Search

Abstract Background There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. Results After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with q val = 0.029 and q val = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. Conclusions Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses indicated that dietary folate and alcohol intake may be associated with genomic regions with tumor suppressor activity such as the GSDMD and HOXA5 genes. These results were in line with the hypothesis that epigenetic mechanisms play a role in the association between folate and alcohol, although further studies are warranted to clarify the importance of these mechanisms in cancer.

Background There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. Methods and Results We conducted a case-cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country-specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice-weighted Cox regression models and pooled results using random-effects meta-analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88-0.99]), cheese (HR, 0.98 [95% CI, 0.96-1.00]), and fish (HR, 0.87 [95% CI, 0.75-1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02-1.12]) and butter (HR, 1.02 [95% CI, 1.00-1.04]). Conclusions This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix.

Purpose: To describe the patterns of ultra-processed foods (UPFs) consumption in the Netherlands; to test if exposure to the food environment is associated with UPFs consumption; and if this association differed across educational levels and neighbourhood urbanisation., Methods: Cross-sectional study using 2015-data of 8104 older adults from the Dutch EPIC cohort. Proportion of UPFs consumption was calculated from a validated food-frequency questionnaire. Exposure to the food environment was defined as proximity and availability of supermarkets, fast-food restaurants, full-service restaurants, convenience stores, candy stores and cafés. Consumption of UPFs was expressed as both percentage of total grams and total kilocalories., Results: The study population was aged 70(± 10 SD) years and 80.5% was female. Average UPFs consumption was 17.8% of total food intake in grams and 37% of total energy intake. Those who consumed greater amounts of UPFs had a poorer overall diet quality. Adjusted linear regression models showed that closer proximity and larger availability to any type of food retailer was associated with lower UPFs consumption (both in grams and kilocalories). Somewhat stronger significant associations were found for proximity to restaurants (β = - 1.6%, 95% confidence interval (CI) = - 2.6; - 0.6), and supermarkets (β = - 2.2%, 95%CI = - 3.3; - 1.1); i.e., Individuals living within 500 m from the closest supermarket, as compared to 1500 m, had 2.6% less calories from UPFs. No differences were found on analyses stratified for urbanisation and education., Conclusions: Using various measures of exposure to the food environment, we found that exposure to restaurants and supermarkets was associated with somewhat lower consumption of UPFs., (© 2020. The Author(s).)

Background: Epidemiological evidence indicates that diets rich in plant foods are associated with a lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre. This study examined the associations of major plant foods, their subtypes and dietary fibre with risk of IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC)., Methods: We conducted a prospective analysis of 490 311 men and women without a history of myocardial infarction or stroke at recruitment (12.6 years of follow-up, n cases = 8504), in 10 European countries. Dietary intake was assessed using validated questionnaires, calibrated with 24-h recalls. Multivariable Cox regressions were used to estimate hazard ratios (HR) of IHD., Results: There was a lower risk of IHD with a higher intake of fruit and vegetables combined [HR per 200 g/day higher intake 0.94, 95% confidence interval (CI): 0.90-0.99, P-trend = 0.009], and with total fruits (per 100 g/day 0.97, 0.95-1.00, P-trend = 0.021). There was no evidence for a reduced risk for fruit subtypes, except for bananas. Risk was lower with higher intakes of nuts and seeds (per 10 g/day 0.90, 0.82-0.98, P-trend = 0.020), total fibre (per 10 g/day 0.91, 0.85-0.98, P-trend = 0.015), fruit and vegetable fibre (per 4 g/day 0.95, 0.91-0.99, P-trend = 0.022) and fruit fibre (per 2 g/day 0.97, 0.95-1.00, P-trend = 0.045). No associations were observed between vegetables, vegetables subtypes, legumes, cereals and IHD risk., Conclusions: In this large prospective study, we found some small inverse associations between plant foods and IHD risk, with fruit and vegetables combined being the most strongly inversely associated with risk. Whether these small associations are causal remains unclear., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Higher dairy consumption has been associated with lower type 2 diabetes (T2D) risk, whereas dairy product subtypes appear to differ in their T2D risk association. We investigated whether replacing one type of milk or yogurt product with another is associated with T2D incidence., Methods: Participants of the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) cohort (n = 35 982) were included in the present study. Information on milk and yogurt consumption at baseline was obtained by a validated food frequency questionnaire. T2D cases were identified by self-report or linkage to the hospital discharge registry, and validated by consulting the general practitioner. Multivariable Cox proportional hazard models were used to estimate associations., Results: During a mean of 15 years of follow-up, 1467 indecent T2D cases were validated. Median total milk and yogurt intake was 1.5 servings (25th percentile to 75th percentile: 0.8-2.4). After adjustment for demographic and cardiovascular risk factors, replacement of one serving (200 g) of whole-fat milk [hazard ratio (HR) = 0.93, 95% confidence interval (CI) = 0.60-1.44], buttermilk (HR = 0.88, 95% CI = 0.58-1.34), skimmed milk (HR = 0.87, 95% CI = 0.57-1.32) or skimmed fermented milk (HR = 0.99, 95% CI = 0.63-1.54) with whole-fat yogurt was not associated with T2D risk. Substitutions among other milk and yogurt products were also not associated with T2D risk. Sensitivity analysis investigating T2D risk halfway follow-up suggested a lower risk for substitutions with whole-fat yogurt., Conclusions: No evidence was found for the association between substitutions among milk and yogurt products and the risk of incident T2D, although we cannot exclude possible attenuation of results as a result of dietary changes over time. This analysis should be repeated in a population with a wider consumption range of whole-fat yogurt., (© 2020 The Authors. Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)

Background and Aims: It is still unclear whether a healthy diet can prevent heart failure (HF). Therefore, this study aimed to investigate the association between adherence to a Mediterranean-style diet, reflected by modified Mediterranean Diet Scores (mMDS), and the incidence of HF in men and women., Methods and Results: This observational study comprised 9316 men and 27,645 women from the EPIC-NL cohort free from cardiovascular disease at baseline. Dietary intakes were assessed using a validated food frequency questionnaire. mMDS was calculated using a 9-point scale based on consumption of vegetables, legumes, fruit, nuts, seeds, grains, fish, fat ratio, dairy, meat and alcohol. HF events were ascertained by linkage to nation-wide registries. Multivariable Hazard Ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazards regression models. Over a median follow-up of 15 years (IQR 14-16), 633 HF events occurred: 144 in men (1.5%) and 489 in women (1.8%). The median mMDS was 4 (IQR 3-5). There was significant effect modification by sex (P-value for interaction <0.001), therefore results are stratified for men and women. For men, a higher mMDS associated with lower HF risk (HR: 0.88; 95% CI: 0.79, 0.98 per point increase in mMDS; HR upper category: 0.53; 95% CI: 0.33, 0.86), whereas no association was found in women (HR: 0.98; 95% CI: 0.93, 1.04 per point increase; HR upper category: 1.07; 95% CI: 0.83, 1.36)., Conclusion: Adherence to a Mediterranean-style diet may reduce HF risk, particularly in men. The underlying reasons for the differences in findings between men and women need further study., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Purpose: A healthy diet may contribute to the primary prevention of heart failure (HF), but evidence is still inconclusive. We aimed to study the association between adherence to the Dutch dietary guidelines and incidence of HF., Methods: We studied 37,468 participants aged 20-70 years and free of HF at baseline from the EPIC-NL cohort. At baseline (1993-1997), data were collected on demographics, lifestyle, and presence of chronic diseases. Dietary intake was assessed using a 178-item validated food frequency questionnaire. Dietary intake data were used to calculate scores on the Dutch Healthy Diet 2015 Index (DHD15-index) measuring adherence to the Dutch dietary guidelines. The DHD15-index is based on the average daily intake of 14 food groups resulting in a total score ranging between 0 and 140, with higher scores indicating better adherence. HF morbidity and mortality during follow-up were ascertained through linkage with national registries. Cox proportional hazards analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between DHD15 adherence and HF risk, adjusting for sociodemographic and lifestyle characteristics., Results: The average score on the DHD15-index was 71 (SD = 15). During a median follow-up of 15.2 years (IQR 14.1-16.5), 674 HF events occurred. After adjustment for demographic and lifestyle characteristics, higher scores on the DHD15-index were associated with lower risk of HF (HR Q4vsQ1 0.73; 95% CI 0.58-0.93; P trend 0.001)., Conclusion: In a large Dutch population of middle-aged adults, higher adherence to the Dutch dietary guidelines was associated with lower risk of HF.

Background: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis., Methods and Findings: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities., Conclusions: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: FI and CL are Academic Editors on PLOS Medicine’s editorial board. LAL is Employee and shareholder of Regeneron Pharmaceuticals Inc. ASB has received grants unrelated to this work from AstraZeneca, Biogen, Bioverativ, Merck, Novartis and Sanofi, and personal fees from Novartis. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.

Background: Adults with a low socioeconomic position (SEP) are more likely to engage in unhealthy diets as compared to adults with high SEP. However, individual-level educational interventions aiming to improve food choices have shown limited effectiveness in adults with low SEP. Environmental-level interventions such as nudging strategies however, may be more likely to benefit low SEP groups. We aimed to review the evidence for the effectiveness of nudges as classified according to interventions in proximal physical micro-environments typology (TIPPME) to promote healthy purchases, food choice, or affecting energy intake or content of purchases, within real-life food purchasing environments. Second, we aimed to investigate the potentially moderating role of SEP., Methods: We systematically searched PubMed, EMBASE, and PsycINFO until 31 January 2018. Studies were considered eligible for inclusion when they i) complied with TIPPME intervention definitions; ii) studied actual purchases, food choice, or energy intake or content of purchases, iii) and were situated in real-life food purchasing environments. Risk of bias was assessed using a quality assessment tool and evidence was synthesized using harvest plots., Results: From the 9210 references identified, 75 studies were included. Studies were generally of weak to moderate quality. The most frequently studied nudges were information (56%), mixed (24%), and position nudges (13%). Harvest plots showed modest tendencies towards beneficial effects on outcomes for information and position nudges. Less evidence was available for other TIPPME nudging interventions for which the harvest plots did not show compelling patterns. Only six studies evaluated the effects of nudges across levels of SEP (e.g., educational level, food security status, job type). Although there were some indications that nudges were more effective in low SEP groups, the limited amount of evidence and different proxies of SEP used warrant caution in the interpretation of findings., Conclusions: Information and position nudges may contribute to improving population dietary behaviours. Evidence investigating the moderating role of SEP was limited, although some studies reported greater effects in low SEP subgroups. We conclude that more high-quality studies obtaining detailed data on participant's SEP are needed., Registration: This systematic review is registered in the PROSPERO database ( CRD42018086983 ).

Background: High carbohydrate intake raises blood triglycerides, glucose, and insulin; reduces HDLs; and may increase risk of coronary heart disease (CHD). Epidemiological studies indicate that high dietary glycemic index (GI) and glycemic load (GL) are associated with increased CHD risk., Objectives: The aim of this study was to determine whether dietary GI, GL, and available carbohydrates are associated with CHD risk in both sexes., Methods: This large prospective study-the European Prospective Investigation into Cancer and Nutrition-consisted of 338,325 participants who completed a dietary questionnaire. HRs with 95% CIs for a CHD event, in relation to intake of GI, GL, and carbohydrates, were estimated using covariate-adjusted Cox proportional hazard models., Results: After 12.8 y (median), 6378 participants had experienced a CHD event. High GL was associated with greater CHD risk [HR 1.16 (95% CI: 1.02, 1.31) highest vs. lowest quintile, p-trend 0.035; HR 1.18 (95% CI: 1.07, 1.29) per 50 g/day of GL intake]. The association between GL and CHD risk was evident in subjects with BMI (in kg/m2) ≥25 [HR: 1.22 (95% CI: 1.11, 1.35) per 50 g/d] but not in those with BMI <25 [HR: 1.09 (95% CI: 0.98, 1.22) per 50 g/d) (P-interaction = 0.022). The GL-CHD association did not differ between men [HR: 1.19 (95% CI: 1.08, 1.30) per 50 g/d] and women [HR: 1.22 (95% CI: 1.07, 1.40) per 50 g/d] (test for interaction not significant). GI was associated with CHD risk only in the continuous model [HR: 1.04 (95% CI: 1.00, 1.08) per 5 units/d]. High available carbohydrate was associated with greater CHD risk [HR: 1.11 (95% CI: 1.03, 1.18) per 50 g/d]. High sugar intake was associated with greater CHD risk [HR: 1.09 (95% CI: 1.02, 1.17) per 50 g/d]., Conclusions: This large pan-European study provides robust additional support for the hypothesis that a diet that induces a high glucose response is associated with greater CHD risk., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Background: Low socio-economic position is associated with consumption of lower quality diets, which may be partly explained by the cost of healthier diets. Therefore, we aimed to investigate the mediating role of dietary costs in the association between educational level and diet quality., Methods: We used cross-sectional data from Dutch older adults (N = 9399) in the EPIC-NL cohort. Participants provided information about their own and their partners' highest attained educational level (as proxy for socio-economic position). Dietary behavior was assessed using a food frequency questionnaire from which we derived two diet-quality scores, including the Dutch Healthy Diet index 2015 (DHD15-index) and the Dietary Approaches to Stop Hypertension (DASH) diet. Dietary cost estimates were based on food price data from food stores, and linked to reported consumption of food items. Multiple regression analyses and bootstrapping were used examine the mediating role of dietary cost in the association between educational level and diet quality., Results: Mean age of participants was 70 (SD: 10) years and 77% were women. Dietary costs significantly mediated the association between educational level and diet quality, except for high versus middle individual educational level and the DHD15-index. Depending on the dietary and educational indicator, dietary costs explained between 2 and 7% of the association between educational level and diet quality. Furthermore, associations were found to be modified by sex and age. For the DHD15-index, mediation effects were only present in females and adults older than 65 years, and for the DASH diet mediation effects were only present in females and strongest amongst adults older than 65 years compared to adults younger than 65 years., Conclusion: Dietary costs seems to play a modest role in explaining educational differences in diet quality in an older Dutch population. Further research is needed to investigate which other factors may explain SEP differences in diet quality.

Background: Dietary guidelines on pure fruit juice consumption vary from country to country regarding the inclusion of pure fruit juice in the recommendations as an acceptable alternative for fruit. Current epidemiological evidence on the association between pure fruit juice consumption and diabetes risk is scarce., Objective: We studied the association of both pure fruit juice and fruit consumption with diabetes risk and investigated the differences between low and high fruit consumers in the association of pure fruit juice consumption with diabetes risk., Methods: This prospective cohort study included 36,147 participants in the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) Study aged 20-69 y at baseline. Fruit juice and fruit consumption were assessed using a validated food-frequency questionnaire; amounts of consumption were divided into 5 categories and quintiles, respectively. Incident type 2 diabetes cases were mainly self-reported and verified against medical records. Cox regression was used to estimate adjusted HRs and 95% CIs., Results: After an average follow-up of 14.6 y, 1477 verified incident cases of type 2 diabetes were documented. Compared with no consumption, pure fruit juice consumption was not significantly associated with type 2 diabetes, with adjusted HRs ranging from 0.92 (95% CI: 0.79, 1.09) to 1.03 (95% CI: 0.83, 1.26). The associations did not differ between participants with low and high fruit consumption. None of the categories of fruit consumption were associated with type 2 diabetes (lowest quintile as reference). Adjusted HRs ranged between 0.93 (95% CI: 0.78, 1.10) and 1.00 (95% CI: 0.84, 1.19). Adjustment for the Dutch Healthy Diet Index, as an overall measure of dietary quality, strongly attenuated the observed associations of type 2 diabetes with both fruit juice and fruit consumption., Conclusions: We found no evidence for associations between pure fruit juice and fruit consumption and diabetes risk after adjustment for overall dietary quality for participants in the EPIC-NL study. This trial was registered at https://www.trialregister.nl/trial/6939 as NL6939., (Copyright © The Author(s) 2020.)

Background and Aims: A higher dairy product intake has been associated to higher blood concentrations of 15:0 (pentadecanoic acid), 17:0 (margaric acid), and 14:0 (myristic acid). This study investigates whether a diet high in dairy products influences cholesteryl ester fatty acid concentrations of these specific fatty acids (FA)., Methods and Results: In a randomized multiple cross-over study, 13 men and 17 women aged 22 ± 4 years with a BMI of 21.6 ± 2.2 kg/m 2 received 3 isocaloric intervention diets (dairy, meat or grain) in random order. For this post-hoc analysis, FA in plasma cholesteryl esters were measured using gas chromatography. We performed a linear mixed model per centered log-ratio transformed FA, adjusting for period, and the interaction between diet and period. Consumed total fat intake per controlled intervention diet was 31.0 ± 0.9 en%/day (dairy), 31.5 ± 0.6 en%/day (meat), and 28.4 ± 1.2 en%/day (grain), respectively. The dairy diet led to higher relative concentrations of 15:0 when compared to diets high in meat and grain, (β; 0.27, 95%CI: 0.18,0.37; p = 1.2 × 10 -5 , and β: 0.15; 95%CI: 0.06,0.24; p = 1.2 × 10 -2 , respectively). The dairy diet also led to higher 14:0 when compared to the meat diet (β: 0.34; 95%CI: 0.21,0.46; p = 6.0 × 10 -5 ), but not when compared to the grain diet. 17:0 did not differ between diets., Conclusion: The plasma cholesteryl ester fraction after a diet high in dairy was characterized by higher 15:0 levels. Concentrations of 14:0 were only higher when comparing the FA profile after a diet high in dairy when compared to a diet high in meat., Clinical Trial Registration: ClinicalTrials.gov, NCT01314040., (Copyright © 2020 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Pharmacological lowering of inflammation has proven effective in reducing recurrent cardiovascular event rates. Aim of the current study is to evaluate lifestyle changes (smoking cessation, weight loss, physical activity level increase, alcohol moderation, and a summary lifestyle improvement score) in relation to change in plasma C-reactive protein (CRP) concentration in patients with established cardiovascular disease., Methods: In total, 1794 patients from the UCC-SMART cohort with stable cardiovascular disease and CRP levels ≤10 mg/L, who returned for a follow-up study visit after median 9.9 years (IQR 5.4-10.8), were included. The relation between changes in smoking status, weight, physical activity, alcohol consumption, a summary lifestyle improvement score and change in plasma CRP concentration was evaluated with linear regression analyses., Results: Smoking cessation was related to a 0.40 mg/L decline in CRP concentration (β-coefficient -0.40; 95%CI -0.73,-0.07). Weight loss (per 1SD = 6.4 kg) and increase in physical activity (per 1 SD = 48 MET hours per week) were related to a decrease in CRP concentration (β-coefficients -0.25; 95%CI -0.33,-0.16 and -0.09; 95%CI -0.17,-0.01 per SD). Change in alcohol consumption was not related to CRP difference. Every point higher in the summary lifestyle improvement score was related to a decrease in CRP concentration of 0.17 mg/L (β-coefficient -0.17; 95%CI -0.26,-0.07)., Conclusions: Smoking cessation, increase in physical activity, and weight loss are related to a decrease in CRP concentration in patients with stable cardiovascular disease. Patients with the highest summary lifestyle improvement score have the most decrease in CRP concentration. These results may indicate that healthy lifestyle changes contribute to lowering systemic inflammation, potentially leading to a lower cardiovascular risk in patients with established cardiovascular disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P.M. Ridker, has received investigator initiated research grants from Kowa, Novartis, Pfizer, AstraZeneca, NHLBI, NCI. Dr Ridker has served as a consultant to Corvidia, Inflammazome, Novartis, Amgen, Merck, and Civi Bio. Dr Ridker is listed as co-inventor on patents related to the use of inflammatory biomarkers in CVD and diabetes that are no longer active. F.W. Asselbergs reports grants from UCL Hospitals NIHR Biomedical Research Centre, outside the submitted work. The other authors have nothing to declare., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Multiple observational studies and small-scale intervention studies suggest that high vitamin K intake is associated with improved markers for cardiovascular health. Circulating phylloquinone solely represents phylloquinone (vitamin K1) intake, while dephosphorylated uncarboxylated Matrix Gla Protein (dp-ucMGP) represents both phylloquinone and menaquinone (vitamin K2) intake. This study aims to investigate the causal relationship between genetically predicted vitamin K concentrations and the risk of CHD via a two-sample Mendelian Randomization approach., Design: We used data from three studies: the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD case-cohort study, CARDIOGRAMplusC4D and the UK Biobank, resulting in 103,097 CHD cases. Genetically predicted vitamin K concentrations were measured using SNPs related to circulating phylloquinone and dp-ucMGP. We calculated a genetic risk score (GRS) including four SNPs (rs2108622, rs2192574, rs4645543 and rs6862071) related to circulating phylloquinone levels from a genome wide association study. Rs4236 was used as an instrumental variable for dp-ucMGP. Inverse-variance weighted (IVW) analysis was used to obtain Risk Ratios (RRs) for the causal relationship between phylloquinone and dp-ucMGP concentrations and CHD risk., Results: Using the genetic score for circulating phylloquinone, we found that circulating phylloquinone was not causally related to CHD risk (RR 1.00 (95%-CI: 0.98; 1.04)). Lower genetically predicted dp-ucMGP concentration was associated with a lower CHD risk with a RR of 0.96 (95%-CI: 0.93; 0.99) for every 10 μg/L decrease in dp-ucMGP., Conclusions: This study did not confirm a causal relationship between circulating phylloquinone and lower CHD risk. However, lower dp-ucMGP levels may be causally related with a decreased CHD risk. This inconsistent result may reflect the influence of menaquinones in the association with CHD., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To identify differences in dietary quality, dietary greenhouse gas (GHG) emissions and food consumption over 20 years in a Dutch cohort., Design: Participants (n 8932) filled out an FFQ in 1993-1997 and in 2015. The Dutch Healthy Diet index 2015 (DHD15-index) score, GHG emissions and consumption of food groups (g/4184 kJ (1000 kcal)) were compared between the time points with paired t tests., Setting: The Netherlands., Participants: European Prospective Investigation into Cancer and Nutrition - Netherlands (EPIC-NL) cohort, aged 18-65 years at baseline., Results: Total energy intake decreased by -678 (95 % CI -4908, 3377) kJ/d (-162 (95 % CI -1173, 807) kcal/d) for men and -372 (95 % CI -3820, 3130) kJ/d (-89 (95 % CI -913, 748) kcal/d) for women. DHD15-index scores increased by 11 % (from 64·8 to 71·9 points) and 13 % (from 65·2 to 73·6 points) in men and women, respectively (P < 0·0001), mainly due to an increased (shell)fish and nuts/seeds/nut paste consumption. After energy intake adjustment, dietary-related GHG emissions increased by 5 % in men (2·48-2·61 kg CO2-eq/4184 kJ (1000 kcal), P < 0·0001) and were similar in women (0·4 %, 2·70-2·71 kg CO2-eq/4184 kJ (1000 kcal), P = 0·3930) due to the increased consumption of (shell)fish, nuts/seeds/nut paste, poultry and higher GHG-intensive red meats such as beef., Conclusions: This Dutch cohort analyses showed more healthy diets without mitigated GHG emissions over a 20-year period, at similar energy intakes. Higher consumption of (shell)fish and poultry was not yet at the expense of red and processed meat. Lower consumption of animal-based foods is needed to achieve healthier as well as environmentally friendly diets.

Introduction: Beverage consumption is a modifiable risk factor for type 2 diabetes (T2D), but there is insufficient evidence to inform the suitability of substituting 1 type of beverage for another., Objective: The aim of this study was to estimate the risk of T2D when consumption of sugar-sweetened beverages (SSBs) was replaced with consumption of fruit juice, milk, coffee, or tea., Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study of 8 European countries (n = 27,662, with 12,333 cases of incident T2D, 1992-2007), beverage consumption was estimated at baseline by dietary questionnaires. Using Prentice-weighted Cox regression adjusting for other beverages and potential confounders, we estimated associations of substituting 1 type of beverage for another on incident T2D., Results: Mean ± SD of estimated consumption of SSB was 55 ± 105 g/d. Means ± SDs for the other beverages were as follows: fruit juice, 59 ± 101 g/d; milk, 209 ± 203 g/d; coffee, 381 ± 372 g/d; and tea, 152 ± 282 g/d. Substituting coffee for SSBs by 250 g/d was associated with a 21% lower incidence of T2D (95% CI: 12%, 29%). The rate difference was -12.0 (95% CI: -20.0, -5.0) per 10,000 person-years among adults consuming SSBs ≥250 g/d (absolute rate = 48.3/10,000). Substituting tea for SSBs was estimated to lower T2D incidence by 22% (95% CI: 15%, 28%) or -11.0 (95% CI: -20.0, -2.6) per 10,000 person-years, whereas substituting fruit juice or milk was estimated not to alter T2D risk significantly., Conclusions: These findings indicate a potential benefit of substituting coffee or tea for SSBs for the primary prevention of T2D and may help formulate public health recommendations on beverage consumption in different populations., (Copyright © American Society for Nutrition 2019.)

Purpose: The relationship of total, saturated, mono-unsaturated and poly-unsaturated fatty acids (SFA, MUFA, PUFA) with coronary heart disease (CHD) is debated. We hypothesized that the association of dairy-derived FA with CHD may be different than the association of meat-derived FA with CHD. We therefore aimed to directly compare association of FA intakes from dairy and meat with risk of CHD using substitution models., Methods: Baseline (1993-1997) FA intake was measured using a validated food frequency questionnaire among 35,767 participants from the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort (EPIC-NL). Incident CHD events (n = 2374) were obtained through linkage with national registries during a mean follow-up of 15 years. Association of FA from dairy substituted with FA from meat with CHD risk was estimated through multivariable Cox regression., Results: Participants consumed 81.9 (SD 28.7) grams of FA per day, of which 17.9 (SD 5.2) was from dairy and 15.3 (SD 9.5) from meat. Substituting 1 en% of dairy-derived SFA with meat-derived SFA was associated with higher CHD risk (HR 1.06, 95% CI 1.02-1.10), but substituting dairy-derived MUFA or PUFA did not (HR MUFA 1.03, 95% CI 0.97-1.09; HR PUFA 1.17, 95% CI 0.90-1.53)., Conclusions: Our modelling suggests that substituting dairy SFA with meat SFA is associated with a higher risk of CHD, but substituting dairy MUFA or PUFA with meat FA is not. These results need to be replicated in other cohorts with different fat intakes, preferably with larger variation in the intake of MUFA and PUFA from dairy and meat.

Objectives: The aim of this study is to determine whether combinations of specific Life's Simple 7 (LS7) components are associated with reduced risk for heart failure (HF)., Background: The American Heart Association recommends the concept of LS7: healthy behaviors that have been shown to reduce cardiovascular disease., Methods: A total of 37,803 participants from the EPIC-NL (European Prospective Investigation Into Cancer and Nutrition-Netherlands) cohort were included (mean age: 49.4 ± 11.9 years, 74.7% women). The LS7 score ranged from 0 to 14 and was calculated by assigning 0, 1, or 2 points for smoking, physical activity, body mass index, diet, blood pressure, total cholesterol, and blood glucose. An overall ideal score (11 to 14 points) was present in 23.2% of participants, an intermediate score (9 or 10 points) in 35.3%, and an inadequate score (0 to 8 points) in 41.5%., Results: Over a median follow-up period of 15.2 years (interquartile range: 14.1 to 16.5 years), 690 participants (1.8%) developed HF. In Cox proportional hazards models, ideal and intermediate LS7 scores were associated with reduced risk for HF compared with the inadequate category (hazard ratio: 0.45 [95% confidence interval (CI): 0.34 to 0.60] and hazard ratio: 0.53 [95% CI: 0.44 to 0.64], respectively). Our analyses show that combinations with specific LS7 components, notably glucose, body mass index, smoking, and blood pressure, are associated with a lower incidence of HF., Conclusions: A healthy lifestyle, as reflected in an ideal LS7 score, was associated with a 55% lower risk for HF compared with an inadequate LS7 score. Preventive strategies that target combinations of specific LS7 components could have a significant impact on decreasing incident HF in the population at large., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There is uncertainty about the relevance of animal foods to the pathogenesis of ischemic heart disease (IHD). We examined meat, fish, dairy products, and eggs and risk for IHD in the pan-European EPIC cohort (European Prospective Investigation Into Cancer and Nutrition)., Methods: In this prospective study of 409 885 men and women in 9 European countries, diet was assessed with validated questionnaires and calibrated with 24-hour recalls. Lipids and blood pressure were measured in a subsample. During a mean of 12.6 years of follow-up, 7198 participants had a myocardial infarction or died of IHD. The relationships of animal foods with risk were examined with Cox regression with adjustment for other animal foods and relevant covariates., Results: The hazard ratio (HR) for IHD was 1.19 (95% CI, 1.06-1.33) for a 100-g/d increment in intake of red and processed meat, and this remained significant after exclusion of the first 4 years of follow-up (HR, 1.25 [95% CI, 1.09-1.42]). Risk was inversely associated with intakes of yogurt (HR, 0.93 [95% CI, 0.89-0.98] per 100-g/d increment), cheese (HR, 0.92 [95% CI, 0.86-0.98] per 30-g/d increment), and eggs (HR, 0.93 [95% CI, 0.88-0.99] per 20-g/d increment); the associations with yogurt and eggs were attenuated and nonsignificant after exclusion of the first 4 years of follow-up. Risk was not significantly associated with intakes of poultry, fish, or milk. In analyses modeling dietary substitutions, replacement of 100 kcal/d from red and processed meat with 100 kcal/d from fatty fish, yogurt, cheese, or eggs was associated with ≈20% lower risk of IHD. Consumption of red and processed meat was positively associated with serum non-high-density lipoprotein cholesterol concentration and systolic blood pressure, and consumption of cheese was inversely associated with serum non-high-density lipoprotein cholesterol., Conclusions: Risk for IHD was positively associated with consumption of red and processed meat and inversely associated with consumption of yogurt, cheese, and eggs, although the associations with yogurt and eggs may be influenced by reverse causation bias. It is not clear whether the associations with red and processed meat and cheese reflect causality, but they were consistent with the associations of these foods with plasma non-high-density lipoprotein cholesterol and for red and processed meat with systolic blood pressure, which could mediate such effects.

The association between intake of different dairy products and the risk of stroke remains unclear. We therefore investigated substitutions between dairy product subgroups and risk of stroke. We included 36 886 Dutch men and women. Information about dairy product intake was collected through a FFQ. Dairy products were grouped as low-fat milk, whole-fat milk, buttermilk, low-fat yogurt, whole-fat yogurt, cheese and butter. Incident stroke cases were identified in national registers. We used Cox proportional hazards regression to calculate associations for substitutions between dairy products with the rate of stroke. During a median follow-up of 15·2 years we identified 884 stroke cases (503 ischaemic and 244 haemorrhagic). Median intake of total dairy products was four servings/d. Low-fat yogurt substituted for whole-fat yogurt was associated with a higher rate of ischaemic stroke (hazard ratio (HR) = 2·58 (95 % CI 1·11, 5·97)/serving per d). Whole-fat yogurt as a substitution for any other subgroup was associated with a lower rate of ischaemic stroke (HR between 0·33 and 0·36/serving per d). We did not observe any associations for haemorrhagic stroke. In conclusion, whole-fat yogurt as a substitution for low-fat yogurt, cheese, butter, buttermilk or milk, regardless of fat content, was associated with a lower rate of ischaemic stroke.

Background: Population-specificity of exploratory dietary patterns limits their generalizability in investigations with type 2 diabetes incidence., Objective: The aim of this study was to derive country-specific exploratory dietary patterns, investigate their association with type 2 diabetes incidence, and replicate diabetes-associated dietary patterns in other countries., Methods: Dietary intake data were used, assessed by country-specific questionnaires at baseline of 11,183 incident diabetes cases and 14,694 subcohort members (mean age 52.9 y) from 8 countries, nested within the European Prospective Investigation into Cancer and Nutrition study (mean follow-up time 6.9 y). Exploratory dietary patterns were derived by principal component analysis. HRs for incident type 2 diabetes were calculated by Prentice-weighted Cox proportional hazard regression models. Diabetes-associated dietary patterns were simplified or replicated to be applicable in other countries. A meta-analysis across all countries evaluated the generalizability of the diabetes-association., Results: Two dietary patterns per country/UK-center, of which overall 3 dietary patterns were diabetes-associated, were identified. A risk-lowering French dietary pattern was not confirmed across other countries: pooled HRFrance per 1 SD: 1.00; 95% CI: 0.90, 1.10. Risk-increasing dietary patterns, derived in Spain and UK-Norfolk, were confirmed, but only the latter statistically significantly: HRSpain: 1.09; 95% CI: 0.97, 1.22 and HRUK-Norfolk: 1.12; 95% CI: 1.04, 1.20. Respectively, this dietary pattern was characterized by relatively high intakes of potatoes, processed meat, vegetable oils, sugar, cake and cookies, and tea., Conclusions: Only few country/center-specific dietary patterns (3 of 18) were statistically significantly associated with diabetes incidence in this multicountry European study population. One pattern, whose association with diabetes was confirmed across other countries, showed overlaps in the food groups potatoes and processed meat with identified diabetes-associated dietary patterns from other studies. The study demonstrates that replication of associations of exploratory patterns with health outcomes is feasible and a necessary step to overcome population-specificity in associations from such analyses., (Copyright © American Society for Nutrition 2019.)

Objective: To estimate the causal association between intake of dairy products and incident type 2 diabetes., Research Design and Methods: The analysis included 21,820 European individuals (9,686 diabetes cases) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study. Participants were genotyped, and rs4988235 (LCT-12910C>T), a single nucleotide polymorphism (SNP) for lactase persistence (LP) that enables digestion of dairy sugar, i.e., lactose, was imputed. Baseline dietary intakes were assessed with diet questionnaires. We investigated the associations between imputed SNP dosage for rs4988235 and intake of dairy products and other foods through linear regression. Mendelian randomization (MR) estimates for the milk-diabetes relationship were obtained through a two-stage least squares regression., Results: Each additional LP allele was associated with a higher intake of milk (β 17.1 g/day, 95% CI 10.6-23.6) and milk beverages (β 2.8 g/day, 95% CI 1.0-4.5) but not with intake of other dairy products. Other dietary intakes associated with rs4988235 included fruits (β -7.0 g/day, 95% CI -12.4 to -1.7 per additional LP allele), nonalcoholic beverages (β -18.0 g/day, 95% CI -34.4 to -1.6), and wine (β -4.8 g/day, 95% CI -9.1 to -0.6). In instrumental variable analysis, LP-associated milk intake was not associated with diabetes (hazard ratio per 15 g/day 0.99, 95% CI 0.93-1.05)., Conclusions: rs4988235 was associated with milk intake but not with intake of other dairy products. This MR study does not suggest that milk intake is associated with diabetes, which is consistent with previous observational and genetic associations. LP may be associated with intake of other foods as well, but owing to the modest associations, we consider it unlikely that this caused the observed null result., (© 2019 by the American Diabetes Association.)

Purpose: The association between dietary saturated fatty acids (SFA) intake and type 2 diabetes (T2D) remains unclear. This study aimed at investigating the association between SFA intake and T2D risk based on (1) individual SFA (differing in carbon chain length), (2) food sources of SFA and (3) the substituting macronutrients., Methods: 37,421 participants from the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) cohort were included in this study. Baseline dietary intake was assessed by a validated food frequency questionnaire. T2D risks were estimated by Cox regression models adjusted for non-dietary and dietary covariates., Results: 893 incident T2D cases were documented during 10.1-year follow-up. We observed no association between total SFA and T2D risk. Marginally inverse associations were found for lauric acid (HR per 1 SD of energy%, 95% CI 0.92, 0.85-0.99), myristic acid (0.89, 0.79-0.99), margaric acid (0.84, 0.73-0.97), odd-chain SFA (pentadecylic plus margaric acids; 0.88, 0.79-0.99), and cheese derived SFA (0.90, 0.83-0.98). Soft and liquid fats derived SFA was found related to higher T2D risk (1.08, 1.01-1.17). When substituting SFA by proteins, carbohydrates and polyunsaturated fatty acids, significantly higher risks of T2D were observed (HRs per 1 energy% ranging from 1.05 to 1.15)., Conclusion: In this Dutch population, total SFA does not relate to T2D risk. Rather, the association may depend on the types and food sources of SFA. Cheese-derived SFA and individual SFA that are commonly found in cheese, were significantly related to lower T2D risks. We cannot exclude the higher T2D risks found for soft and liquid fats derived SFA and for substituting SFA with other macronutrients are influenced by residual confounding by trans fatty acids or limited intake variation in polyunsaturated fatty acids and vegetable protein.

Background: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D., Methods: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography-mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis., Results: The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95% CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)]., Conclusions: Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.

Background: The effect of individual saturated fatty acids (SFAs) on serum cholesterol levels depends on their carbon-chain length. Whether the association with myocardial infarction (MI) also differs across individual SFAs is unclear. We examined the association between consumption of individual SFAs, differing in chain lengths ranging from 4 through 18 carbons, and risk of MI., Methods: We used data from 22,050 and 53,375 participants from EPIC-Norfolk (UK) and EPIC-Denmark, respectively. Baseline SFA intakes were assessed through validated, country-specific food frequency questionnaires. Cox regression analysis was used to estimate associations between intakes of individual SFAs and MI risk, for each cohort separately., Results: During median follow-up times of 18.8 years in EPIC-Norfolk and 13.6 years in Denmark, respectively, 1204 and 2260 MI events occurred. Mean (±SD) total SFA intake was 13.3 (±3.5) en% in EPIC-Norfolk, and 12.5 (±2.6) en% in EPIC-Denmark. After multivariable adjustment, intakes of C12:0 (lauric acid) and C14:0 (myristic acid) inversely associated with MI risk in EPIC-Denmark (HR upper versus lowest quintile: 0.80 (95%CI: 0.66, 0.96) for both SFAs). Intakes in the third and fourth quintiles of C4:0-C10:0 also associated with lower MI risk in EPIC-Denmark. Moreover, substitution of C16:0 (palmitic acid) and C18:0 (stearic acid) with plant proteins resulted in a reduction of MI risk in EPIC-Denmark (HR per 1 energy%: 0.86 (95%CI: 0.78, 0.95) and 0.87 (95%CI: 0.79, 0.96) respectively). No such associations were found in EPIC-Norfolk., Conclusion: The results from the present study suggest that the association between SFA and MI risk depends on the carbon chain-length of the SFA., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Dietary guidelines for pure fruit juice consumption differ between countries, regarding the question whether pure fruit juice is an acceptable alternative for fruit. Currently, little is known about pure fruit juice consumption and the risk of CVD. In this prospective cohort study, we studied the association of pure fruit juice and fruit consumption with the incidence of fatal and non-fatal CVD, CHD and stroke and investigated the differences in association with pure fruit juice consumption between low and high fruit consumers. A validated FFQ was used to estimate dietary intake of 34 560 participants (26·0 % men and 74·0 % women) aged 20-69 years from the European Prospective Investigation into Cancer and Nutrition-Netherlands study. Adjusted hazard ratios (HR) were estimated using Cox regression after average follow-up of 14·6 years. Compared with no consumption, pure fruit juice consumption up to 7 glasses/week - but not consumption of ≥8 glasses - was significantly associated with reduced risk of CVD and CHD, with HR from 0·83 (95 % CI 0·73, 0·95) to 0·88 (95 % CI 0·80, 0·97). Consumption of 1-4 and 4-8 glasses/week was significantly associated with lower risk of stroke with HR of 0·80 (95 % CI 0·64, 0·99) and 0·76 (95 % CI 0·61, 0·94), respectively. Associations did not differ considerably between low and high fruit consumers. The highest three quintiles of fruit consumption (≥121 g/d) were significantly associated with lower incidence of CVD, with HR of 0·87 (95 % CI 0·78, 0·97) and 0·88 (95 % CI 0·80, 0·98). In conclusion, although we observed favourable associations of moderate pure fruit juice consumption with CVD, for now consumption of whole fruit should be preferred because the evidence of the health benefits of fruit is more conclusive.

This study investigated the causal relation between circulating phylloquinone (vitamin K 1 ) concentrations and type 2 diabetes by using a Mendelian randomization (MR) approach. We used data from three studies: the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, Diabetes Genetics Replication and Meta-analysis (DIAGRAM), and the UK Biobank, resulting in 69,647 subjects with type 2 diabetes. We calculated a weighted genetic risk score including four genetic variants previously found to be associated with circulating phylloquinone concentrations. Inverse-variance weighted analysis was used to obtain a risk ratio (RR) for the causal relation between circulating phylloquinone concentrations and risk of type 2 diabetes. Presence of pleiotropy and the robustness of the results were assessed using MR-Egger and weighted-median analyses. Genetically predicted concentrations of circulating phylloquinone were associated with lower risk of type 2 diabetes with an RR of 0.93 (95% CI 0.89; 0.97) per every natural logarithm (Ln)-nmol/L-unit increase in circulating phylloquinone. The MR-Egger and weighted median analyses showed RRs of 0.94 (0.86; 1.02) and 0.93 (0.88; 0.98), respectively, indicating no pleiotropy. In conclusion, our study supports that higher circulating phylloquinone may be causally related with lower risk of type 2 diabetes, highlighting the importance of sufficient phylloquinone in the human diet., (© 2018 by the American Diabetes Association.)

Background: There is growing evidence that exposure to ultrafine particles (UFP; particles smaller than [Formula: see text]) may play an underexplored role in the etiology of several illnesses, including cardiovascular disease (CVD)., Objectives: We aimed o investigate the relationship between long-term exposure to ambient UFP and incident cardiovascular and cerebrovascular disease (CVA). As a secondary objective, we sought to compare effect estimates for UFP with those derived for other air pollutants, including estimates from two-pollutant models., Methods: Using a prospective cohort of 33,831 Dutch residents, we studied the association between long-term exposure to UFP (predicted via land use regression) and incident disease using Cox proportional hazard models. Hazard ratios (HR) for UFP were compared to HRs for more routinely monitored air pollutants, including particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]), PM with aerodynamic diameter [Formula: see text] ([Formula: see text]), and [Formula: see text]., Results: Long-term UFP exposure was associated with an increased risk for all incident CVD [[Formula: see text] per [Formula: see text]; 95% confidence interval (CI): 1.03, 1.34], myocardial infarction (MI) ([Formula: see text]; 95% CI: 1.00, 1.79), and heart failure ([Formula: see text]; 95% CI: 1.17, 2.66). Positive associations were also estimated for [Formula: see text] ([Formula: see text]; 95% CI: 1.01, 1.48 per [Formula: see text]) and coarse PM ([Formula: see text]; HR for all [Formula: see text]; 95% CI: 1.01, 1.45 per [Formula: see text]). CVD was not positively associated with [Formula: see text] (HR for all [Formula: see text]; 95% CI: 0.75, 1.28 per [Formula: see text]). HRs for UFP and CVAs were positive, but not significant. In two-pollutant models ([Formula: see text] and [Formula: see text]), positive associations tended to remain for UFP, while HRs for [Formula: see text] and [Formula: see text] generally attenuated towards the null., Conclusions: These findings strengthen the evidence that UFP exposure plays an important role in cardiovascular health and that risks of ambient air pollution may have been underestimated based on conventional air pollution metrics. https://doi.org/10.1289/EHP3047.

Background: Initiating and maintaining a healthy lifestyle -including healthy eating and sufficient physical activity- is key for cardiometabolic health. A health-promoting environment can facilitate a healthy lifestyle, and may be especially helpful to reach individuals with a lower socio-economic status (SES). In the Supreme Nudge project, we will study the effects of pricing and nudging strategies in the supermarket - one of the most important point-of-choice settings for food choices - and of a context-specific mobile physical activity promotion app. This paper describes the stepwise and theory-based design of Supreme Nudge, which aims to develop, implement and evaluate environmental changes for a sustained impact on lifestyle behaviours and cardiometabolic health in low SES adults., Methods: Supreme Nudge uses a multi-disciplinary and mixed methods approach, integrating participatory action research, qualitative interviews, experimental pilot studies, and a randomized controlled trial in a real-life (supermarket) setting. First, we will identify the needs, characteristics and preferences of the target group as well as of the participating supermarket chain. Second, we will conduct a series of pilot studies to test novel, promising and feasible intervention components. Third, a final selection of intervention components will be implemented in a full-scale randomised controlled supermarket trial. Approximately 1000 low SES adults will be recruited across 8-12 supermarkets and randomised at supermarket level to receive 1) no intervention (control); 2) environmental nudges such as food product placement or promotion; 3) nudges and a tailored physical activity app that provides time- and context specific feedback; 4) pricing interventions, nudges, and the physical activity app. The effects on dietary behaviours and physical activity will be evaluated at 3, 6 and 12 months, and on cardiometabolic health at 6 and 12 months. Finally, we will evaluate the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) of the intervention, and we will use insights from System Innovation and Transition Management theories to define the best strategies for implementation and upscaling beyond the study period., Discussion: The Supreme Nudge project is likely to generate thorough evidence relevant for policy and practice on the effects of a mixed method and multi-disciplinary intervention targeting dietary behaviours and physical activity., Trial Registration: The real-life trial has been registered on 30 May 2018, NTR7302 .

Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. We aimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A-encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 µg/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population., (© 2018 by the American Diabetes Association.)

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 (I 2 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.

Objective: Meat intake has been consistently shown to be positively associated with incident type 2 diabetes. Part of that association may be mediated by body iron status, which is influenced by genetic factors. We aimed to test for interactions of genetic and dietary factors influencing body iron status in relation to the risk of incident type 2 diabetes., Research Design and Methods: The case-cohort comprised 9,347 case subjects and 12,301 subcohort participants from eight European countries. Single nucleotide polymorphisms (SNPs) were selected from genome-wide association studies on iron status biomarkers and candidate gene studies. A ferritin-related gene score was constructed. Multiplicative and additive interactions of heme iron and SNPs as well as the gene score were evaluated using Cox proportional hazards regression., Results: Higher heme iron intake (per 1 SD) was associated with higher ferritin levels (β = 0.113 [95% CI 0.082; 0.144]), but not with transferrin (-0.019 [-0.043; 0.006]) or transferrin saturation (0.016 [-0.006; 0.037]). Five SNPs located in four genes (rs1799945 [ HFE H63D], rs1800562 [ HFE C282Y], rs236918 [ PCK7 ], rs744653 [ SLC40A1 ], and rs855791 [ TMPRSS6 V736A]) were associated with ferritin. We did not detect an interaction of heme iron and the gene score on the risk of diabetes in the overall study population ( P add = 0.16, P mult = 0.21) but did detect a trend toward a negative interaction in men ( P add = 0.04, P mult = 0.03)., Conclusions: We found no convincing evidence that the interplay of dietary and genetic factors related to body iron status associates with type 2 diabetes risk above the level expected from the sum or product of the two individual exposures., (© 2017 by the American Diabetes Association.)