected nutrients, food groups and items, including carbohydrate, fat, protein, dairy products, fish, meat, fruit and vegetables, energy, fibre, alcohol, lycopene and selenium. Cases were matched on age and diary date to at least one control within study (n=3528). Prostate cancer risk was calculated, using conditional logistic regression (adjusted for baseline covariates) and expressed as odds ratios in each quintile of intake (±95% confidence intervals). Prostate cancer risk was also investigated by localised or advanced stage and by cancer detection method. Results: There were no strong associations between prostate cancer risk and 37 dietary factors. Conclusions: Prostate cancer risk, including by disease stage, was not strongly associated with dietary factors measured by food diaries in middle-aged and older UK men.

Background Despite convincing evidence in the Mediterranean region, the cardiovascular benefit of the Mediterranean diet is not well established in non-Mediterranean countries and the optimal criteria for defining adherence are unclear. The population attributable fraction (PAF) of adherence to this diet is also unknown. Methods In the UK-based EPIC-Norfolk prospective cohort, we evaluated habitual diets assessed at baseline (1993–1997) and during follow-up (1998–2000) using food-frequency questionnaires (n = 23,902). We estimated a Mediterranean diet score (MDS) using cut-points projected from the Mediterranean dietary pyramid, and also three other pre-existing MDSs. Using multivariable-adjusted Cox regression with repeated measures of MDS and covariates, we examined prospective associations between each MDS with incident cardiovascular diseases (CVD) by 2009 and mortality by 2013, and estimated PAF for each outcome attributable to low MDS. Results We observed 7606 incident CVD events (2818/100,000 person-years) and 1714 CVD deaths (448/100,000). The MDS based on the Mediterranean dietary pyramid was significantly associated with lower incidence of the cardiovascular outcomes, with hazard ratios (95 % confidence intervals) of 0.95 (0.92–0.97) per one standard deviation for incident CVD and 0.91 (0.87–0.96) for CVD mortality. Associations were similar for composite incident ischaemic heart disease and all-cause mortality. Other pre-existing MDSs showed similar, but more modest associations. PAF due to low dietary pyramid based MDS (

BACKGROUND: Selenium status is suboptimal in many Europeans and may be a risk factor for the development of various cancers, including those of the liver and biliary tract. OBJECTIVE: We wished to examine whether selenium status in advance of cancer onset is associated with hepatobiliary cancers in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. DESIGN: We assessed prediagnostic selenium status by measuring serum concentrations of selenium and selenoprotein P (SePP; the major circulating selenium transfer protein) and examined the association with hepatocellular carcinoma (HCC; n = 121), gallbladder and biliary tract cancers (GBTCs; n = 100), and intrahepatic bile duct cancer (IHBC; n = 40) risk in a nested case-control design within the EPIC study. Selenium was measured by total reflection X-ray fluorescence, and SePP was determined by a colorimetric sandwich ELISA. Multivariable ORs and 95% CIs were calculated by using conditional logistic regression. RESULTS: HCC and GBTC cases, but not IHBC cases, showed significantly lower circulating selenium and SePP concentrations than their matched controls. Higher circulating selenium was associated with a significantly lower HCC risk (OR per 20-μg/L increase: 0.41; 95% CI: 0.23, 0.72) but not with the risk of GBTC or IHBC. Similarly, higher SePP concentrations were associated with lowered HCC risk only in both the categorical and continuous analyses (HCC: P-trend ≤ 0.0001; OR per 1.5-mg/L increase: 0.37; 95% CI: 0.21, 0.63). CONCLUSION: These findings from a large prospective cohort provide evidence that suboptimal selenium status in Europeans may be associated with an appreciably increased risk of HCC development., Funding for this study was provided jointly by the French National Cancer Institute [L’Institut National du Cancer; grant 2009-139; principal investigator (PI): MJ] and the Health Research Board of Ireland (award HRA_PHS/2013/397; PI: DJH) as well as the Deutsche Forschungsgemeinschaft (grant SCHO 849/4-1; PI: LS). The coordination of the European Prospective Investigation into Cancer and Nutrition (EPIC) is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); the Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and the Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and the National Research Council (Italy); the Dutch Ministry of Public Health, Welfare, and Sports (VWS), the Netherlands Cancer Registry, LK research funds, Dutch Prevention funds, Dutch ZON (Zorg Onderzoek Nederland), the World Cancer Research Fund, and Statistics Netherlands (Netherlands); the Nordic Centre of Excellence Programme on Food, Nutrition, and Health (Norway); the Health Research Fund (FIS; PI13/00061 to Granada) and regional governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236), and Navarra (ISCIII RETIC; RD06/0020) (Spain); the Swedish Cancer Society, the Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden); and Cancer Research UK [14136 to EPIC-Norfolk; C570/A16491 to EPIC-Oxford] and the Medical Research Council (1000143 to EPIC-Norfolk) (United Kingdom). LS was supported by Deutsche Forschungsgemeinschaft (GraKo 1208, SCHO849/4-1) and the Federal Ministry of Economics and Technology (BMWi; KF2263202CS2)

Background: We have identified a strong association between daytime napping and increased mortality risk from respiratory diseases, but little is known about the relationship between daytime napping and respiratory morbidity.\ud Methods: Data were drawn from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. Participants reported napping habits during 1998-2000, and were followed up for respiratory disease hospital admissions until March 2009. Cox proportional hazards regression was used to examine the association between daytime napping and respiratory disease incidence risk. \ud Results: The study sample included 10978 men and women with a mean age of 61.9 years old, and a total of 946 incident respiratory disease cases were recorded. After adjustment for age, sex, social class, education, marital status, employment status, nightshift work, body mass index (BMI), physical activity, smoking, alcohol intake, self-reported general health, hypnotic drug use, habitual sleep duration and pre-existing health conditions, daytime napping was associated with an increase in the overall respiratory incidence risk [Hazard Ratio (HR) =1.32, 95% confidence interval (CI) 1.15, 1.52 for napping

Background and aims Few studies have prospectively examined the relationship between daytime napping and risk of type 2 diabetes. We aimed to study the effects of daytime napping and the joint effects of napping and sleep duration in predicting type 2 diabetes risk in a middle- to older-aged British population. Methods and results In 1998–2000, 13 465 individuals with no known diabetes participating in the European Prospective Investigation into Cancer-Norfolk study reported daytime napping habit and 24-h sleep duration. Incident type 2 diabetes cases were identified through multiple data sources until 31 July 2006. After adjustment for age and sex, daytime napping was associated with a 58% higher diabetes risk. Further adjustment for education, marital status, smoking, alcohol intake, physical activity, comorbidities and hypnotic drug use had little influence on the association, but additional adjustment for BMI and Waist Circumference attenuated the Odds ratio (OR) (95% CI) to 1.30 (1.01, 1.69). The adjusted ORs (95% CI) associated with short and long sleep duration were 1.46 (1.10, 1.90) and 1.64 (1.16, 2.32), respectively. When sleep duration and daytime napping were examined together, the risk of developing diabetes more than doubled for those who took day naps and had less than 6 h of sleep, compared to those who did not nap and had 6–8 h of sleep. Conclusion Daytime napping was associated with an increased risk of type 2 diabetes, particularly when combined with short sleep duration. Further physiological studies are needed to confirm the interaction between different domains of sleep in relation to diabetes risk., Highlights • Daytime napping was independently associated with a 30% increase in diabetes risk. • The association was partly explained by adiposity. • Short and long sleep was associated with a 46% and 64% increase in diabetes risk. • The risk of diabetes more than doubled for those taking day naps and sleep for < 6 h.

Background: Life expectancy is increasing in Europe, yet a substantial proportion of adults still die prematurely before the age of 70 years. We sought to estimate the joint and relative contributions of tobacco smoking, hypertension, obesity, physical inactivity, alcohol and poor diet towards risk of premature death. Methods: We analysed data from 264,906 European adults from the EPIC prospective cohort study, aged between 40 and 70 years at the time of recruitment. Flexible parametric survival models were used to model risk of death conditional on risk factors, and survival functions and attributable fractions (AF) for deaths prior to age 70 years were calculated based on the fitted models. Results: We identified 11,930 deaths which occurred before the age of 70. The AF for premature mortality for smoking was 31 % (95 % confidence interval (CI), 31–32 %) and 14 % (95 % CI, 12–16 %) for poor diet. Important contributions were also observed for overweight and obesity measured by waist-hip ratio (10 %; 95 % CI, 8–12 %) and high blood pressure (9 %; 95 % CI, 7–11 %). AFs for physical inactivity and excessive alcohol intake were 7 % and 4 %, respectively. Collectively, the AF for all six risk factors was 57 % (95 % CI, 55–59 %), being 35 % (95 % CI, 32–37 %) among never smokers and 74 % (95 % CI, 73–75 %) among current smokers. Conclusions: While smoking remains the predominant risk factor for premature death in Europe, poor diet, overweight and obesity, hypertension, physical inactivity, and excessive alcohol consumption also contribute substantially. Any attempt to minimise premature deaths will ultimately require all six factors to be addressed., This work was supported by the French Social Affairs & Health Ministry, Department of Health (Direction Générale de la Santé). The work undertaken by David C Muller for this project was performed during the tenure of an IARC-Australia fellowship supported by Cancer Council Australia. Elio Riboli was supported by the Imperial College Biomedical Research Centre funded by the National Institute of Health Research of UK. 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); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy 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); Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada, Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk) (United Kingdom). The sponsors did not have any input into study design, study conduct, data collection, analysis, or interpretation nor did they influence the preparation, review, or approval of the manuscript.

BACKGROUND: The American Heart Association has prioritised seven cardiovascular health metrics to reduce the cardiovascular burden, including: body mass index, healthy diet, physical activity, smoking status, blood pressure, glycated haemoglobin A1c and total cholesterol. The aim of the current study was to assess the association between the American Heart Association-defined health metrics and the risk of cardiovascular events in the EPIC-Norfolk prospective study. DESIGN: Prospective cohort study. METHODS: An overall cardiovascular health score was calculated based on the number of health metrics including ideal, intermediate or poor. Cox proportional hazards models were used to describe the association of the seven metrics separately and the overall health score with risk of coronary heart disease, stroke and cardiovascular disease. A total of 10,043 participants was included in the analysis (follow-up 1993-2008). For all individual health metrics a more ideal status was associated with a lower risk of cardiovascular events. RESULTS AND CONCLUSION: As for the overall cardiovascular health score, those in the highest (i.e. healthiest) category (score 12-14) had an adjusted hazard ratio for coronary heart disease of 0.07 (95% confidence interval (CI) 0.02-0.29, P

BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of ∼100 common, low-penetrance PrCa susceptibility variants identified so far by genome-wide association studies implicate RAD51B and RAD23B. METHODS: Genotype data from the iCOGS array were imputed to the 1000 genomes phase 3 reference panel for 21 780 PrCa cases and 21 727 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. We subsequently performed single variant, gene and pathway-level analyses using 81 303 SNPs within 20 Kb of a panel of 179 DNA-repair genes. RESULTS: Single SNP analyses identified only the previously reported association with RAD51B. Gene-level analyses using the SKAT-C test from the SNP-set (Sequence) Kernel Association Test (SKAT) identified a significant association with PrCa for MSH5. Pathway-level analyses suggested a possible role for the translesion synthesis pathway in PrCa risk and Homologous recombination/Fanconi Anaemia pathway for PrCa aggressiveness, even though after adjustment for multiple testing these did not remain significant. CONCLUSIONS: MSH5 is a novel candidate gene warranting additional follow-up as a prospective PrCa-risk locus. MSH5 has previously been reported as a pleiotropic susceptibility locus for lung, colorectal and serous ovarian cancers.

Little is known about cause-specific long-term mortality beyond 30 days in pneumonia. We aimed to compare the mortality of patients with hospitalized pneumonia compared to age- and sex-matched controls beyond 30 days. Participants were drawn from the European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population study. Hospitalized pneumonia cases were identified from record linkage (ICD-10: J12-J18). For this study we excluded people with hospitalized pneumonia who died within 30 days. Each case identified was matched to four controls and followed up until the end June 2012 (total 15 074 person-years, mean 6·1 years, range 0·08-15·2 years). Cox regression models were constructed to examine the all-cause, respiratory and cardiovascular mortality using date of pneumonia onset as baseline with binary pneumonia status as exposure. A total of 2465 men and women (503 cases, 1962 controls) [mean age (s.d.) 64·5 (8·3) years] were included in the study. Between a 30-day to 1-year period, hazard ratios (HRs) of all-cause and cardiovascular mortality were 7·3 [95% confidence interval (CI) 5·4-9·9] and 5·9 (95% CI 3·5-9·7), respectively (with very few respiratory deaths within the same period) in cases compared to controls after adjusting for age, sex, asthma, smoking status, pack years, systolic and diastolic blood pressure, diabetes, physical activity, waist-to-hip ratio, prevalent cardiovascular and respiratory diseases. All outcomes assessed also showed increased risk of death in cases compared to controls after 1 year; respiratory cause of death being the most significant during that period (HR 16·4, 95% CI 8·9-30·1). Hospitalized pneumonia was associated with increased all-cause and specific-cause mortality beyond 30 days.

PURPOSE: Sedentariness has been proposed as an independent risk factor for poor health. However, few studies have considered associations of sedentary time (ST) with physical functional health independent of time spent in moderate-to-vigorous physical activity (MVPA). METHODS: Community-based men and women (n = 8623, 48-92 yr old) in the European Prospective Investigation of Cancer-Norfolk study attended a health examination for objective measurement of physical capability, including grip strength (Smedley dynamometer (kg)), usual walking speed (UWS (cm·s(-1))), and timed chair stand speed (TCSS (stands per minute)). Of these, 4051 participants wore an accelerometer (GT1M ActiGraph) for 7 d to estimate time spent in MVPA (MVPA, ≥1952 counts per minute) and ST (ST, 0.05). CONCLUSIONS: More time spent in MVPA was associated with higher physical capability, but there were no independent ST associations.

Background: Chronic inflammation and oxidative stress are thought to be involved in colorectal cancer development. These processes may contribute to leakage of bacterial products, such as lipopolysaccharide (LPS) and flagellin, across the gut barrier. The objective of this study, nested within a prospective cohort, was to examine associations between circulating LPS and flagellin serum antibody levels and colorectal cancer risk. Methods: A total of 1,065 incident colorectal cancer cases (colon, n = 667; rectal, n = 398) were matched (1:1) to control subjects. Serum flagellin- and LPS-specific IgA and IgG levels were quantitated by ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI), adjusting for multiple relevant confouding factors. Results: Overall, elevated anti-LPS and anti-flagellin biomarker levels were not associated with colorectal cancer risk. After testing potential interactions by various factors relevant for colorectal cancer risk and anti-LPS and anti-flagellin, sex was identified as a statistically significant interaction factor (Pinteraction < 0.05 for all the biomarkers). Analyses stratified by sex showed a statistically significant positive colorectal cancer risk association for men (fully-adjusted OR for highest vs. lowest quartile for total anti-LPS + flagellin, 1.66; 95% CI, 1.10–2.51; Ptrend, 0.049), whereas a borderline statistically significant inverse association was observed for women (fully-adjusted OR, 0.70; 95% CI, 0.47–1.02; Ptrend, 0.18). Conclusion: In this prospective study on European populations, we found bacterial exposure levels to be positively associated to colorectal cancer risk among men, whereas in women, a possible inverse association may exist. Impact: Further studies are warranted to better clarify these preliminary observations. Cancer Epidemiol Biomarkers Prev; 25(2); 291–301. ©2016 AACR.