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Funder: Dutch Kidney Foundation, AIMS: A potassium replete diet is associated with lower blood pressure (BP) and lower risk of cardiovascular disease (CVD). Whether these associations differ between men and women and whether they depend on daily sodium intake is unknown. METHODS AND RESULTS: An analysis was performed in 11 267 men and 13 696 women from the EPIC-Norfolk cohort. Twenty-four hour excretion of sodium and potassium, reflecting intake, was estimated from sodium and potassium concentration in spot urine samples using the Kawasaki formula. Linear and Cox regression were used to explore the association between potassium intake, systolic BP (SBP), and CVD events (defined as hospitalization or death due to CVD). After adjustment for confounders, interaction by sex was found for the association between potassium intake and SBP (P < 0.001). In women, but not in men, the inverse slope between potassium intake and SBP was steeper in those within the highest tertile of sodium intake compared with those within the lowest tertile of sodium intake (P < 0.001 for interaction by sodium intake). Both in men and women, higher potassium intake was associated with a lower risk of CVD events, but the hazard ratio (HR) associated with higher potassium intake was lower in women than in men [highest vs. lowest potassium intake tertile: men: HR 0.93, 95% confidence interval (CI) 0.87-1.00; women: HR 0.89, 95% CI 0.83-0.95, P = 0.033 for interaction by sex]. CONCLUSION: The association between potassium intake, SBP, and CVD events is sex specific. The data suggest that women with a high sodium intake in particular benefit most from a higher potassium intake with regard to SBP.

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.

Background: Higher anticholinergic burden from medications is associated with increased risk of cardiovascular disease and cognitive function decline. A mechanistic pathway has never been established. We aimed to determine whether chronic inflammation may mediate these associations. Methods: Participants were drawn from the European Prospective Investigation into Cancer, Norfolk cohort (40-79 years at baseline). The anticholinergic cognitive burden score (ACB) was calculated at baseline/first (1HC) (1993/97) and second (2HC) (1998/2000) health checks. Plasma fibrinogen and C-reactive protein (CRP) were measured during 1HC and Tumour Necrosis Factor alpha (TNF-α) and interleukin 6 (IL-6) during 2HC. Cross-sectional associations between ACB and inflammatory markers were examined for 1HC and 2HC, respectively. The prospective association was also examined between 1HC ACB and 2HC inflammatory markers. All models adjusted for age, sex, lifestyle factors, co-morbidities and medications. Results: 17,678 and 22,051 participants were included in cross-sectional analyses for CRP, and fibrinogen, respectively. A total of 5,101 participants with available data for TNF-α and IL-6 were included in the longitudinal analyses. Cross-sectionally, a point increase in the ACB was associated with a significant increase in all inflammatory markers (beta (standard error): fibrinogen – 0.035g/l (0.006), pConclusion: Higher anticholinergic burden was significantly associated with higher inflammatory markers. Inflammation may mediate the relationship between exposure to anticholinergic medications and adverse outcomes

Summary Background The use of high-dose vitamin D supplementation has increased in recent years. However, relatively little is known about the safety of long-term high doses. Aims To investigate the safety of a monthly high-dose of vitamin D3 supplementation taken for up to 4 years. Methods Data were collected in a randomized, double blind, placebo-controlled trial of 5108 adults aged 50–84 years old from Auckland, New Zealand. Participants were given monthly doses of 100,000 IU vitamin D3 or placebo, for a median of 3.3 years (range 2.5–4.2 years). They answered an open-ended question in a monthly questionnaire about any adverse events they attributed to the study capsules, which were coded blindly. Incidence rates per person months were calculated for categories of adverse events. Cox regression model used to calculate hazard ratio of time to first adverse-event. Results In total, 419 (16.5%) participants taking vitamin D and 399 (15.8%) taking placebo reported ≥1 adverse event. Compared to placebo, the hazard ratio (HR) of reporting first adverse event in the vitamin D group was 1.03 (95% CI: 0.90, 1.18; p = 0.63). Despite a slightly higher incidence of recurrent adverse events in vitamin D arm, the incidence rate ratio (1.17) was not significantly higher in vitamin D (95% CI: 0.97, 1.41; p = 0.10). All regression results were adjusted for age, sex, and ethnicity. There was no difference between study arms in terms of participants’ allocation perception (p = 0.52). Conclusion Monthly supplementation of 100,000 IU vitamin D3 for a median of 3.3 years did not affect participant-reported adverse events. Trial registration clinicaltrials.gov Identifier: ACTRN12611000402943; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12611000402943 .

BACKGROUND: Maintenance of skeletal muscle in older age is critical to reducing frailty and the risk of falls and fractures. Nutrition has established importance for muscle health in general, but less research has looked at associations of dietary intake of specific micronutrients on skeletal muscle mass in older adults. AIMS: This study aimed to investigate the influence of dietary and circulating magnesium on skeletal muscle mass in a UK population of 14,340 middle to older-aged men and women participating in the EPIC-Norfolk cohort study. METHODS: Dietary nutrient intakes were estimated from 7-day food diaries and fat-free mass (FFM) by bioelectrical impedance analysis. Multivariable regression was used to investigate associations of FFM-based indices of muscle mass with quintiles of dietary magnesium intake or serum magnesium concentration groups. All analyses were stratified by sex, and regression models were adjusted for relevant covariates. RESULTS: Significant positive trends in FFM measures were evident across magnesium dietary intake quintiles for both sexes (all p < 0.001; n = 6350 men; n = 7990 women) and both

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.

Research on Mediterranean diet (MD) adherence and musculoskeletal health is limited. The current study determined if adherence to the alternative MD score (aMED) and MD score (MDS), quantified from 7-d food diaries, was associated with fracture incidence, bone density (calcaneal broadband ultrasound attenuation (BUA)) and fat free mass (expressed over BMI (FFMBMI) using bioelectrical impedance) in 25,450 men and women recruited to the European Prospective Investigation into Cancer study in Norfolk, UK. During 17.4 years of follow up (443,178 total person years) 2195 incident fractures occurred. Higher aMED adherence was associated with 23% reduced total (Q5&ndash, Q1 HR 0.77, 95% CI 0.67, 0.88, p-trend &lt, 0.01) and 21% reduced hip (Q5&ndash, Q1 HR 0.79, 95% CI 0.65, 0.96, p-trend = 0.01) fracture incidence, and significantly higher BUA (Q5&ndash, Q1 1.0 dB/MHz 95% CI 0.2, 1.9, 0.01) and FFMBMI (Q5&ndash, Q1 0.05 kg/(kg/m2) 95% CI 0.04, 0.06, 0.01), comparing extreme adherence quintiles. Higher MDS was also associated with reduced total fractures (Q5&ndash, Q1 HR 0.83, 95% CI 0.71, 0.96, p-trend = 0.03) and significantly higher BUA (Q5&ndash, Q1 1.4 dB/MHz 95% CI 0.5, 2.3, Q1 0.03 kg/(kg/m2) 95% CI 0.01, 0.04, 0.01). This evidence supports the need to develop interventions to enhance MD adherence, particularly in women, where evidence for associations was stronger.

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.

$\textbf{BACKGROUND}$: Adults with low concentrations of 25-hydroxyvitamin D (25[OH]D) in blood have an increased risk of falls and fractures, but randomised trials of vitamin D supplementation have had inconsistent results. We aimed to assess the effect of high-dose vitamin D supplementation on fractures and falls. $\textbf{METHODS}$: The Vitamin D Assessment (ViDA) Study was a randomised, double-blind, placebo-controlled trial of healthy volunteers aged 50-84 years conducted at one centre in Auckland, New Zealand. Participants were randomly assigned to receive either an initial oral dose of 200 000 IU (5·0 mg) colecalciferol (vitamin D3) followed by monthly 100 000 IU (2·5 mg) colecalciferol or equivalent placebo dosing. The prespecified primary outcome was cardiovascular disease and secondary outcomes were respiratory illness and fractures. Here, we report secondary outcome data for fractures and post-hoc outcome data for falls. Cox proportional hazards models were used to estimate hazard ratios (HRs) for time to first fracture or time to first fall in individuals allocated vitamin D compared with placebo. The analysis of fractures included all participants who gave consent and was by intention-to-treat; the analysis of falls included all individuals who returned one or more questionnaires. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000402943. $\textbf{FINDINGS}$: Between April 5, 2011, and Nov 6, 2012, 5110 participants were recruited and randomly assigned either colecalciferol (n=2558) or placebo (n=2552). Two participants allocated placebo withdrew consent after randomisation; thus, a total of 5108 individuals were included in the analysis of fractures. The mean age of participants was 65·9 years (SD 8·3) and 2971 (58%) were men. The mean concentration of 25(OH)D in blood was 63 nmol/L (SD 24) at baseline, with 1534 (30%) having 25(OH)D concentrations lower than 50 nmol/L. Follow-up was until July 31, 2015, with a mean treatment duration of 3·4 years (SD 0·4, range 2·5-4·2). During follow-up, 2638 participants reported having a fall, 1312 (52%) of 2539 in the vitamin D group compared with 1326 (53%) of 2517 in the placebo group. The HR for falls-adjusted for age, sex, ethnic origin, history of recent fall, physical activity, and baseline 25(OH)D-was 0·99 (95% CI 0·92-1·07; p=0·82) for vitamin D compared with placebo. Non-vertebral fractures were reported in 292 individuals, 156 (6%) of 2558 in the vitamin D group and 136 (5%) of 2550 in the placebo group. The adjusted HR for fractures was 1·19 (95% CI 0·94-1·50; p=0·15) for vitamin D compared with placebo. 123 (2%) people died during the trial, 65 assigned vitamin D and 58 allocated placebo; the difference between treatment groups was not significant. $\textbf{INTERPRETATION}$: High-dose bolus vitamin D supplementation of 100 000 IU colecalciferol monthly over 2·5-4·2 years did not prevent falls or fractures in this healthy, ambulatory, adult population. Further research is needed to ascertain the effects of daily vitamin D dosing, with or without calcium. $\textbf{FUNDING}$: Health Research Council of New Zealand and Accident Compensation Corporation of New Zealand.

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A, with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

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

INTRODUCTION: Dutch cardiovascular disease (CVD) prevention guidelines recommend the use of modified SCORE risk charts to estimate 10-year risk of fatal and nonfatal CVD (myocardial infarction, cerebrovascular disease and congestive heart failure). This combined risk is derived from the SCORE mortality risk using multipliers. These multipliers have been shown to underestimate overall CVD risk. We aimed to compare the current Dutch risk charts with charts that estimate a broader range of clinically relevant CVD using updated multipliers. METHODS: We constructed new risk charts for 10-year CVD using updated, recently published multipliers from the EPIC-Norfolk study, based on ratios of fatal CVD to clinically relevant CVD (fatal plus nonfatal CVD requiring hospitalisation for ischaemic heart disease, cardiac failure, cerebrovascular disease, peripheral artery disease, and aortic aneurysm). Our primary outcome was the proportion of the three risk categories, i. e. 'high risk' (>20% 10-year risk), 'intermediate risk' (10-19%) and 'low risk' (

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.

MOTIVATION: The use of single nucleotide polymorphism (SNP) interactions to predict complex diseases is getting more attention during the past decade, but related statistical methods are still immature. We previously proposed the SNP Interaction Pattern Identifier (SIPI) approach to evaluate 45 SNP interaction patterns/patterns. SIPI is statistically powerful but suffers from a large computation burden. For large-scale studies, it is necessary to use a powerful and computation-efficient method. The objective of this study is to develop an evidence-based mini-version of SIPI as the screening tool or solitary use and to evaluate the impact of inheritance mode and model structure on detecting SNP-SNP interactions. RESULTS: We tested two candidate approaches: the 'Five-Full' and 'AA9int' method. The Five-Full approach is composed of the five full interaction models considering three inheritance modes (additive, dominant and recessive). The AA9int approach is composed of nine interaction models by considering non-hierarchical model structure and the additive mode. Our simulation results show that AA9int has similar statistical power compared to SIPI and is superior to the Five-Full approach, and the impact of the non-hierarchical model structure is greater than that of the inheritance mode in detecting SNP-SNP interactions. In summary, it is recommended that AA9int is a powerful tool to be used either alone or as the screening stage of a two-stage approach (AA9int+SIPI) for detecting SNP-SNP interactions in large-scale studies. AVAILABILITY AND IMPLEMENTATION: The 'AA9int' and 'parAA9int' functions (standard and parallel computing version) are added in the SIPI R package, which is freely available at https://linhuiyi.github.io/LinHY_Software/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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.

Background Calcific aortic valve stenosis (CAVS) is the most prevalent heart valve disease in Western societies. The American Heart Association 2020 Strategic Impact Goals introduced the concept of ideal cardiovascular health, which includes seven cardiovascular health metrics, namely body mass index, a healthy diet, physical activity, smoking status, blood pressure, fasting plasma glucose and cholesterol levels. Several prospective studies have shown that compared to people who meet few of the criteria of ideal cardiovascular health, those with ideal cardiovascular health have an 80–90% lower risk of cardiovascular events. Whether or not ideal cardiovascular health is associated with CAVS risk is unknown. The purpose of this study was to assess the association between ideal cardiovascular health status and the risk of CAVS. Methods In this analysis of the EPIC-Norfolk study, 21,856 participants were followed for 11.5 years and 430 of them developed CAVS. A cardiovascular health score was calculated based on the number of the seven health metrics. Results In comparison to individuals in the bottom quartile of ideal cardiovascular health (CAVS event rate of 2,9%), those in the top quartile of the ideal cardiovascular health score had a relative risk of CAVS of 0,45 (95% CI 0,31-0,65, AVS event rate of 0,8%). Conclusions In apparently healthy individuals, modifiable clinical and lifestyle-related risk factors for CVD are strongly associated with the risk of CAVS, thereby suggesting that CAVS may be a preventable disease.

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.

AIM: Crowdsourcing is the process of simplifying and outsourcing numerous tasks to many untrained individuals. Our aim was to assess the performance and repeatability of crowdsourcing in the classification of normal and glaucomatous discs from optic disc images.METHODS: Optic disc images (N = 127) with pre-determined disease status were selected by consensus agreement from grading experts from a large cohort study. After reading brief illustrative instructions, we requested that knowledge workers (KWs) from a crowdsourcing platform (Amazon MTurk) classified each image as normal or abnormal. Each image was classified 20 times by different KWs. Two study designs were examined to assess the effect of varying KW experience and both study designs were conducted twice for consistency. Performance was assessed by comparing the sensitivity, specificity and area under the receiver operating characteristic curve (AUC).RESULTS: Overall, 2,540 classifications were received in under 24 hours at minimal cost. The sensitivity ranged between 83-88% across both trials and study designs, however the specificity was poor, ranging between 35-43%. In trial 1, the highest AUC (95%CI) was 0.64(0.62-0.66) and in trial 2 it was 0.63(0.61-0.65). There were no significant differences between study design or trials conducted.CONCLUSIONS: Crowdsourcing represents a cost-effective method of image analysis which demonstrates good repeatability and a high sensitivity. Optimisation of variables such as reward schemes, mode of image presentation, expanded response options and incorporation of training modules should be examined to determine their effect on the accuracy and reliability of this technique in retinal image analysis.

Importance: Previous randomized controlled trials have provided inconsistent results on the effect of vitamin D supplementation on cancer incidence. Objective: To determine if monthly high-dose vitamin D supplementation, without calcium, reduces cancer incidence and cancer mortality in the general population. Design: Randomized, double-blind, placebo-controlled trial, participants recruited from April 2011 to November 2012, follow-up until December 2015. Setting: Recruited mostly from family practices in Auckland, New Zealand. Participants: Community-resident adults, aged 50-84 years. Out of 47,905 adults invited from family practices, and 163 from community groups, 5,110 participants were randomized to vitamin D3 (n=2,558) or placebo (n=2,552). Two participants withdrew consent, and all others (n=5,108) were included in the primary analysis. Intervention: Oral vitamin D3, initial bolus dose of 200,000 IU, followed one month later by monthly doses of 100,000 IU, or placebo, for median of 3.3 years (range: 2.5–4.2 years). Main Outcomes and Measures: The post-hoc primary outcome was all primary neoplasms (invasive and in-situ), aside from non-melanoma skin cancers, diagnosed from randomization to stopping the study medication (31 July 2015). Secondary outcomes were all neoplasms: from randomization to 31 December 2015; from >12 months after randomization to both stopping the study medication and also to 31 December 2015; and fatal neoplasms from randomization to 31 December 2015., Major funding was provided by the Health Research Council of New Zealand (grant 10/400), and by the Accident Compensation Corporation of New Zealand.

Importance Pharmacological enhancers of lipoprotein lipase (LPL) are in preclinical or early clinical development for cardiovascular prevention. Studying whether these agents will reduce cardiovascular events or diabetes risk when added to existing lipid-lowering drugs would require large outcome trials. Human genetics studies can help prioritize or deprioritize these resource-demanding endeavors. Objective To investigate the independent and combined associations of genetically determined differences in LPL-mediated lipolysis and low-density lipoprotein cholesterol (LDL-C) metabolism with risk of coronary disease and diabetes. Design, Setting, and Participants In this genetic association study, individual-level genetic data from 392 220 participants from 2 population-based cohort studies and 1 case-cohort study conducted in Europe were included. Data were collected from January 1991 to July 2018, and data were analyzed from July 2014 to July 2018. Exposures Six conditionally independent triglyceride-lowering alleles in LPL, the p.Glu40Lys variant in ANGPTL4, rare loss-of-function variants in ANGPTL3, and LDL-C–lowering polymorphisms at 58 independent genomic regions, including HMGCR, NPC1L1, and PCSK9. Main Outcomes and Measures Odds ratio for coronary artery disease and type 2 diabetes. Results Of the 392 220 participants included, 211 915 (54.0%) were female, and the mean (SD) age was 57 (8) years. Triglyceride-lowering alleles in LPL were associated with protection from coronary disease (approximately 40% lower odds per SD of genetically lower triglycerides) and type 2 diabetes (approximately 30% lower odds) in people above or below the median of the population distribution of LDL-C–lowering alleles at 58 independent genomic regions, HMGCR, NPC1L1, or PCSK9. Associations with lower risk were consistent in quintiles of the distribution of LDL-C–lowering alleles and 2 × 2 factorial genetic analyses. The 40Lys variant in ANGPTL4 was associated with protection from coronary disease and type 2 diabetes in groups with genetically higher or lower LDL-C. For a genetic difference of 0.23 SDs in LDL-C, ANGPTL3 loss-of-function variants, which also have beneficial associations with LPL lipolysis, were associated with greater protection against coronary disease than other LDL-C–lowering genetic mechanisms (ANGPTL3 loss-of-function variants: odds ratio, 0.66; 95% CI, 0.52-0.83; 58 LDL-C–lowering variants: odds ratio, 0.90; 95% CI, 0.89-0.91; P for heterogeneity = .009). Conclusions and Relevance Triglyceride-lowering alleles in the LPL pathway are associated with lower risk of coronary disease and type 2 diabetes independently of LDL-C–lowering genetic mechanisms. These findings provide human genetics evidence to support the development of agents that enhance LPL-mediated lipolysis for further clinical benefit in addition to LDL-C–lowering therapy.

Background and aims Long-term statin use increases survival. However, the adherence to and persistence with statin use are challenging and this influences the success of statin treatment. Our aim was to explore if monthly vitamin D supplementation (100,000-IU) improves the adherence to and persistence with long-term statin use in older adults. Methods We conducted a secondary analysis of a trial comparing data on dispensed statin prescriptions, between participants allocated to vitamin D supplementation or placebo, for those taking statin therapy. Primary outcomes were defined as adherence to (proportion of days covered by prescriptions ≥80%) and persistence (non-discontinuation of the statin therapy following an allowed 30 days gap between refills) with all statins over a 24-month measurement period of statin therapy. Secondary outcomes were defined as adherence and persistence at other measurement periods for all types of statins and for individual statins. Results Overall, 2494 participants were on long-term statins at follow-up (vitamin D = 1243, placebo = 1251). Compared with placebo, monthly vitamin D supplementation did not improve the proportion with adherence (risk ratio: 1.01, p=0.62), but improved the persistence probability of taking all statins after 24 months (hazard ratio: 1.15, p=0.02). In further analyses, significant differences were observed in the adherence to simvastatin, the first-line statin therapy. Conclusions Monthly vitamin D supplementation improved persistence with statins use over a 24-month measurement period in older adults on long-term statin therapy, especially for participants on simvastatin. The role of vitamin D supplementation as an adjunct therapy for patients on long-term statins merits further investigation.

PURPOSE: A common missense variant in the SIX6 gene (rs33912345) is strongly associated with primary open-angle glaucoma (POAG). We aimed to examine the association of rs33912345 with optic disc and retinal nerve fiber layer (RNFL) measures in a European population. METHODS: We examined participants of the population-based EPIC-Norfolk Eye Study. Participants underwent confocal laser scanning tomography (Heidelberg Retina Tomograph II, HRT) to estimate optic disc rim area and vertical cup-disc ratio (VCDR). Scanning laser polarimetry (GDxVCC) was used to estimate average RNFL thickness. The mean of right and left eye values was considered for each participant. Genotyping was performed using the Affymetrix UK Biobank Axiom Array. Multivariable linear regression with the optic nerve head parameter as outcome variable and dosage of rs33912345 genotype as primary explanatory variable was used, adjusted for age, sex, disc area, axial length and intraocular pressure. We further repeated analyses stratified into age tertiles. RESULTS: In total, 5,433 participants with HRT data and 3,699 participants with GDxVCC data were included. Each “C” allele of rs33912345 was associated with a smaller rim area (-0.030mm(2) [95% CI -0.040, -0.020], P=5.4x10(-9)), a larger VCDR (0.025 [95% CI 0.017, 0.033], P=3.3x10(-10)) and a thinner RNFL (-0.39μm [95% CI -0.62, -0.15], P=0.001). The RNFL association was strongest in the oldest age tertile, whereas rim area and VCDR associations were strongest in the youngest and oldest age tertiles. CONCLUSIONS: The protein coding SIX6 variant rs33912345, previously associated with POAG, has a functional effect on glaucoma-associated optic nerve head traits in Europeans.

OBJECTIVES: To describe the research methods for the development of a new open source, cross-platform tool which processes data from the European Prospective Investigation into Cancer and Nutrition Norfolk Food Frequency Questionnaire (EPIC-Norfolk FFQ). A further aim was to compare nutrient and food group values derived from the current tool (FETA, FFQ EPIC Tool for Analysis) with the previously validated but less accessible tool, CAFÉ (Compositional Analyses from Frequency Estimates). The effect of text matching on intake data was also investigated. DESIGN: Cross-sectional analysis of a prospective cohort study-EPIC-Norfolk. SETTING: East England population (city of Norwich and its surrounding small towns and rural areas). PARTICIPANTS: Complete FFQ data from 11 250 men and 13 602 women (mean age 59 years; range 40-79 years). OUTCOME MEASURES: Nutrient and food group intakes derived from FETA and CAFÉ analyses of EPIC-Norfolk FFQ data. RESULTS: Nutrient outputs from FETA and CAFÉ were similar; mean (SD) energy intake from FETA was 9222 kJ (2633) in men, 8113 kJ (2296) in women, compared with CAFÉ intakes of 9175 kJ (2630) in men, 8091 kJ (2298) in women. The majority of differences resulted in one or less quintile change (98.7%). Only mean daily fruit and vegetable food group intakes were higher in women than in men (278 vs 212 and 284 vs 255 g, respectively). Quintile changes were evident for all nutrients, with the exception of alcohol, when text matching was not executed; however, only the cereals food group was affected. CONCLUSIONS: FETA produces similar nutrient and food group values to the previously validated CAFÉ but has the advantages of being open source, cross-platform and complete with a data-entry form directly compatible with the software. The tool will facilitate research using the EPIC-Norfolk FFQ, and can be customised for different study populations.

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

The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure(1). The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion(2,3). However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)(4-8). Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.

Although observational studies suggest positive vitamin D-lung function associations, randomized trials are inconsistent. We examined effects of vitamin D supplementation on lung function. We recruited 442 adults (50-84 years, 58% male) into a randomized, double-blinded, placebo-controlled trial. Participants received, for 1.1 years (median; range = 0.9-1.5 years), either (1) vitamin D₃ 200,000 IU, followed by monthly 100,000 IU doses (n = 226); or (2) placebo monthly (n = 216). At baseline and follow-up, spirometry yielded forced expiratory volume in 1 s (FEV1; primary outcome). Mean (standard deviation) 25-hydroxyvitamin D increased from 61 (24) nmol/L at baseline to 119 (45) nmol/L at follow-up in the vitamin D group, but was unchanged in the placebo group. There were no significant lung function improvements (vitamin D versus placebo) in the total sample, vitamin D-deficient participants or asthma/chronic obstructive pulmonary disease (COPD) participants. However, among ever-smokers (n = 217), the mean (95% confidence interval) FEV1 increase in the vitamin D versus placebo was 57 (4, 109) mL (p = 0.03). FEV1 increases were larger among vitamin D-deficient ever-smokers (n = 54): 122 (8, 236) mL (p = 0.04). FEV1 improvements were largest among ever-smokers with asthma/COPD (n = 60): 160 (53, 268) mL (p = 0.004). Thus, vitamin D supplementation did not improve lung function among everyone, but benefited ever-smokers, especially those with vitamin D deficiency or asthma/COPD.

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.

Observational studies suggest that vitamin D deficiency is associated with higher risk of pain. However, evidence on the effect of vitamin D supplementation on pain is limited and contradictory. The aim of this study was to compare the effect of monthly high-dose vitamin D supplementation on a pain impact questionnaire (PIQ-6) score and prescription of analgesics in the general population. We performed a randomized, double-blind, placebo-controlled trial of 5108 community-dwelling participants, aged 50 to 84 years, who were randomly assigned to receive monthly 100,000-IU capsules of vitamin D3 (n = 2558) or placebo (n = 2550) for a median of 3.3 years. The PIQ-6 was administered at baseline, year 1, and final follow-up. Analgesic prescription data were collected from Ministry of Health. There was no difference in mean PIQ-6 score at the end of follow-up (adjusted mean difference: 0.06; P = 0.82) between the vitamin D (n = 2041) and placebo (n = 2014) participants. The proportion of participants dispensed one or more opioids was similar in the vitamin D group (n = 559, 21.9%) compared with placebo (n = 593, 23.3%); the relative risk (RR) adjusted for age, sex, and ethnicity was 0.94 (P = 0.24). Similar results were observed for dispensing of nonsteroidal anti-inflammatory drugs (RR = 0.94; P = 0.24) and other nonopioids (RR = 0.98; P = 0.34). Focusing on vitamin D deficient participants (

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P, B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.

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.

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published

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.

OBJECTIVES: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. DESIGN: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. SETTING: Multiple institutions that were members of international PRACTICAL consortium. PARTICIPANTS: All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. MAIN OUTCOME MEASURES: Prediction with hazard score of age of onset of aggressive cancer in validation set. RESULTS: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. CONCLUSIONS: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

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

Graphical abstract, Highlights • Physical capability predicts mortality in community-based British men and women. • Mortality associations are similar in mid- (48–69 years) and late-life (70+ years). • Co-morbidity burden and shared risk factors did not explain associations. • Biological mechanisms linking physical capability and mortality could be explored., Introduction Low physical capability predicts mortality, perhaps by association with co-morbidity. However, few studies include participants 0.05) and those with lower physical capability had higher mortality risk. For example, in those

[Objectives]: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis., [Methods]: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies., [Results]: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10−9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures., [Conclusion]: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism., ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK and the European Union framework programme 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We would like to acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. CABRIO was supported by the Instituto de Salud Carlos III and Fondos FEDER from the EU (PI 11/1092 and PI12/615). The AOGC study was funded by the Australian National Health and Medical Research Council (Project grant 511132). Lothian Birth Cohort 1921 phenotype collection was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Genotyping of the cohorts was funded by the BBSRC. The work was undertaken by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. Research work on Slovenian case and control samples was funded by Slovenian Research Agency (project no. P3-0298 and J3-2330). The Danish National Birth Cohort (DNBC) is a result of major grants from the Danish National Research Foundation, the Danish Pharmacists’ Fund, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Fund of the Danish Health Insurance Societies. The DNBC biobank is a part of the Danish National Biobank resource, which is supported by the Novo Nordisk Foundation. Dr Bjarke Feenstra is supported by an Oak Foundation Fellowship. The Framingham Study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and R01 AR061162; DPK and R01 AR 050066; DK). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA‐II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. This research was performed within the Genetic Factors for Osteoporosis (GEFOS) consortium, funded by the European Commission (HEALTH-F2-2008-201865-GEFOS).

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.

EPIC-Norfolk infrastructure and core functions are supported by grants from the Medical Research Council (G0401527) and Cancer Research UK (C864/A8257). The clinic for the third health examination was funded by Research into Ageing (262). MPYC was supported by a joint Medical Research Council/Royal College of Ophthalmologists clinical training fellowship (G1001939/1) and the International Glaucoma Association. APK was a Wellcome Trust clinical research fellow (094791Z/10/Z). DGH, PJF, and JB were supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, and PF received additional support from The Richard Desmond Charitable Trust. Objectives : To report the distribution of intraocular pressure (IOP) by age and sex and the prevalence of glaucoma. Design: Community based cross sectional observational study. Setting: EPIC-Norfolk cohort in Norwich and the surrounding rural and urban areas. Participants: 8623 participants aged 48-92 recruited from the community who underwent ocular examination to identify glaucoma. Main outcome measures: Prevalence and characteristics of glaucoma, distribution of IOP, and the sensitivity and specificity of IOP for case finding for glaucoma. Results: The mean IOP in 8401 participants was 16.3 mm Hg (95% confidence interval 16.2 mm Hg to 16.3 mm Hg; SD 3.6 mm Hg). In 363 participants (4%), glaucoma was present in either eye; 314 (87%) had primary open angle glaucoma. In the remaining participants, glaucoma was suspected in 607 (7%), and 863 (10.0%) had ocular hypertension. Two thirds (242) of those with glaucoma had previously already received the diagnosis. In 76% of patients with newly diagnosed primary open angle glaucoma (83/107), the mean IOP was under the threshold for ocular hypertension (21 mm Hg). No one IOP threshold provided adequately high sensitivity and specificity for diagnosis of glaucoma. Conclusions: In this British community, cases of glaucoma, suspected glaucoma, and ocular hypertension represent a large number of potential referrals to the hospital eye service. The use of IOP for detection of those with glaucoma is inaccurate and probably not viable. Publisher PDF

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.