Background: The Healthy Reference Diet (HRD) was created to formulate dietary guidelines that would be healthy and sustainable. We aimed to construct a diet score measuring adherence to the HRD and to explore its association with cardiovascular events and environmental impact. Methods and Results: We included 35 496 participants from the population‐based EPIC‐NL (European Prospective Investigation into Cancer and Nutrition‐Netherlands) study. HRD scores were calculated using data from food frequency questionnaires (0–140). Data on morbidity and mortality were retrieved through linkage with national and death registries. Data on environmental impact indicators were obtained from life cycle assessments. Associations between adherence to the HRD and cardiovascular events were estimated with Cox proportional hazard models. Linear regression analysis was conducted for the adherence to the HRD and each environmental indicator. High adherence to the HRD was associated with 14%, 12%, and 11% lower risks of cardiovascular disease (hazard ratio [HR] _Q4vsQ1 , 0.86 [95% CI, 0.78–0.94]), coronary heart disease (HR _Q4vsQ1 , 0.88 [95% CI, 0.78–1.00]), and total stroke (HR _Q4vsQ1 , 0.89 [95% CI, 0.72–1.10]), respectively. High HRD adherence was associated with 2.4% (95% CI, −5.0 to 0.2) lower greenhouse gas emissions, 3.9% (95% CI, −5.2 to −2.6) less land use, 0.5% (95% CI, −2.6 to 1.6), less freshwater eutrophication, 3.3% (95% CI, −5.8 to −0.8), less marine eutrophication, 7.7% (95% CI, −10.8 to −4.6), less terrestrial acidification, and 32.1 % (95% CI, 28.5–35.7) higher blue water use. Conclusions: High adherence to the HRD was associated with lower risk of cardiovascular disease, coronary heart disease, and modestly lower levels of most environmental indicators but a higher level of blue water use.

To investigate the associations between major foods and dietary fibre with subtypes of stroke in a large prospective cohort. We analysed data on 418 329 men and women from nine European countries, with an average of 12.7 years of follow-up. Diet was assessed using validated country-specific questionnaires which asked about habitual intake over the past year, calibrated using 24-h recalls. Multivariable-adjusted Cox regressions were used to estimate hazard ratios (HRs) for ischaemic and haemorrhagic stroke associated with consumption of red and processed meat, poultry, fish, dairy foods, eggs, cereals, fruit and vegetables, legumes, nuts and seeds, and dietary fibre. For ischaemic stroke (4281 cases), lower risks were observed with higher consumption of fruit and vegetables combined (HR; 95% CI per 200 g/day higher intake, 0.87; 0.82–0.93, P-trend < 0.001), dietary fibre (per 10 g/day, 0.77; 0.69–0.86, P-trend < 0.001), milk (per 200 g/day, 0.95; 0.91–0.99, P-trend = 0.02), yogurt (per 100 g/day, 0.91; 0.85–0.97, P-trend = 0.004), and cheese (per 30 g/day, 0.88; 0.81–0.97, P-trend = 0.008), while higher risk was observed with higher red meat consumption which attenuated when adjusted for the other statistically significant foods (per 50 g/day, 1.07; 0.96–1.20, P-trend = 0.20). For haemorrhagic stroke (1430 cases), higher risk was associated with higher egg consumption (per 20 g/day, 1.25; 1.09–1.43, P-trend = 0.002). Risk of ischaemic stroke was inversely associated with consumption of fruit and vegetables, dietary fibre, and dairy foods, while risk of haemorrhagic stroke was positively associated with egg consumption. The apparent differences in the associations highlight the importance of examining ischaemic and haemorrhagic stroke subtypes separately.

The association between single health behaviours and incidence of and premature mortality from major chronic diseases, including myocardial infarction, stroke, diabetes mellitus, and cancer, has been demonstrated thoroughly. However, the association of several healthy behaviours with Disability-Adjusted Life Years (DALYs), which is a measure for total health combining Years Lost due to Disability and the Years of Life Lost due to premature mortality, has not been studied yet. A prospective cohort study was conducted among 33,066 healthy men and women aged 20 to 70 years recruited into the EPIC-NL study during 1993 to 1997. Participants’ smoking status, BMI, physical activity, and adherence to a Mediterranean-style diet (excluding alcohol) were investigated separately and combined into a simple health behaviour score ranging from 0 to 4. Participants were followed until the end of 2007 for occurrence of and mortality from the most important chronic diseases. The association between lifestyle (separate lifestyle factors and a simple health behaviour score) and DALYs were adjusted for relevant confounders. After a median follow-up of 12.4 years, 6,647 disease incidences and 1,482 deaths were documented. Non-smoking, low BMI (BMI <25), being physically active, and adherence to a Mediterranean diet were all associated with a significantly lower disease burden. Persons adhering to all four healthy lifestyle characteristics lived a minimum of 2 years longer in good health (DALYs: −2.13; 95% CI: −2.65 to −1.62) than persons with none. Due to our non-extinct cohort, the total number of DALYs, and consequently the estimates, is underestimated. Therefore, true lifetime health benefits of a healthy lifestyle will be even larger. Non-smoking, a low BMI, being physically active, and adherence to a Mediterranean diet were associated with a lower disease burden. Each additional healthy lifestyle factor contributed to a longer life in good health.

DNA methylation profiles are responsive to environmental stimuli and metabolic shifts. This makes DNA methylation a potential biomarker of environmental-related and lifestyle-driven diseases of adulthood. Therefore, we investigated if white blood cells’ (WBCs) DNA methylation profiles are associated with myocardial infarction (MI) occurrence. Whole-genome DNA methylation was investigated by microarray analysis in 292 MI cases and 292 matched controls from the large prospective Italian European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (EPICOR study). Significant signals (false discovery rate (FDR) adjusted P < 0.05) were replicated by mass spectrometry in 317 MI cases and 262 controls from the Dutch EPIC cohort (EPIC-NL). Long interspersed nuclear element-1 (LINE-1) methylation profiles were also evaluated in both groups. A differentially methylated region (DMR) within the zinc finger and BTB domain-containing protein 12 (ZBTB12) gene body and LINE-1 hypomethylation were identified in EPICOR MI cases and replicated in the EPIC-NL sample (ZBTB12-DMR meta-analysis: effect size ± se = −0.016 ± 0.003, 95 % CI = −0.021;−0.011, P = 7.54 × 10−10; LINE-1 methylation meta-analysis: effect size ± se = −0.161 ± 0.040, 95 % CI = −0.239;−0.082, P = 6.01 × 10−5). Moreover, cases with shorter time to disease had more pronounced ZBTB12-DMR hypomethylation (meta-analysis, men: effect size ± se = −0.0059 ± 0.0017, P TREND = 5.0 × 10−4; women: effect size ± se = −0.0053 ± 0.0019, P TREND = 6.5 × 10−3) and LINE-1 hypomethylation (meta-analysis, men: effect size ± se = −0.0010 ± 0.0003, P TREND = 1.6 × 10−3; women: effect size ± se = −0.0008 ± 0.0004, P TREND = 0.026) than MI cases with longer time to disease. In the EPIC-NL replication panel, DNA methylation profiles improved case-control discrimination and reclassification when compared with traditional MI risk factors only (net reclassification improvement (95 % CI) between 0.23 (0.02–0.43), P = 0.034, and 0.89 (0.64–1.14), P < 1 × 10−5). Our data suggest that specific methylation profiles can be detected in WBCs, in a preclinical condition, several years before the occurrence of MI, providing an independent signature of cardiovascular risk. We showed that prediction accuracy can be improved when DNA methylation is taken into account together with traditional MI risk factors, although further confirmation on a larger sample is warranted. Our findings support the potential use of DNA methylation patterns in peripheral blood white cells as promising early biomarkers of MI.

Background and Purpose: The few epidemiological studies that addressed the association between age at menopause and ischemic and hemorrhagic stroke risk in women had conflicting findings. We aimed to investigate whether age at (natural and surgical) menopause is a risk factor for total, ischemic, and hemorrhagic stroke in women. Methods: We analyzed data from 16 244 postmenopausal women, aged 26 to 70 years at recruitment who were enrolled in the European Prospective Investigation into Cancer and Nutrition–Netherlands cohort between 1993 and 1997. Participants were followed for the occurrence of stroke until January 1, 2011. At baseline, participants filled in questionnaires about health, reproductive history including age at menopause, diet, and lifestyle. Cox regression was used to investigate the association between age at menopause and stroke. All analyses were adjusted for age, smoking, systolic blood pressure, and body mass index. Results: Mean age of menopause was 46.4 (7.0) years. A total of 830 strokes (571 ischemic, 162 hemorrhagic, 97 unclassified) were identified. Earlier menopause was associated with an increased risk of total stroke. Compared with women who experienced menopause between 50 and 54 years old, women who underwent menopause before age 40 years had 1.48× higher risk (95% CI, 1.19–1.85) of total stroke. In continuous analyses, we observed a 2% lower total stroke risk for each year menopause was delayed (hazard ratio, 0.98 [95% CI, 0.97–0.99]). The risk between earlier menopause and stroke was confined to ischemic stroke, earlier menopause was not associated with hemorrhagic stroke. The association with age at menopause was stronger for natural menopause (hazard ratio <40 versus 50–54 years, 1.74 [95% CI, 1.12–2.70]) than for surgical menopause (hazard ratio <40 versus 50–54 years, 1.26 [95% CI, 0.84–1.89]). Conclusions: The risk of total and ischemic stroke decreased with an increase in age at menopause. Whether this should have clinical consequences such as intensified risk factor control should be subject of further studies.

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values 105 mL·min ^–1 ·1.73 m ^–2 , compared with those with eGFR between 60 and 105 mL·min ^–1 ·1.73 m ^–2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR 105 mL·min ^–1 ·1.73 m ^–2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.