We investigated the risk of ischemic stroke and its subtypes when red meat or poultry was substituted with fish. A total of 57,053 participants aged 50⁻65 years at baseline were included in the ...Danish Diet, Cancer and Health study. All participants filled in a food-frequency questionnaire at recruitment. Potential ischemic stroke cases were identified by linkage to the Danish National Patient Register, and all cases were validated and subclassified. Substitutions were investigated as 150 g/week of fish for 150 g/week of red meat or of poultry using multivariable Cox proportional hazard regression models. During 13.5 years of follow-up, 1879 participants developed an ischemic stroke. Replacing red meat or poultry with fish was not associated with the rate of total ischemic stroke, but there was a statistically significant lower rate of large artery atherosclerosis when fish replaced processed (hazard ratio (HR): 0.78; 95% confidence interval (CI): 0.67; 0.90) and unprocessed (HR: 0.87; 95% CI: 0.75; 0.99) red meat. A statistically significant higher rate of cardioembolism was found when poultry was replaced by total fish (HR: 1.42; 95% CI: 1.04; 1.93). When fatty fish replaced unprocessed red meat, a statistically significant lower rate of small-vessel occlusion was found (HR: 0.88; 95% CI: 0.77; 0.99). In conclusion, replacing red meat with fish was not associated with risk of total ischemic stroke but was associated with a lower risk of subtypes of ischemic stroke.
It is unclear whether diet, and in particular certain foods or nutrients, are associated with lung cancer risk. We assessed associations of 92 dietary factors with lung cancer risk in 327 790 ...participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) per SD higher intake/day of each food/nutrient. Correction for multiple comparisons was performed using the false discovery rate and identified associations were evaluated in the Netherlands Cohort Study (NLCS). In EPIC, 2420 incident lung cancer cases were identified during a median of 15 years of follow‐up. Higher intakes of fibre (HR per 1 SD higher intake/day = 0.91, 95% CI 0.87‐0.96), fruit (HR = 0.91, 95% CI 0.86‐0.96) and vitamin C (HR = 0.91, 95% CI 0.86‐0.96) were associated with a lower risk of lung cancer, whereas offal (HR = 1.08, 95% CI 1.03‐1.14), retinol (HR = 1.06, 95% CI 1.03‐1.10) and beer/cider (HR = 1.04, 95% CI 1.02‐1.07) intakes were positively associated with lung cancer risk. Associations did not differ by sex and there was less evidence for associations among never smokers. None of the six associations with overall lung cancer risk identified in EPIC were replicated in the NLCS (2861 cases), however in analyses of histological subtypes, inverse associations of fruit and vitamin C with squamous cell carcinoma were replicated in the NLCS. Overall, there is little evidence that intakes of specific foods and nutrients play a major role in primary lung cancer risk, but fruit and vitamin C intakes seem to be inversely associated with squamous cell lung cancer.
What's new?
Lung cancer is the leading cause of cancer death worldwide, and while smoking is the most significant factor affecting lung cancer risk, other environmental and genetic factors may contribute. Here, the authors looked for an association between the foods people eat and their lung cancer risk. Using an approach they call a diet‐wide association study, modelled after genome‐wide association studies, they evaluated 92 individual food and nutrient intakes for association with lung cancer risk. No major associations were detected for lung cancer overall, but higher fruit and vitamin C intakes were associated with lower squamous cell lung cancer risk.
Abstract Aim Inflammation is a risk factor for coronary heart disease (CHD). A common deletion-allele in the promoter region of NFKB1 results in lower protein levels of the NF-κB p50 subunit. Recent ...evidence suggests that the NF-κB p50 dimer has anti-inflammatory effects. We aimed to investigate the association of the functional ATTG NFKB1 insertion/deletion variant with risk of CHD in three independent prospective studies of generally healthy men and women. Methods and results The NFKB1 ins/del polymorphism was genotyped in studies of CHD nested within the Diet, Cancer and Health (DCH) study, the Health Professionals Follow-up (HPFS) and the Nurses’ Health (NHS) studies, totaling 1008, 428 and 439 cases, respectively. The minor allele frequency in the combined sample was 0.38 among controls. In a pooled analysis, the relative risk (RR) among heterozygous men and women was 1.22 (95% CI: 1.07–1.40), compared to the most common ins/ins genotype. The RR among homozygotes was 1.20 (95% CI: 0.94–1.53). There was no evidence of an allele-dosage effect, and in a dominant model the RR among del-allele carriers was 1.22 (95% CI: 1.07–1.39). The risk was similar in women and men (RR was 1.20 in women and 1.23 in men, respectively). The NFKB1 variant was not associated with plasma lipid levels, but del-carriers had lower levels of C-reactive protein. Conclusions The NFKB1 promoter variant, previously shown to cause partial depletion of NF-κB p50, was associated with a higher risk of CHD in three independent prospective studies of generally healthy Caucasians.
Current epidemiologic evidence indicates that smoking is associated with a lower endometrial cancer risk. However, it is unknown if this association is causal or confounded. To further elucidate the ...role of smoking in endometrial cancer risk, we conducted complementary observational and Mendelian randomization (MR) analyses.
The observational analyses included 286,415 participants enrolled in the European Prospective Investigation into Cancer and Nutrition and 179,271 participants in the UK Biobank, and multivariable Cox proportional hazards models were used. In two-sample MR analyses, genetic variants robustly associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants) were selected and their association with endometrial cancer risk (12,906 cancer/108,979 controls from the Endometrial Cancer Association Consortium) was examined.
In the observational analysis, lifetime amount of smoking and ever having smoked regularly were associated with a lower endometrial cancer risk. In the MR analysis accounting for body mass index, a genetic predisposition to a higher lifetime amount of smoking was not associated with endometrial cancer risk (OR per 1-SD increment: 1.15; 95% confidence interval: 0.91-1.44). Genetic predisposition to ever having smoked regularly was not associated with risk of endometrial cancer.
Smoking was inversely associated with endometrial cancer in the observational analyses, although unsupported by the MR. Additional studies are required to better understand the possible confounders and mechanisms underlying the observed associations between smoking and endometrial cancer.
The results from this analysis indicate that smoking is unlikely to be causally linked with endometrial cancer risk.
Selenium (Se) may help prevent breast cancer (BC) development. Owing to limited observational evidence, we investigated whether prediagnostic Se status and/or variants in the selenoprotein genes are ...associated with BC risk in a large European cohort. Se status was assessed by plasma measures of Se and its major circulating proteins, selenoprotein P (SELENOP) and glutathione peroxidase 3 (GPX3), in matched BC case-control pairs (2208 for SELENOP; 1785 for GPX3 and Se) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Single nucleotide polymorphisms (SNPs, n = 452) in 55 selenoprotein and Se metabolic pathway genes and an additional 18 variants previously associated with Se concentrations were extracted from existing genotyping data within EPIC for 1564 case-control pairs. Multivariable-adjusted logistic regression models were used to calculate the odds ratios (ORs) and 95 % confidence intervals (CIs) of the association between Se status markers, SNP variants and BC risk. Overall, there was no statistically significant association of Se status with BC risk. However, higher GPX3 activity was associated with lower risk of premenopausal BC (4th versus 1st quartile, OR = 0.54, 95 % CI: 0.30–0.98, Ptrend = 0.013). While none of the genetic variant associations (P ≤ 0.05) retained significance after multiple testing correction, rs1004243 in the SELENOM selenoprotein gene and two SNPs in the related antioxidant TXN2 gene (rs4821494 and rs5750261) were associated with respective lower and higher risks of BC at a significance threshold of P ≤ 0.01. Fourteen SNPs in twelve Se pathway genes (P ≤ 0.01) in interaction with Se status were also associated with BC risk. Higher Se status does not appear to be associated with BC risk, although activity of the selenoenzyme GPX3 may be inversely associated with premenopausal BC risk, and SNPs in the Se pathway alone or in combination with suboptimal Se status may influence BC risk.
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•Largest prospective analysis of the association of Se status biomarkers and Se pathway genetic variation with BC risk.•Higher Se status does not appear to be associated with BC risk overall.•Higher activity of the GPX3 selenoenzyme may reduce risk of BC in premenopausal women.•Inherited SNPs in several selenoprotein and Se related genes could impact BC risk alone or in combination with Se status.
Significance/what's new: Higher selenium (Se) status may not markedly help prevent breast cancer development, though higher activity of the glutathione peroxidase 3 selenoenzyme (GPX3; that contains Se in the form of selenocysteine) may reduce risk of breast cancer in premenopausal women. Additionally, inherited common genetic variants in several selenoprotein and Se-related genes could impact breast cancer risk alone or in combination with Se status.
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.
A sizeable proportion of systematic variability due to variables expressing 'batch' and 'sample position' within 'chip' was identified, with values of the partial R
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 (
= 600 and
= 427, respectively) were associated to smoking status than the SVA correction (
= 96).
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.
Ischemic stroke is a major health problem worldwide, but the influence of dietary factors on stroke risk is not well known. This study aimed to investigate the risk of ischemic stroke and its ...subtypes with a higher intake from linoleic acid and a concomitant lower intake from saturated fatty acids, monounsaturated fatty acids, or glycemic carbohydrates.
In the Danish prospective Diet, Cancer, and Health Study of 57 053 participants aged 50 to 64 years at baseline, information on diet was collected using a validated semiquantitative food frequency questionnaire. Information on ischemic stroke was obtained from the Danish National Patient Register, and cases were all validated and subclassified according to the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Substitution of linoleic acid for saturated fatty acid, monounsaturated fatty acid, or glycemic carbohydrates was investigated in relation to the risk of ischemic stroke and subtypes. Cox proportional hazards regression was used to estimate the associations with ischemic stroke adjusting for appropriate confounders.
During 13.5 years of follow-up 1879 participants developed ischemic stroke. A slightly lower risk of ischemic stroke was found with a 5% higher intake of linoleic acid and a concomitant lower intake of saturated fatty acid (hazard ratio, 0.98; 95% confidence interval, 0.83-1.16), monounsaturated fatty acid (hazard ratio, 0.80; 95% confidence interval, 0.63-1.02), and glycemic carbohydrates (hazard ratio, 0.92; 95% confidence interval, 0.78-1.09), although not statistically significant. Similar patterns of association were found for large-artery atherosclerosis and small-vessel occlusions.
This study suggests that replacing saturated fatty acid, glycemic carbohydrate, or monounsaturated fatty acid with linoleic acid may be associated with a lower risk of ischemic stroke.
Younger age at menarche, a marker of pubertal timing in girls, is associated with higher risk of later type 2 diabetes. We aimed to confirm this association and to examine whether it is explained by ...adiposity.
The prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from 26 research centers across eight European countries. We tested the association between age at menarche and incident type 2 diabetes using Prentice-weighted Cox regression in 15,168 women (n = 5,995 cases). Models were adjusted in a sequential manner for potential confounding and mediating factors, including adult BMI.
Mean menarcheal age ranged from 12.6 to 13.6 years across InterAct countries. Each year later menarche was associated with 0.32 kg/m2 lower adult BMI. Women in the earliest menarche quintile (8-11 years, n = 2,418) had 70% higher incidence of type 2 diabetes compared with those in the middle quintile (13 years, n = 3,634), adjusting for age at recruitment, research center, and a range of lifestyle and reproductive factors (hazard ratio HR, 1.70; 95% CI, 1.49-1.94; P < 0.001). Adjustment for BMI partially attenuated this association (HR, 1.42; 95% CI, 1.18-1.71; P < 0.001). Later menarche beyond the median age was not protective against type 2 diabetes.
Women with history of early menarche have higher risk of type 2 diabetes in adulthood. Less than half of this association appears to be mediated by higher adult BMI, suggesting that early pubertal development also may directly increase type 2 diabetes risk.
Abstract
Background
Risk stratification in patients with type 2 diabetes continues to be an important priority in the management of diabetes-related morbidity and mortality. International guidelines ...generally recognize patients with diabetes and cardiovascular disease as high-risk patients. Risk stratification is, however, more uncertain in diabetes patients without cardiovascular disease. Micro- and macroalbuminuria have previously been identified as predictors of cardiovascular events and mortality in general cohorts of diabetes patients. However, less is known about the predictive value of albuminuria in patients with diabetes but without established cardiovascular disease.
Purpose
We aimed to examine the association between albuminuria level and the risk of ischemic stroke, myocardial infarction, and all-cause mortality in patients with type 2 diabetes and without a diagnosis of cardiovascular disease.
Methods
We linked Danish nationwide registries to identify patients with type 2 diabetes and without cardiovascular disease from May 2005 through June 2015. Based on two consecutive measurements of the urinary albumin excretion rate or albumin-to-creatinine ratio patients were stratified in categories of normoalbuminuria, microalbuminuria, and macroalbuminuria. Patients were followed for the outcomes ischemic stroke, myocardial infarction, and all-cause mortality until December 31, 2015. Five-year risk of outcomes were presented as cumulative incidence functions (with death as a competing event). Associations between albuminuria level and incidence of ischemic stroke, myocardial infarction, and all-cause mortality were evaluated with Cox proportional hazard regression adjusted for cardiovascular risk factors.
Results
The study population included 78,841 patients with type 2 diabetes (44.7% females, mean age 63.2). When comparing patients with microalbuminuria to patients with normoalbuminuria in an age- and sex-adjusted analysis, we found hazard ratios (HRs) of 1.45 (95% CI: 1.24–1.69), 1.45 (95% CI: 1.24–1.70), and 1.50 (95% CI: 1.39–1.61) for ischemic stroke, myocardial infarction, and all-cause mortality, respectively. Furthermore, macroalbuminuria was associated with HRs of 2.05 (95% CI: 1.70–2.48), 2.25 (95% CI: 1.86–2.71), and 2.03 (95% CI: 1.85–2.23) for ischemic stroke, myocardial infarction, and all-cause mortality, respectively. Similar results were found after adjusting for cardiovascular risk factors.
Conclusions
In this nationwide cohort study of patients with type 2 diabetes but without cardiovascular disease, patients with micro- and macroalbuminuria had a higher risk of incident ischemic stroke, myocardial infarction, and all-cause mortality. This finding supports that patients with micro- or macroalbuminuria should be screened regularly and followed closely in clinical practice. Moreover, these findings suggest that patients with type 2 diabetes and micro- or macroalbuminuria may benefit from intensive vascular risk reduction.
CD36 is a cholesterol receptor involved in the uptake of oxidized low-density lipoprotein cholesterol and development of atherosclerotic plaques. Cross-sectional studies have shown correlations ...between plasma CD36 and atherosclerosis but no prospective study has examined the association yet. We prospectively examined the association between plasma CD36 levels and risk of incident coronary heart disease (CHD) in a Danish population.
Plasma CD36 levels were measured in a case-cohort study nested within the Danish population-based cohort, the Diet, Cancer and Health Study. A total of 1963 incident CHD events occurred between baseline (1993–1997) and 2008, and a sub-cohort of 1759 participants were randomly selected as reference. Cox proportional hazard regression models were used to compute the hazard ratio (HR) and corresponding 95% confidence interval (CI).
After adjusting for CHD risk factors, including history of hypercholesterolemia and diabetes, elevated plasma CD36 levels were not associated with higher CHD risk in the total population, and the HR comparing the highest versus lowest tertile of CD36 levels was 1.02 (95% CI: 0.84–1.23). High CD36 levels were only found to be associated with risk of CHD in combination with prevalent diabetes (HR = 2.83, 95% CI: 1.08–7.45) vs. the joint reference group of lowest CD36 tertile and no diabetes.
Plasma CD36 levels were not predictive of CHD risk in the general population.
•This is the first prospective cohort study to assess the association between plasma CD36 and coronary heart disease risk.•Plasma CD36 was not associated with risk of coronary heart disease in the Danish population.•There was a suggestion of higher risk of coronary heart disease among participants with both high CD36 levels and diabetes.
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