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Abstract Background Whether cancer risk associated with a higher body mass index (BMI), a surrogate measure of adiposity, differs among adults with and without cardiovascular diseases (CVD) and/or type 2 diabetes (T2D) is unclear. The primary aim of this study was to evaluate separate and joint associations of BMI and CVD/T2D with the risk of cancer. Methods This is an individual participant data meta-analysis of two prospective cohort studies, the UK Biobank (UKB) and the European Prospective Investigation into Cancer and nutrition (EPIC), with a total of 577,343 adults, free of cancer, T2D, and CVD at recruitment. We used Cox proportional hazard regressions to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and incidence of obesity-related cancer and in turn overall cancer with a multiplicative interaction between BMI and the two cardiometabolic diseases (CMD). HRs and 95% CIs for separate and joint associations for categories of overweight/obesity and CMD status were estimated, and additive interaction was quantified through relative excess risk due to interaction (RERI). Results In the meta-analysis of both cohorts, BMI (per ~ 5 kg/m2) was positively associated with the risk of obesity-related cancer among participants without a CMD (HR: 1.11, 95%CI: 1.07,1.16), among participants with T2D (HR: 1.11, 95% CI: 1.05,1.18), among participants with CVD (HR: 1.17, 95% CI: 1.11,1.24), and suggestively positive among those with both T2D and CVD (HR: 1.09, 95% CI: 0.94,1.25). An additive interaction between obesity (BMI ≥ 30 kg/m2) and CVD with the risk of overall cancer translated into a meta-analytical RERI of 0.28 (95% CI: 0.09–0.47). Conclusions Irrespective of CMD status, higher BMI increased the risk of obesity-related cancer among European adults. The additive interaction between obesity and CVD suggests that obesity prevention would translate into a greater cancer risk reduction among population groups with CVD than among the general population.

Purpose: The EAT-Lancet reference diet has been proposed as a healthy dietary pattern to reduce food-related climate impacts, but little is known regarding associations with bodyweight development. This study investigated adherence to the EAT-Lancet diet in midlife and development in weight and waist circumference (WC) after five years. Design: The Danish Diet, Cancer and Health cohort recruited participants in 1993–1997. At baseline, data on diet, lifestyle, and anthropometry were collected. Participants self-reported weight and WC five years later. In total, 44,194 participants were included in analyses of weight (43,678 for WC). Baseline adherence to the EAT-Lancet diet was scored 0–14 points. Multiple linear regression was used to estimate associations between the EAT-Lancet diet and development in weight and WC after five years. Poisson regression was used to estimate risk ratios (RR) of obesity (≥30 kg/m2) or elevated WC. Results: Adherence to the EAT-Lancet diet was not associated with follow-up weight, adjusting for baseline weight and confounders (11–14 vs 0–7 points β: -0.08, 95% CI: -0.27, 0.11 kg), but was associated with lower follow-up WC adjusting for baseline WC and confounders (β: -0.38, 95% CI: -0.69, -0.07 cm), and was associated with lower risk of obesity and elevated WC (RR 0.89, 95% CI: 0.82, 0.98, and 0.95, 95% CI: 0.93, 0.96, respectively). Conclusion: Adherence to the EAT-Lancet diet in midlife was associated with lower WC but not weight after five years follow up, taking baseline into account. Our findings suggest that greater adherence to the EAT-Lancet diet does not contribute to development of obesity.

Abstract Background Amino acid metabolism is dysregulated in colorectal cancer patients; however, it is not clear whether pre-diagnostic levels of amino acids are associated with subsequent risk of colorectal cancer. We investigated circulating levels of amino acids in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. Methods Concentrations of 13-21 amino acids were determined in baseline fasting plasma or serum samples in 654 incident colorectal cancer cases and 654 matched controls in EPIC. Amino acids associated with colorectal cancer risk following adjustment for the false discovery rate (FDR) were then tested for associations in the UK Biobank, for which measurements of 9 amino acids were available in 111,323 participants, of which 1221 were incident colorectal cancer cases. Results Histidine levels were inversely associated with colorectal cancer risk in EPIC (odds ratio [OR] 0.80 per standard deviation [SD], 95% confidence interval [CI] 0.69–0.92, FDR P-value=0.03) and in UK Biobank (HR 0.93 per SD, 95% CI 0.87–0.99, P-value=0.03). Glutamine levels were borderline inversely associated with colorectal cancer risk in EPIC (OR 0.85 per SD, 95% CI 0.75–0.97, FDR P-value=0.08) and similarly in UK Biobank (HR 0.95, 95% CI 0.89–1.01, P=0.09) In both cohorts, associations changed only minimally when cases diagnosed within 2 or 5 years of follow-up were excluded. Conclusions Higher circulating levels of histidine were associated with a lower risk of colorectal cancer in two large prospective cohorts. Further research to ascertain the role of histidine metabolism and potentially that of glutamine in colorectal cancer development is warranted.

Abstract Background The association between protein intake and prostate cancer risk remains unclear. Aims To prospectively investigate the associations of dietary intakes of total protein, protein from different dietary sources, and amino acids with prostate cancer risk and mortality. Methods In 131,425 men from the European Prospective Investigation into Cancer and Nutrition, protein and amino acid intakes were estimated using validated dietary questionnaires. Multivariable‐adjusted Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results During a mean follow‐up of 14.2 years, 6939 men were diagnosed with prostate cancer and 914 died of the disease. Dairy protein was positively associated with overall prostate cancer risk in the three highest fifths compared to the lowest (HRQ3=1.14 (95% CI 1.05–1.23); HRQ4=1.09 (1.01–1.18); HRQ5=1.10 (1.02–1.19)); similar results were observed for yogurt protein (HRQ3=1.14 (1.05–1.24); HRQ4=1.09 (1.01–1.18); HRQ5=1.12 (1.04–1.21)). For egg protein intake and prostate cancer mortality, no association was observed by fifths, but there was suggestive evidence of a positive association in the analysis per standard deviation increment. There was no strong evidence of associations with different tumour subtypes. Discussion Considering the weak associations and many tests, the results must be interpreted with caution. Conclusion This study does not provide strong evidence for an association of intakes of total protein, protein from different dietary sources or amino acids with prostate cancer risk or mortality. However, our results may suggest some weak positive associations, which need to be confirmed in large‐scale, pooled analyses of prospective data.

Abstract Background Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. Methods We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. Results Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. Conclusions These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.

Abstract Background Metabolomics is a promising molecular tool for identifying novel etiological pathways leading to cancer. In an earlier prospective study among pre- and postmenopausal women not using exogenous hormones, we observed a higher risk of breast cancer associated with higher blood concentrations of one metabolite (acetylcarnitine) and a lower risk associated with higher blood concentrations of seven others (arginine, asparagine, phosphatidylcholines (PCs) aa C36:3, ae C34:2, ae C36:2, ae C36:3, and ae C38:2). Methods To identify determinants of these breast cancer-related metabolites, we conducted a cross-sectional analysis to identify their lifestyle and anthropometric correlates in 2358 women, who were previously included as controls in case-control studies nested within the European Prospective Investigation into Cancer and Nutrition cohort and not using exogenous hormones at blood collection. Associations of each metabolite concentration with 42 variables were assessed using linear regression models in a discovery set of 1572 participants. Significant associations were evaluated in a validation set (n = 786). Results For the metabolites previously associated with a lower risk of breast cancer, concentrations of PCs ae C34:2, C36:2, C36:3, and C38:2 were negatively associated with adiposity and positively associated with total and saturated fat intakes. PC ae C36:2 was also negatively associated with alcohol consumption and positively associated with two scores reflecting adherence to a healthy lifestyle. Asparagine concentration was negatively associated with adiposity. Arginine and PC aa C36:3 concentrations were not associated to any of the factors examined. For the metabolite previously associated with a higher risk of breast cancer, acetylcarnitine, a positive association with age was observed. Conclusions These associations may indicate possible mechanisms underlying associations between lifestyle and anthropometric factors, and risk of breast cancer. Further research is needed to identify potential non-lifestyle correlates of the metabolites investigated.

Abstract Smoking is a well-established risk factor for cancer, and cancer patients have a high risk of venous thromboembolism (VTE). Conflicting results have been reported on the association between smoking and risk of VTE, and the effect of smoking on VTE-risk in subjects with cancer is scarcely studied. We aimed to investigate the association between smoking and VTE in subjects with and without cancer in a large population-based cohort. The Scandinavian Thrombosis and Cancer (STAC) cohort included 144,952 participants followed from 1993–1997 to 2008–2012. Information on smoking habits was derived from self-administered questionnaires. Active cancer was defined as the first two years following the date of cancer diagnosis. Former smokers (n = 35,890) and those with missing information on smoking status (n = 3680) at baseline were excluded. During a mean follow up of 11 years, 10,181 participants were diagnosed with cancer, and 1611 developed incident VTE, of which 214 were cancer-related. Smoking was associated with a 50% increased risk of VTE (HR 1.49, 95% CI 1.12–1.98) in cancer patients, whereas no association was found in cancer-free subjects (HR 1.07, 95% CI 0.96–1.20). In cancer patients, the risk of VTE among smokers remained unchanged after adjustment for cancer site and metastasis. Stratified analyses showed that smoking was a risk factor for VTE among those with smoking-related and advanced cancers. In conclusion, smoking was associated with increased VTE risk in subjects with active cancer, but not in those without cancer. Our findings imply a biological interaction between cancer and smoking on the risk of VTE.

In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.

BackgroundMembrane CD36 is a fatty acid transporter implicated in the pathogenesis of metabolic disease. We aimed to evaluate the association between plasma CD36 levels and diabetes risk and to examine if the association was independent of adiposity among Danish population.MethodsWe conducted a case-cohort study nested within the Danish Diet, Cancer and Health study among participants free of cardiovascular disease, diabetes and cancer and with blood samples and anthropometric measurements (height, weight, waist circumference, and body fat percentage) at baseline (1993 to 1997). CD36 levels were measured in 647 incident diabetes cases that occurred before December 2011 and a total of 3,515 case-cohort participants (236 cases overlap).ResultsHigher plasma CD36 levels were associated with higher diabetes risk after adjusting for age, sex and other lifestyle factors. The hazard ratio (HR) comparing high versus low tertile of plasma CD36 levels was 1.36 (95% confidence interval [CI], 1.00 to 1.86). However, the association lost its significance after further adjustment for different adiposity indices such as body mass index (HR, 1.23; 95% CI, 0.87 to 1.73), waist circumference (HR, 1.21; 95% CI, 0.88 to 1.68) or body fat percentage (HR, 1.20; 95% CI, 0.86 to 1.66). Moreover, raised plasma CD36 levels were moderately associated with diabetes risk among lean participants, but the association was not present among overweight/obese individuals.ConclusionHigher plasma CD36 levels were associated with higher diabetes risk, but the association was not independent of adiposity. In this Danish population, the association of CD36 with diabetes risk could be either mediated or confounded by adiposity.

Abstract Background Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases. Methods In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs. Results During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and women with healthy lifestyles. Conclusion Pre-diagnostic healthy lifestyle behaviours were strongly inversely associated with the risk of cancer and cardiometabolic diseases, and with the prognosis of these diseases by reducing risk of multimorbidity.

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.

Polyphenols are bioactive compounds from plants with antioxidant properties that may have a protective role against body weight gain, with adipose tissue and systemic oxidative stress as potential targets. We aimed to investigate the dietary intake of individual polyphenols and their association with 5-year body weight change in a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 349,165 adult participants from nine European countries. Polyphenol intake was estimated through country-specific validated dietary questionnaires and the Phenol-Explorer database. Body weight was obtained at recruitment and after a mean follow-up time of 5 years. Associations were estimated using multilevel mixed linear regression models. From 91 polyphenols included, the majority (n = 67) were inversely associated with 5-year body weight change after FDR-correction (q < 0.05). The greatest inverse associations were observed for quercetin 3-O-rhamnoside (change in weight for doubling in intake: −0.071 (95% CI: −0.085; −0.056) kg/5 years). Only 13 polyphenols showed positive associations with body weight gain, mainly from the subclass hydroxycinnamic acids (HCAs) with coffee as the main dietary source, such as 4-caffeoylquinic acid (0.029 (95% CI: 0.021; 0.038) kg/5 years). Individual polyphenols with fruit, tea, cocoa and whole grain cereals as the main dietary sources may contribute to body weight maintenance in adults. Individual HCAs may have different roles in body weight change depending on their dietary source.

Background Dietary vitamin K (K1 and K2) may reduce atherosclerotic cardiovascular disease (ASCVD) risk via several mechanisms. However, studies linking vitamin K intake with incident ASCVD are limited. We aimed to determine the relationship between dietary vitamin K intake and ASCVD hospitalizations. Methods and Results In this prospective cohort study, participants from the Danish Diet, Cancer, and Health Study, with no prior ASCVD, completed a food‐frequency questionnaire at baseline and were followed up for hospital admissions of ASCVD; ischemic heart disease, ischemic stroke, or peripheral artery disease. Intakes of vitamin K1 and vitamin K2 were estimated from the food‐frequency questionnaire, and their relationship with ASCVD hospitalizations was determined using Cox proportional hazards models. Among 53 372 Danish citizens with a median (interquartile range) age of 56 (52–60) years, 8726 individuals were hospitalized for any ASCVD during 21 (17–22) years of follow‐up. Compared with participants with the lowest vitamin K1 intakes, participants with the highest intakes had a 21% lower risk of an ASCVD‐related hospitalization (hazard ratio, 0.79; 95% CI: 0.74–0.84), after multivariable adjustments for relevant demographic covariates. Likewise for vitamin K2, the risk of an ASCVD‐related hospitalization for participants with the highest intakes was 14% lower than participants with the lowest vitamin K2 intake (hazard ratio, 0.86; 95% CI, 0.81–0.91). Conclusions Risk of ASCVD was inversely associated with diets high in vitamin K1 or K2. The similar inverse associations with both vitamin K1 and K2, despite very different dietary sources, highlight the potential importance of vitamin K for ASCVD prevention.

Background: Mycotoxins have been suggested to contribute to a spectrum of adverse health effects in humans, including at low concentrations. The recognition of these food contaminants being carcinogenic, as co-occurring rather than as singularly present, has emerged from recent research. The aim of this study was to assess the potential associations of single and multiple mycotoxin exposures with renal cell carcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: Food questionnaire data from the EPIC cohort were matched to mycotoxin food occurrence data compiled by the European Food Safety Authority (EFSA) from European Member States to assess long-term dietary mycotoxin exposures, and to associate these with the risk of renal cell carcinoma (RCC, n = 911 cases) in 450,112 EPIC participants. Potential confounding factors were taken into account. Analyses were conducted using Cox’s proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) with mycotoxin exposures expressed as µg/kg body weight/day. Results: Demographic characteristics differed between the RCC cases and non-cases for body mass index, age, alcohol intake at recruitment, and other dietary factors. In addition, the mycotoxin exposure distributions showed that a large proportion of the EPIC population was exposed to some of the main mycotoxins present in European foods such as deoxynivalenol (DON) and derivatives, fumonisins, Fusarium toxins, Alternaria toxins, and total mycotoxins. Nevertheless, no statistically significant associations were observed between the studied mycotoxins and mycotoxin groups, and the risk of RCC development. Conclusions: These results show an absence of statistically significant associations between long-term dietary mycotoxin exposures and RCC risk. However, these results need to be validated in other cohorts and preferably using repeated dietary exposure measurements. In addition, more occurrence data of, e.g., citrinin and fumonisins in different food commodities and countries in the EFSA database are a prerequisite to establish a greater degree of certainty.

Cadmium exposure has been associated with cardiovascular disease. Cigarette smoking is a key source of cadmium exposure and thus a potential confounder in observational studies of environmental cadmium and cardiovascular disease that include tobacco smokers. We leveraged up to 20 years of follow-up in the Danish Diet, Cancer and Health cohort to test the hypothesis that cadmium exposure is associated with acute myocardial infarction (AMI) among people who never smoked. Between 1993 and 1997, 19,394 never-smoking participants (ages 50–64 years) were enrolled and provided a urine sample. From this sample, we randomly selected a subcohort of 600 males and 600 females. We identified 809 AMI cases occurring between baseline and the end of 2015 using the Danish National Patient Registry. We quantified cadmium, creatinine, and osmolality in baseline urine samples. Using an unweighted case-cohort approach, we estimated adjusted hazard ratios (aHR) for AMI in Cox proportional hazards models with age as the time axis. Participants had relatively low concentrations of urinary cadmium, as expected for never smokers (median = 0.20; 25th, 75th = 0.13, 0.32 μg cadmium/g creatinine). We did not find strong evidence to support an association between higher urinary cadmium and AMI when comparing the highest versus lowest quartile (aHR = 1.16; 95% CI: 0.86 – 1.56) and per IQR increment in cadmium concentration (aHR = 1.02; 95% CI: 0.93 – 1.12). Results were not materially different across strata defined by sex. Results were generally similar using creatinine or osmolality to account for differences in urine dilution. While cadmium exposure has been identified as a risk factor for cardiovascular disease, we did not find strong evidence that urinary cadmium at relatively low-levels is associated with AMI among people who have never smoked.

Abstract Background Metabolomics is a promising molecular tool to identify novel etiologic pathways leading to cancer. Using a targeted approach, we prospectively investigated the associations between metabolite concentrations in plasma and breast cancer risk. Methods A nested case-control study was established within the European Prospective Investigation into Cancer cohort, which included 1624 first primary incident invasive breast cancer cases (with known estrogen and progesterone receptor and HER2 status) and 1624 matched controls. Metabolites (n = 127, acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose, sphingolipids) were measured by mass spectrometry in pre-diagnostic plasma samples and tested for associations with breast cancer incidence using multivariable conditional logistic regression. Results Among women not using hormones at baseline (n = 2248), and after control for multiple tests, concentrations of arginine (odds ratio [OR] per SD = 0.79, 95% confidence interval [CI] = 0.70–0.90), asparagine (OR = 0.83 (0.74–0.92)), and phosphatidylcholines (PCs) ae C36:3 (OR = 0.83 (0.76–0.90)), aa C36:3 (OR = 0.84 (0.77–0.93)), ae C34:2 (OR = 0.85 (0.78–0.94)), ae C36:2 (OR = 0.85 (0.78–0.88)), and ae C38:2 (OR = 0.84 (0.76–0.93)) were inversely associated with breast cancer risk, while the acylcarnitine C2 (OR = 1.23 (1.11–1.35)) was positively associated with disease risk. In the overall population, C2 (OR = 1.15 (1.06–1.24)) and PC ae C36:3 (OR = 0.88 (0.82–0.95)) were associated with risk of breast cancer, and these relationships did not differ by breast cancer subtype, age at diagnosis, fasting status, menopausal status, or adiposity. Conclusions These findings point to potentially novel pathways and biomarkers of breast cancer development. Results warrant replication in other epidemiological studies.

The studies showing health benefits of flavonoids and their impact on cancer mortality are incomplete. Here, the authors perform a prospective cohort study in Danish participants and demonstrate an inverse association between regular flavonoid intake and both cardiovascular and cancer related mortality.

Air pollutants such as NO2 and PM2.5 have consistently been linked to mortality, but only few previous studies have addressed associations with long-term exposure to black carbon (BC) and ozone (O3).We investigated the association between PM2.5, PM10, BC, NO2, and O3 and mortality in a Danish cohort of 49,564 individuals who were followed up from enrollment in 1993–1997 through 2015. Residential address history from 1979 onwards was combined with air pollution exposure obtained by the state-of-the-art, validated, THOR/AirGIS air pollution modelling system, and information on residential traffic noise exposure, lifestyle and socio-demography.We observed higher risks of all-cause as well as cardiovascular disease (CVD) mortality with higher long-term exposure to PM2.5, PM10, BC, and NO2. For PM2.5 and CVD mortality, a hazard ratio (HR) of 1.29 (95% CI: 1.13–1.47) per 5 μg/m3 was observed, and correspondingly HRs of 1.16 (95% CI: 1.05–1.27) and 1.11 (95% CI: 1.04–1.17) were observed for BC (per 1 μg/m3) and NO2 (per 10 μg/m3), respectively. Adjustment for noise gave slightly lower estimates for the air pollutants and CVD mortality. Inverse relationships were observed for O3. None of the investigated air pollutants were related to risk of respiratory mortality. Stratified analyses suggested that the elevated risks of CVD and all-cause mortality in relation to long-term PM, NO2 and BC exposure were restricted to males.This study supports a role of PM, BC, and NO2 in all-cause and CVD mortality independent of road traffic noise exposure. Keywords: Particulate matter, NO2, Black carbon, Ozone, CVD, Mortality, Epidemiology

Abstract Background Few published breast cancer (BC) risk prediction models consider the heterogeneity of predictor variables between estrogen-receptor positive (ER+) and negative (ER-) tumors. Using data from two large cohorts, we examined whether modeling this heterogeneity could improve prediction. Methods We built two models, for ER+ (ModelER+) and ER- tumors (ModelER-), respectively, in 281,330 women (51% postmenopausal at recruitment) from the European Prospective Investigation into Cancer and Nutrition cohort. Discrimination (C-statistic) and calibration (the agreement between predicted and observed tumor risks) were assessed both internally and externally in 82,319 postmenopausal women from the Women’s Health Initiative study. We performed decision curve analysis to compare ModelER+ and the Gail model (ModelGail) regarding their applicability in risk assessment for chemoprevention. Results Parity, number of full-term pregnancies, age at first full-term pregnancy and body height were only associated with ER+ tumors. Menopausal status, age at menarche and at menopause, hormone replacement therapy, postmenopausal body mass index, and alcohol intake were homogeneously associated with ER+ and ER- tumors. Internal validation yielded a C-statistic of 0.64 for ModelER+ and 0.59 for ModelER-. External validation reduced the C-statistic of ModelER+ (0.59) and ModelGail (0.57). In external evaluation of calibration, ModelER+ outperformed the ModelGail: the former led to a 9% overestimation of the risk of ER+ tumors, while the latter yielded a 22% underestimation of the overall BC risk. Compared with the treat-all strategy, ModelER+ produced equal or higher net benefits irrespective of the benefit-to-harm ratio of chemoprevention, while ModelGail did not produce higher net benefits unless the benefit-to-harm ratio was below 50. The clinical applicability, i.e. the area defined by the net benefit curve and the treat-all and treat-none strategies, was 12.7 × 10− 6 for ModelER+ and 3.0 × 10− 6 for ModelGail. Conclusions Modeling heterogeneous epidemiological risk factors might yield little improvement in BC risk prediction. Nevertheless, a model specifically predictive of ER+ tumor risk could be more applicable than an omnibus model in risk assessment for chemoprevention.

Introduction: High arsenic concentration in drinking water is associated with a higher incidence rate of stroke, but only few studies have investigated an association with arsenic in drinking water at low concentration (

Abstract Background It has been suggested that the acidity of the diet may be related to increased risk of type 2 diabetes. To investigate this hypothesis, we tested if the acidity of the diet, measured as the Potential Renal Acid Load (PRAL) score, was associated with incident diabetes and diabetes-related intermediary traits. Methods A total of 54,651 individuals from the Danish Diet, Cancer and Health (DCH) cohort were included in the prospective cox regression analyses of incident diabetes over a 15 years follow-up period. Moreover, 5724 Danish individuals with baseline data from the Inter99 cohort were included in the cross sectional, multivariate and logistic regression analyses of measures of insulin sensitivity, insulin release and glucose tolerance status derived from an oral glucose tolerance test (OGTT). Results In the DCH cohort a trend analysis showed that quintiles of PRAL score were, after multifactorial adjustment, associated with a higher incidence of diabetes (p trend = 6 × 10− 7). HR for incident diabetes was 1.24 (1.14; 1.35) (p = 7 × 10− 7) between first and fifth PRAL score quintile. In Inter99 higher PRAL score associated with insulin resistance as estimated by lower BIGTT-Si (an OGTT-derived index of insulin sensitivity) (p = 4 × 10− 7) and Matsuda index of insulin sensitivity (p = 2 × 10− 5) as well as higher HOMA-IR (p = 0.001). No association was observed for measures of insulin release, but higher PRAL score was associated with lower OGTT-based disposition index. Conclusions A high dietary acidity load is associated with a higher risk of diabetes among middle-aged Danes. Although adjustment for BMI attenuated the effect sizes the association remained significant. The increased risk of diabetes may be related to our finding that a high dietary acidity load associates with impaired insulin sensitivity.

Abstract Background Receptor activator of nuclear factor kappa-B (RANK)-signaling is involved in tumor growth and spread in experimental models. Binding of RANK ligand (RANKL) to RANK activates signaling, which is inhibited by osteoprotegerin (OPG). We have previously shown that circulating soluble RANKL (sRANKL) and OPG are associated with breast cancer risk. Here we extend these findings to provide the first data on pre-diagnosis concentrations of sRANKL and OPG and risk of breast cancer-specific and overall mortality after a breast cancer diagnosis. Methods Two thousand six pre- and postmenopausal women with incident invasive breast cancer (1620 (81%) with ER+ disease) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed-up for mortality. Pre-diagnosis concentrations of sRANKL and OPG were quantified in baseline serum samples using an enzyme-linked immunosorbent assay and electrochemiluminescent assay, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer-specific and overall mortality were calculated using Cox proportional hazards regression models. Results Especially in women with ER+ disease, higher circulating OPG concentrations were associated with higher risk of breast cancer-specific (quintile 5 vs 1 HR 1.77 [CI 1.03, 3.04]; ptrend 0.10) and overall mortality (q5 vs 1 HR 1.39 [CI 0.94, 2.05]; ptrend 0.02). sRANKL and the sRANKL/OPG ratio were not associated with mortality following a breast cancer diagnosis. Conclusions High pre-diagnosis endogenous concentrations of OPG, the decoy receptor for RANKL, were associated with increased risk of death after a breast cancer diagnosis, especially in those with ER+ disease. These results need to be confirmed in well-characterized patient cohorts.

Abstract Introduction Prospective studies investigating flavonoid intake and dementia risk are scarce. The aims of this study were to examine associations between flavonoid intake and the risk of incident dementia and to investigate whether this association differs in the presence of lifestyle risk factors for dementia. Methods We examined associations in 55,985 participants of the Danish Diet, Cancer, and Health Study followed for 23 years. The Phenol‐Explorer database was used to estimate flavonoid intakes. Information on incident dementia and dementia subtypes was obtained using Danish patient and prescription registries. Hazard ratios (HRs) were calculated using restricted cubic splines in multivariable‐adjusted Cox proportional hazards models. Results For incident dementia, moderate compared to low intakes of flavonols (HR: 0.90 [0.82, 0.99]), flavanol oligo+polymers (HR: 0.87 [0.79, 0.96]), anthocyanins (HR: 0.84 [0.76, 0.93]), flavanones (HR: 0.89 [0.80, 0.99]), and flavones (HR: 0.85 [0.77, 0.95]) were associated with a lower risk. For vascular dementia, moderate intakes of flavonols (HR: 0.69 [0.53, 0.89]) and flavanol oligo + polymers (HR: 0.65 [0.51, 0.83]) were associated with lower risk. Flavonoid intakes were not significantly associated with Alzheimer's disease or unspecified dementia. The inverse association between total flavonoid intake and incident dementia was stronger in “ever” smokers than in “never” smokers and in those without hypercholesterolemia versus those with hypercholesteremia. Furthermore, the inverse association of vascular dementia with a moderate total flavonoid intake was stronger in “ever” smokers and those who were “normal” to “overweight” versus “never” smokers or those who were “obese,” respectively. Conclusion A moderate intake of flavonoid‐rich foods may help to reduce dementia risk.

BackgroundPrior 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 findingsWe 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.ConclusionsOur 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.

The chromosome 15q25.1 locus is a leading susceptibility region for lung cancer. Here, the authors interrogate three GWAS cohorts with 42,901 individuals to investigate potential pathological pathways such as gated channel activity and neuroactive ligand receptor interaction in lung cancer etiology.

Summary: Background: Flavonoids, compounds found in plant-based foods and beverages, might ameliorate vascular damage and atherosclerosis. Therefore, our aim was to assess the association between flavonoid intake and hospital admissions due to atherosclerotic cardiovascular disease. Methods: In this prospective cohort study, participants from the Danish Diet, Cancer, and Health Study were cross-linked with Danish nationwide registries. Eligible participants were aged 50–65 years, had no previous history of atherosclerotic cardiovascular disease, and had completed a food-frequency questionnaire at baseline. We examined associations between flavonoid intake (calculated from food-frequency questionnaires with use of the Phenol-Explorer database) and hospital admissions for atherosclerotic cardiovascular disease, ischaemic heart disease, ischaemic stroke, or peripheral arterial disease. We obtained hazard ratios (HRs) using restricted cubic splines based on Cox proportional hazards models. Findings: Of the participants recruited to the Danish Diet, Cancer, and Health study between 1993 and 1997, our study population was comprised of 53 552 participants, with a median follow-up of 21 years (IQR 15–22). During follow-up, 8773 participants were admitted to hospital for atherosclerotic cardiovascular disease. We observed non-linear associations between flavonoid intake and hospital admissions, plateauing at total flavonoid intakes of approximately 1000 mg per day. Compared with an intake of 175 mg per day, an intake of 1000 mg per day was associated with a 14% lower risk of atherosclerotic cardiovascular disease (HR 0·86, 95% CI 0·81–0·91). For disease subtypes, we observed a 9% lower risk of ischaemic heart disease (0·91, 0·85–0·98), a non-significant 9% lower risk of ischaemic stroke (0·91, 0·82–1·01), and a 32% lower risk of peripheral artery disease (0·68, 0·60–0·78). The overall associations were stronger in smokers than in non-smokers, as well as stronger in consumers of high (>20 g per day) quantities of alcohol than in those consuming low-to-moderate (≤20 g per day) quantities. Interpretation: Our results suggest that ensuring an adequate consumption of flavonoid-rich foods, particularly in subpopulations at risk of atherosclerosis such as smokers and consumers of high quantities of alcohol might mitigate some of the risk of atherosclerotic cardiovascular disease. More studies are needed to support and validate these data. Funding: Danish Cancer Society.

Abstract Background Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features. In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis. Results A sizeable proportion of systematic variability due to variables expressing ‘batch’ and ‘sample position’ within ‘chip’ was identified, with values of the partial R2 statistics equal to 9.5 and 11.4% of total variation, respectively. After application of ComBat or the residuals’ methods, the contribution was 1.3 and 0.2%, respectively. The SVA technique resulted in a reduced variability due to ‘batch’ (1.3%) and ‘sample position’ (0.6%), and in a diminished variability attributable to ‘chip’ within a batch (0.9%). After ComBat or the residuals’ corrections, a larger number of significant sites (k = 600 and k = 427, respectively) were associated to smoking status than the SVA correction (k = 96). Conclusions The three correction methods removed systematic variation in DNA methylation data, as assessed by the PC-PR2, which lent itself as a useful tool to explore variability in large dimension data. SVA produced more conservative findings than ComBat in the association between smoking and DNA methylation.

Abstract Background Accumulating evidence suggests that individual circulating saturated fatty acids (SFAs) are heterogeneous in their associations with cardio-metabolic diseases, but evidence about associations of SFAs with metabolic markers of different pathogenic pathways is limited. We aimed to examine the associations between plasma phospholipid SFAs and the metabolic markers of lipid, hepatic, glycaemic and inflammation pathways. Methods We measured nine individual plasma phospholipid SFAs and derived three SFA groups (odd-chain: C15:0 + C17:0, even-chain: C14:0 + C16:0 + C18:0, and very-long-chain: C20:0 + C22:0 + C23:0 + C24:0) in individuals from the subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study across eight European countries. Using linear regression in 15,919 subcohort members, adjusted for potential confounders and corrected for multiple testing, we examined cross-sectional associations of SFAs with 13 metabolic markers. Multiplicative interactions of the three SFA groups with pre-specified factors, including body mass index (BMI) and alcohol consumption, were tested. Results Higher levels of odd-chain SFA group were associated with lower levels of major lipids (total cholesterol (TC), triglycerides, apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB)) and hepatic markers (alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT)). Higher even-chain SFA group levels were associated with higher levels of low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C) ratio, triglycerides, ApoB, ApoB/A1 ratio, ALT, AST, GGT and CRP, and lower levels of HDL-C and ApoA1. Very-long-chain SFA group levels showed inverse associations with triglycerides, ApoA1 and GGT, and positive associations with TC, LDL-C, TC/HDL-C, ApoB and ApoB/A1. Associations were generally stronger at higher levels of BMI or alcohol consumption. Conclusions Subtypes of SFAs are associated in a differential way with metabolic markers of lipid metabolism, liver function and chronic inflammation, suggesting that odd-chain SFAs are associated with lower metabolic risk and even-chain SFAs with adverse metabolic risk, whereas mixed findings were obtained for very-long-chain SFAs. The clinical and biochemical implications of these findings may vary by adiposity and alcohol intake.

Abstract Background A breast cancer diagnosis affects an individual’s affiliation to labour market, but the long-term consequences of breast cancer on income in a Danish setting have not been examined. The present study investigated whether breast cancer affected future income among Danish women that participated in the work force. We also examined the roles of sociodemographic factors and prior psychiatric medical treatment. Methods This registry-based cohort study was based on information retrieved from linked Danish nationwide registries. We compared the incomes of 13,101 women (aged 30–59 years) diagnosed with breast cancer (exposed) to those of 60,819 women without breast cancer (unexposed). Changes in income were examined during a 10-year follow-up; for each follow-up year, we calculated the mean annual income and the relative change compared to the income earned one year prior to diagnosis. Expected changes in Danish female income, according to calendar year and age, were estimated based on information from Statistics Denmark. For exposed and unexposed groups, the observed income changes were dichotomized to those above and those below the expected change in income in the Danish female population. We examined the impact of breast cancer on income each year of follow-up with logistic regression models. Analyses were stratified according to educational level, marital status, and prior psychiatric medical treatment. Results Breast cancer had a temporary negative effect on income. The effect was largest during the first three years after diagnosis; thereafter, the gap narrowed between exposed and unexposed cohorts. The odds ratio for an increase in income in the cancer cohort compared to the cancer-free cohort was 0.81 (95% CI 0.77–0.84) after three years. After seven years, no significant difference was observed between cohorts. Stratified analyses demonstrated that the negative effect of breast cancer on income lasted longest among women with high educational levels. Being single or having received psychiatric medical treatment increased the chance to experience an increase in income among women with breast cancer. Conclusion A breast cancer diagnosis led to negative effects on income, which ameliorated over the following seven years. Sociodemographic factors and prior psychiatric medical treatment might influence long-term consequences of breast cancer on income.

Pooling metabolomics data across studies is often desirable to increase the statistical power of the analysis. However, this can raise methodological challenges as several preanalytical and analytical factors could introduce differences in measured concentrations and variability between datasets. Specifically, different studies may use variable sample types (e.g., serum versus plasma) collected, treated, and stored according to different protocols, and assayed in different laboratories using different instruments. To address these issues, a new pipeline was developed to normalize and pool metabolomics data through a set of sequential steps: (i) exclusions of the least informative observations and metabolites and removal of outliers; imputation of missing data; (ii) identification of the main sources of variability through principal component partial R-square (PC-PR2) analysis; (iii) application of linear mixed models to remove unwanted variability, including samples’ originating study and batch, and preserve biological variations while accounting for potential differences in the residual variances across studies. This pipeline was applied to targeted metabolomics data acquired using Biocrates AbsoluteIDQ kits in eight case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Comprehensive examination of metabolomics measurements indicated that the pipeline improved the comparability of data across the studies. Our pipeline can be adapted to normalize other molecular data, including biomarkers as well as proteomics data, and could be used for pooling molecular datasets, for example in international consortia, to limit biases introduced by inter-study variability. This versatility of the pipeline makes our work of potential interest to molecular epidemiologists.

Despite some epidemiological evidence on the protective effects of polyphenol intake on epithelial ovarian cancer (EOC) risk from case-control studies, the evidence is scarce from prospective studies and non-existent for several polyphenol classes. Therefore, we aimed to investigate the associations between the intake of total, classes and subclasses of polyphenols and EOC risk in a large prospective study. The study was conducted in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which included 309,129 adult women recruited mostly from the general population. Polyphenol intake was assessed through validated country-specific dietary questionnaires and the Phenol-Explorer database. During a mean follow-up of 14 years, 1469 first incident EOC cases (including 806 serous, 129 endometrioid, 102 mucinous, and 67 clear cell tumours) were identified. In multivariable-adjusted Cox regression models, the hazard ratio in the highest quartile of total polyphenol intake compared with the lowest quartile (HRQ4vsQ1) was 1.14 (95% CI 0.94–1.39; p-trend = 0.11). Similarly, the intake of most classes and subclasses of polyphenols were not related to either overall EOC risk or any EOC subtype. A borderline statistically significant positive association was observed between phenolic acid intake (HRQ4vsQ1 = 1.20, 95% CI 1.01–1.43; p-trend = 0.02) and EOC risk, especially for the serous subtype and in women with obesity, although these associations did not exceed the Bonferroni correction threshold. The current results do not support any association between polyphenol intake and EOC in our large European prospective study. Results regarding phenolic acid intake need further investigation

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992–2000 and December 2013–December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.

Abstract Background Studies have suggested a link between alcohol intake and adiposity. However, results from longitudinal studies have been inconsistent, and a possible interaction with genetic predisposition to adiposity measures has often not been taken into account. Objective To examine the association between alcohol intake recorded at baseline and subsequent annual changes in body weight (∆BW), waist circumference (ΔWC) and WC adjusted for BMI (ΔWCBMI), and to test for interaction with genetic predisposition scores based on single nucleotide polymorphisms (SNPs) associated with various forms of adiposity. Method This study included a total of 7028 adult men and women from MONICA, the Diet, Cancer and Health cohort (DCH), and the Inter99 studies. We combined 50 adiposity-associated SNPs into four scores indicating genetic predisposition to BMI, WC, WHRBMI and all three traits combined. Linear regression was used to examine the association of alcohol intake (drinks of 12 g (g) alcohol/day) with ΔBW, ΔWC, and ΔWCBMI, and to examine possible interactions with SNP-scores. Results from the analyses of the individual cohorts were combined in meta-analyses. Results Each additional drink/day was associated with a ΔBW/year of −18.0 g (95% confidence interval (CI): −33.4, −2.6, P = 0.02) and a ΔWC of −0.3 mm/year (−0.5, −0.0, P = 0.03). In analyses of women only, alcohol intake was associated with a higher ΔWCBMI of 0.5 mm/year (0.2, 0.9, P = 0.002) per drink/day. Overall, we found no statistically significant interactions between the four SNP-scores and alcohol intake in relation to changes in adiposity measures. However in analyses of women separately, we found interaction between the complete score of all 50 SNPs and alcohol intake in relation to ΔBW (P for interaction = 0.03). No significant interaction was observed among the men. Conclusion Alcohol intake was associated with a decrease in BW and WC among men and women, and an increase in WCBMI among women only. We found no strong indication that these associations depend on a genetic predisposition to adiposity. Trial registration Registry: ClinicalTrials.gov Trial number: CT00289237 , Registered: 19 September 2005 retrospectively registered.

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

The presence of apoC-III on HDL impairs HDL's inverse association with coronary heart disease (CHD). Little is known about modifiable factors explaining variation in HDL subspecies defined according to apoC-III. The aim was to investigate cross-sectional associations of anthropometry and lifestyle with HDL subspecies in 3,631 participants from the Diet, Cancer, and Health study originally selected for a case-cohort study (36% women; age 50–65 years) who were all free of CHD. Greater adiposity and less activity were associated with higher HDL containing apoC-III and lower HDL lacking apoC-III. Per each 15 cm higher waist circumference, the level of HDL containing apoC-III was 2.8% higher (95% CI: 0.4, 5.3; P = 0.024) and the level of HDL not containing apoC-III was 4.7% lower (95% CI: −6.0, −3.4; P =

Abstract Background Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. However, human studies, particularly from prospective settings, are lacking. Methods We used a case-control study design nested within a large prospective cohort to assess the association between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG) (reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139 men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and degree of liver dysfunction, were calculated with conditional logistic regression. Results Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70–81.40; P trend = 0.021). This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for chronic infection with hepatitis B and C viruses. Conclusions These novel findings, based on exposures up to several years prior to diagnosis, support a role for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut barrier failure and exposure to bacterial products in liver diseases is warranted.

Over one hundred loci have been identified to be associated with the familial risk of prostate cancer but the functional effects are poorly understood. Here the authors use single-nucleotide variant and epigentic data to show an underlying genetic architecture marked by histone modification.

Background: Type-2 diabetes (T2D) prevalence is rapidly increasing worldwide. Lifestyle factors, in particular obesity, diet, and physical activity play a significant role in the etiology of the disease. Of dietary patterns, particularly the Mediterranean diet has been studied, and generally a protective association has been identified. However, other regional diets are less explored. Objective: The aim of the present study was to investigate the association between adherence to a healthy Nordic food index and the risk of T2D. The index consists of six food items: fish, cabbage, rye bread, oatmeal, apples and pears, and root vegetables. Methods: Data was obtained from a prospective cohort study of 57,053 Danish men and women aged 50–64 years, at baseline, of whom 7366 developed T2D (median follow-up: 15.3 years). The Cox proportional hazards model was used to assess the association between the healthy Nordic food index and risk of T2D, adjusted for potential confounders. Results: Greater adherence to the healthy Nordic food index was significantly associated with lower risk of T2D after adjusting for potential confounders. An index score of 5−6 points (high adherence) was associated with a statistically significantly 25% lower T2D risk in women (HR: 0.75, 95%CI: 0.61–0.92) and 38% in men (HR: 0.62; 95%CI: 0.53–0.71) compared to those with an index score of 0 points (poor adherence). Conclusion: Adherence to a healthy Nordic food index was found to be inversely associated with risk of T2D, suggesting that regional diets other than the Mediterranean may also be recommended for prevention of T2D.

BackgroundHelping consumers make healthier food choices is a key issue for the prevention of cancer and other diseases. In many countries, political authorities are considering the implementation of a simplified labelling system to reflect the nutritional quality of food products. The Nutri-Score, a five-colour nutrition label, is derived from the Nutrient Profiling System of the British Food Standards Agency (modified version) (FSAm-NPS). How the consumption of foods with high/low FSAm-NPS relates to cancer risk has been studied in national/regional cohorts but has not been characterized in diverse European populations.Methods and findingsThis prospective analysis included 471,495 adults from the European Prospective Investigation into Cancer and Nutrition (EPIC, 1992-2014, median follow-up: 15.3 y), among whom there were 49,794 incident cancer cases (main locations: breast, n = 12,063; prostate, n = 6,745; colon-rectum, n = 5,806). Usual food intakes were assessed with standardized country-specific diet assessment methods. The FSAm-NPS was calculated for each food/beverage using their 100-g content in energy, sugar, saturated fatty acid, sodium, fibres, proteins, and fruits/vegetables/legumes/nuts. The FSAm-NPS scores of all food items usually consumed by a participant were averaged to obtain the individual FSAm-NPS Dietary Index (DI) scores. Multi-adjusted Cox proportional hazards models were computed. A higher FSAm-NPS DI score, reflecting a lower nutritional quality of the food consumed, was associated with a higher risk of total cancer (HRQ5 versus Q1 = 1.07; 95% CI 1.03-1.10, P-trend < 0.001). Absolute cancer rates in those with high and low (quintiles 5 and 1) FSAm-NPS DI scores were 81.4 and 69.5 cases/10,000 person-years, respectively. Higher FSAm-NPS DI scores were specifically associated with higher risks of cancers of the colon-rectum, upper aerodigestive tract and stomach, lung for men, and liver and postmenopausal breast for women (all P < 0.05). The main study limitation is that it was based on an observational cohort using self-reported dietary data obtained through a single baseline food frequency questionnaire; thus, exposure misclassification and residual confounding cannot be ruled out.ConclusionsIn this large multinational European cohort, the consumption of food products with a higher FSAm-NPS score (lower nutritional quality) was associated with a higher risk of cancer. This supports the relevance of the FSAm-NPS as underlying nutrient profiling system for front-of-pack nutrition labels, as well as for other public health nutritional measures.

Background Physical activity enhances the uptake of air pollutants, possibly reducing its beneficial effects. We examined the effects of leisure‐time and transport‐related physical activities on the risk of myocardial infarction (MI), and whether potential benefits on MI are reduced by exposure to traffic‐related air pollution. Methods and Results A group of 57 053 participants (50–65 years of age) from the Danish Diet, Cancer, and Health cohort reported physical activity at baseline (1993–1997) and were linked to registry data on hospital contacts and out‐of‐hospital deaths caused by MI, until December 2015. Nitrogen dioxide levels were estimated at participants’ baseline residences. We used Cox regressions to associate participation in sports, cycling, walking, and gardening with incident and recurrent MI, and tested for interaction by nitrogen dioxide. Of 50 635 participants without MI at baseline, 2936 developed incident MI, and of 1233 participants with MI before baseline, 324 had recurring MI during follow‐up. Mean nitrogen dioxide concentration was 18.7 μg/m3 at baseline (1993–1997). We found inverse statistically significant associations between participation in sports (hazard ratio; 95% confidence interval: 0.85; 0.79–0.92), cycling (0.91; 0.84–0.98), gardening (0.87; 0.80–0.95), and incident MI, while the association with walking was statistically nonsignificant (0.95; 0.83–1.08). Recurrent MI was statistically nonsignificantly inversely associated with cycling (0.80; 0.63–1.02), walking (0.82, 0.57–1.16), and gardening (0.91; 0.71–1.18), and positively with sports (1.06; 0.83–1.35). There was no effect modification of the associations between physical activity and MI by nitrogen dioxide. Conclusions Benefits of physical activity on both the incidence and the recurrence of MI are not reduced by exposure to high levels of air pollution.

Background We investigated the association between the content of linoleic acid in adipose tissue, a biomarker of long‐term intake of linoleic acid, and the risk of ischemic stroke and its subtypes. Methods and Results The Danish cohort study Diet, Cancer and Health included 57 053 patients aged 50 to 65 years at enrollment. All participants had an adipose tissue biopsy performed at enrollment, while information on ischemic stroke during follow‐up was obtained from the Danish National Patient Register. Stroke diagnoses were all validated and classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Cases and a randomly drawn subcohort of 3500 patients had their fatty acid composition in adipose tissue determined by gas chromatography. Hazard ratios with 95% confidence intervals were calculated using weighted Cox proportional hazard regression. During 13.5 years of follow‐up, 1879 ischemic stroke cases were identified, for which 1755 adipose biopsies were available, while adipose biopsies were available for 3203 participants in the subcohort. When comparing the highest and the lowest quartiles of adipose tissue content of linoleic acid there was a negative association with the rate of total ischemic stroke (hazard ratio, 0.78; 95% confidence interval, 0.65–0.93) and large artery atherosclerosis (hazard ratio, 0.61; 95% confidence interval, 0.43–0.88), while there was an indication of a negative association with small‐vessel occlusion (hazard ratio, 0.87; 95% confidence interval, 0.69–1.11). There was no clear association with the rate of cardioembolism. Conclusions The content of linoleic acid in adipose tissue was inversely associated with the risk of total ischemic stroke and stroke caused by large artery atherosclerosis.

The risk of venous thromboembolism (VTE) in patients who survive the first years after a cancer diagnosis after the acute effects of disease and treatment in comparison to a similar background population has been sparsely investigated. The aim of the study was to investigate if incidence rates (IRs) of VTE differed in patients who were alive at least 2 years after a cancer diagnosis without VTE compared with cancer-free references in a population-based cohort study. The study entry was 2 years after a first cancer diagnosis. For each cancer-exposed subject, five reference subjects were identified within the cohort. The IRs were calculated as number of VTEs per 1,000 person years (×10−3 p-y) in total and in distinct cancer types and corresponding reference subjects. Incidence rate ratios (IRRs) were calculated by Poisson's regression. During a mean follow-up of 5.3 years, 110 VTEs occurred among the 7,288 cancer-exposed subjects and 321 VTEs occurred among the 36,297 identified reference subjects. The IR of VTE was higher for cancer-exposed subjects compared with reference subjects, IRs 3.7 × 10−3 p-y, 95% CI: 3.1 to 4.5 and 1.9 × 10−3 p-y, 95% CI: 1.7 to 2.2, respectively. IRs of VTE in most solid cancer types declined to almost the same level as in the reference subjects 2 years after cancer diagnosis, but remained higher in hematological cancers, IRR 4.0, 95% CI: 2.0 to 7.8.

Fatty acids in adipose tissue share dietary sources and metabolic pathways and therefore occur in patterns. The aim of the present study was to investigate the association between adipose tissue fatty acid patterns identified by the data-driven dimension-reducing method treelet transform and the risk of atrial fibrillation. A total of 57,053 Danish men and women aged 50-64 years participating in the Diet, Cancer and Health cohort had an adipose tissue biopsy taken at baseline. During a median follow-up of 14.6 years, a total of 4,710 participants developed atrial fibrillation or atrial flutter. Adipose tissue biopsies were analysed for fatty acid content by gas chromatography for all cases of atrial fibrillation and for a randomly drawn subcohort (n = 3,500) representative for the entire cohort. Hazard ratios with 95% confidence intervals for atrial fibrillation according to quintiles of factor scores were determined by weighted Cox proportional hazards regression analyses for men and women separately. From the 32 fatty acids measured, 7 major factors/patterns of fatty acids were identified using treelet transform. We found that a pattern consisting of n-6 polyunsaturated fatty acids (PUFA) (except linoleic acid) was associated with a lower hazard of atrial fibrillation. Patterns consisting of marine n-3 PUFA and containing n-9 fatty acids were associated with a lower hazard of atrial fibrillation in women. In conclusion, patterns of fatty acids in adipose tissue identified by treelet transform may be differentially associated with the risk of atrial fibrillation.

BACKGROUND AND PURPOSE:National dietary guidelines are intended to promote primary prevention of lifestyle-related diseases, but little is known about their effectiveness in prevention of stroke. METHODS:We used the Danish cohort Diet, Cancer and Health (n = 57 053) to investigate whether adherence to the Danish food-based dietary guidelines was associated with risk of stroke. Adherence was assessed by the Danish Dietary Guidelines Index, score 0 [no adherence] to 6 [complete adherence]. Cox proportional hazards models were used to estimate adjusted hazard ratios and 95% confidence intervals for stroke and subtypes of stroke in men and women separately. RESULTS:Incident stroke was determined in 1357 men and 900 women during follow-up (median 12.5 years and 13.0 years, respectively). A higher Danish Dietary Guidelines Index score was inversely associated with total stroke in men but not in women. In men, a high Index score (≥4) was also inversely associated with total ischemic stroke (hazard ratio 0.75, 95% confidence interval 0.65-0.86), large-artery atherosclerosis (hazard ratio 0.63, 95% confidence interval 0.44-0.92) and small artery occlusion (hazard ratio 0.68, 95% confidence interval 0.54-0.84) compared to a low Index score (

BACKGROUND:The plant-derived omega-3 fatty acid alpha-linolenic acid (ALA) may reduce the risk of cardiovascular disease. OBJECTIVE:We have investigated associations between the content of ALA in adipose tissue and the risk of ischemic stroke and its subtypes. METHODS:Incident cases of ischemic stroke among participants enrolled into the Danish Diet, Cancer and Health cohort (n = 57,053) were identified by linkage with the Danish National Patient Register. Subsequently, all potential cases were validated and classified into ischemic stroke subtypes. The fatty acid composition of adipose tissue was determined by gas chromatography in cases and in a randomly drawn sub-cohort (n = 3500). Statistical analyses were performed using weighted Cox regression. RESULTS:During a median of 13.4 years of follow-up, 1735 cases of total ischemic stroke were identified including 297 cases of large artery atherosclerosis, 772 cases of small-vessel occlusion, 99 cases of cardio-embolism, 91 cases with stroke of other etiology and 476 cases with stroke of undetermined etiology. The median content of ALA in adipose tissue within the sub-cohort was 0.84% (95% central range: 0.53-1.19%). Multivariable analyses showed a U-shaped association between adipose tissue content of ALA and the rate of total ischemic stroke, but this association was not statistically significant (p = 0.172). In analyses of ischemic stroke subtypes, we observed a statistically significant U-shaped association between ALA and the rate of ischemic stroke due to large artery atherosclerosis (p = 0.017), whereas no appreciable association was observed between ALA and the rate of small-vessel occlusion (p = 0.427). A positive but statistically non-significant association was observed between ALA and the rate of ischemic stroke due to cardio-embolism (p = 0.162). CONCLUSIONS:The content of ALA in adipose tissue was statistically non-significantly U-shaped associated with risk of total ischemic stroke. For ischemic stroke subtypes a statistically significant, U-shaped association with large artery atherosclerosis was observed.

BACKGROUND:The risk of coronary heart disease associated with intake of individual trans fatty acids (TFAs) is not clear. Adipose tissue content of TFAs is a biomarker of TFA intake and metabolism. OBJECTIVE:We investigated the rate of myocardial infarction (MI) associated with the adipose tissue content of total 18:1t, isomers of 18:1t (18:1 Δ6-10t and 18:1 Δ11t) and 18:2 Δ9c, 11t. METHODS:A case-cohort study, nested within the Danish Diet, Cancer and Health cohort (n = 57,053), was conducted, which included a random sample (n = 3156) of the total cohort and all incident MI cases (n = 2148) during follow-up (14 years). Information on MI cases was obtained by linkage with nationwide registers and validated. Adipose tissue was taken from the participants buttocks and the fatty acid composition was determined by gas chromatography. RESULTS:Women with higher adipose tissue content of total 18:1t had a 57% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.57; 95% confidence interval, 1.12-2.20; P-trend = 0.011) and women with higher content of 18:1 Δ6-10t had a 76% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.76; 95% confidence interval, 1.23-2.51; P-trend = 0.002). No association between 18:1 Δ11t content and MI rate was observed. In men, no associations between adipose tissue content of total 18:1t and 18:1 Δ6-10t and MI rate were observed. However, men with higher content of 18:1 Δ11t had a 48% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.48; 95% confidence interval, 1.17-1.86; P-trend = 0.003). Adipose tissue content of 18:2 Δ9c, 11t was not associated with MI rate in women or men. CONCLUSIONS:Adipose tissue content of 18:2 Δ9c, 11t was not associated with MI rate in women or men, whereas higher contents of isomers of 18:1t were associated with higher MI rates but the associations for individual 18:1t isomers differed, however, in women and men.

BackgroundCombinations of multiple fatty acids may influence cardiometabolic risk more than single fatty acids. The association of a combination of fatty acids with incident type 2 diabetes (T2D) has not been evaluated.Methods and findingsWe measured plasma phospholipid fatty acids by gas chromatography in 27,296 adults, including 12,132 incident cases of T2D, over the follow-up period between baseline (1991-1998) and 31 December 2007 in 8 European countries in EPIC-InterAct, a nested case-cohort study. The first principal component derived by principal component analysis of 27 individual fatty acids (mole percentage) was the main exposure (subsequently called the fatty acid pattern score [FA-pattern score]). The FA-pattern score was partly characterised by high concentrations of linoleic acid, stearic acid, odd-chain fatty acids, and very-long-chain saturated fatty acids and low concentrations of γ-linolenic acid, palmitic acid, and long-chain monounsaturated fatty acids, and it explained 16.1% of the overall variability of the 27 fatty acids. Based on country-specific Prentice-weighted Cox regression and random-effects meta-analysis, the FA-pattern score was associated with lower incident T2D. Comparing the top to the bottom fifth of the score, the hazard ratio of incident T2D was 0.23 (95% CI 0.19-0.29) adjusted for potential confounders and 0.37 (95% CI 0.27-0.50) further adjusted for metabolic risk factors. The association changed little after adjustment for individual fatty acids or fatty acid subclasses. In cross-sectional analyses relating the FA-pattern score to metabolic, genetic, and dietary factors, the FA-pattern score was inversely associated with adiposity, triglycerides, liver enzymes, C-reactive protein, a genetic score representing insulin resistance, and dietary intakes of soft drinks and alcohol and was positively associated with high-density-lipoprotein cholesterol and intakes of polyunsaturated fat, dietary fibre, and coffee (p < 0.05 each). Limitations include potential measurement error in the fatty acids and other model covariates and possible residual confounding.ConclusionsA combination of individual fatty acids, characterised by high concentrations of linoleic acid, odd-chain fatty acids, and very long-chain fatty acids, was associated with lower incidence of T2D. The specific fatty acid pattern may be influenced by metabolic, genetic, and dietary factors.

Selenium status of the Danish population is below that assumed optimal for the suggested protective effects against chronic diseases, including certain cancers. Fish and shellfish are important dietary sources of selenium in Denmark. We investigated the effect of increased fish and mussel intake on selenium blood concentrations in a population with relatively low habitual dietary selenium intake. We randomly assigned 102 healthy men and women (all non-smokers) aged 48–76 years to an intervention group (n = 51) or a control group (n = 51). Intervention participants received 1000 g fish and mussels/week for 26 weeks (~50 μg selenium/day). Controls received no intervention. Non-fasting blood samples were taken and whole blood selenium was determined using inductively coupled plasma-mass spectrometry (ICP-MS), and plasma selenoprotein P (SelP) was determined by high performance liquid chromatography coupled to ICP-MS. All available observations were included in linear multiple regression analysis to evaluate the effect of the intervention. The difference in mean change for intervention compared with control persons was 14.9 ng/mL (95% CI: 10.2, 19.7) for whole blood selenium, and 7.0 ng/mL (95% CI: 3.1, 10.9) for plasma SelP (Weeks 0–26). Selenium concentrations were significantly increased after 26 weeks of intervention, albeit to a lower degree than expected.

Adult height and sitting height may reflect genetic and environmental factors, including early life nutrition, physical and social environments. Previous studies have reported divergent associations for height and chronic disease mortality, with positive associations observed for cancer mortality but inverse associations for circulatory disease mortality. Sitting height might be more strongly associated with insulin resistance; however, data on sitting height and mortality is sparse. Using the European Prospective Investigation into Cancer and Nutrition study, a prospective cohort of 409,748 individuals, we examined adult height and sitting height in relation to all-cause and cause-specific mortality. Height was measured in the majority of participants; sitting height was measured in ~253,000 participants. During an average of 12.5 years of follow-up, 29,810 deaths (11,931 from cancer and 7,346 from circulatory disease) were identified. Hazard ratios (HR) with 95% confidence intervals (CI) for death were calculated using multivariable Cox regression within quintiles of height. Height was positively associated with cancer mortality (men: HRQ5 vs. Q1 = 1.11, 95%CI = 1.00-1.24; women: HRQ5 vs. Q1 = 1.17, 95%CI = 1.07-1.28). In contrast, height was inversely associated with circulatory disease mortality (men: HRQ5 vs. Q1 = 0.63, 95%CI = 0.56-0.71; women: HRQ5 vs. Q1 = 0.81, 95%CI = 0.70-0.93). Although sitting height was not associated with cancer mortality, it was inversely associated with circulatory disease (men: HRQ5 vs. Q1 = 0.64, 95%CI = 0.55-0.75; women: HRQ5 vs. Q1 = 0.60, 95%CI = 0.49-0.74) and respiratory disease mortality (men: HRQ5 vs. Q1 = 0.45, 95%CI = 0.28-0.71; women: HRQ5 vs. Q1 = 0.60, 95%CI = 0.40-0.89). We observed opposing effects of height on cancer and circulatory disease mortality. Sitting height was inversely associated with circulatory disease and respiratory disease mortality.