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Autophagy is involved in cellular homeostasis and maintenance and may play a role in cardiometabolic health. We aimed to elucidate the role of autophagy in cardiometabolic traits by investigating genetic variants and DNA methylation in autophagy-related genes in relation to cardiovascular diseases and related traits. To address this research question, we implemented a multidirectional approach using several molecular epidemiology tools, including genetic association analysis with genome wide association studies data and exome sequencing data and differential DNA methylation analysis. We investigated the 21 autophagy-related genes in relation to coronary artery disease and a number of cardiometabolic traits (blood lipids, blood pressure, glycemic traits, type 2 diabetes). We used data from the largest genome wide association studies as well as DNA methylation and exome sequencing data from the Rotterdam Study. Single-nucleotide polymorphism rs110389913 in AMBRA1 (p-value = 4.9×10−18) was associated with blood proinsulin levels, whereas rs6587988 in ATG4C and rs10439163 in ATG4D with lipid traits (ATG4C: p-value = 2.5×10−15 for total cholesterol and p-value = 3.1×10−18 for triglycerides, ATG4D: p-value = 9.9×10−12 for LDL and p-value = 1.3×10−10 for total cholesterol). Moreover, rs7635838 in ATG7 was associated with HDL (p-value = 1.9×10−9). Rs2447607 located in ATG7 showed association with systolic blood pressure and pulse pressure. Rs2424994 in MAP1LC3A was associated with coronary artery disease (p-value = 5.8×10−6). Furthermore, we identified association of an exonic variant located in ATG3 with diastolic blood pressure (p-value = 6.75×10−6). Using DNA methylation data, two CpGs located in ULK1 (p-values = 4.5×10−7 and 1×10−6) and two located in ATG4B (2×10−13 and 1.48×10−7) were significantly associated with both systolic and diastolic blood pressure. In addition one CpG in ATG4D was associated with HDL (p-value = 3.21×10−5). Our findings provide support for the role of autophagy in glucose and lipid metabolism, as well as blood pressure regulation. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the criterion validity of the 2015 food-based Dutch dietary guidelines, which were formulated based on evidence on the relation between diet and major chronic diseases. We studied 9701 participants of the Rotterdam Study, a population-based prospective cohort in individuals aged 45 years and over [median 64.1 years (95%-range 49.0-82.8)]. Dietary intake was assessed at baseline with a food-frequency questionnaire. For all participants, we examined adherence (yes/no) to fourteen items of the guidelines: vegetables (≥200 g/day), fruit (≥200 g/day), whole-grains (≥90 g/day), legumes (≥135 g/week), nuts (≥15 g/day), dairy (≥350 g/day), fish (≥100 g/week), tea (≥450 mL/day), ratio whole-grains:total grains (≥50%), ratio unsaturated fats and oils:total fats (≥50%), red and processed meat (<300 g/week), sugar-containing beverages (≤150 mL/day), alcohol (≤10 g/day) and salt (≤6 g/day). Total adherence was calculated as sum-score of the adherence to the individual items (0-14). Information on disease incidence and all-cause mortality during a median follow-up period of 13.5 years (range 0-27.0) was obtained from data collected at our research center and from medical records. Using Cox proportional-hazards models adjusted for confounders, we observed every additional component adhered to was associated with a 3% lower mortality risk (HR 0.97, 95% CI 0.95; 0.98), lower risk of stroke (HR 0.95, 95% CI 0.92; 0.99), chronic obstructive pulmonary disease (HR 0.94, 95% CI 0.91; 0.98), colorectal cancer (HR 0.90, 95% CI 0.84; 0.96), and depression (HR 0.97, 95% CI 0.95; 0.999), but not with incidence of coronary heart disease, type 2 diabetes, heart failure, lung cancer, breast cancer, or dementia. These associations were not driven by any of the individual dietary components. To conclude, adherence to the Dutch dietary guidelines was associated with a lower mortality risk and a lower risk of developing some but not all of the chronic diseases on which the guidelines were based. [ABSTRACT FROM AUTHOR]

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over 1200 research articles and reports (see ). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular factors and low education are important risk factors of dementia. We provide contemporary estimates of the proportion of dementia cases that could be prevented if modifiable risk factors were eliminated, i.e., population attributable risk (PAR). Furthermore, we studied whether the PAR has changed across the last two decades. Methods: We included 7,003 participants of the original cohort (starting in 1990) and 2,953 participants of the extended cohort (starting in 2000) of the Rotterdam Study. Both cohorts were followed for dementia until ten years after baseline. We calculated the PAR of overweight, hypertension, diabetes mellitus, cholesterol, smoking, and education. Additionally, we assessed the PAR of stroke, coronary heart disease, heart failure, and atrial fibrillation. We calculated the PAR for each risk factor separately and the combined PAR taking into account the interaction of risk factors. Results: During 57,996 person-years, 624 participants of the original cohort developed dementia, and during 26,177 person-years, 145 participants of the extended cohort developed dementia. The combined PAR in the original cohort was 0.23 (95 % CI, 0.05-0.62). The PAR in the extended cohort was slightly higher at 0.30 (95 % CI, 0.06-0.76). The combined PAR including cardiovascular diseases was 0.25 (95 % CI, 0.07-0.62) in the original cohort and 0.33 (95 % CI, 0.07-0.77) in the extended cohort. Conclusions: A substantial part of dementia cases could be prevented if modifiable risk factors would be eliminated. Although prevention and treatment options of cardiovascular risk factors and diseases have improved, the preventive potential for dementia has not declined over the last two decades. [ABSTRACT FROM AUTHOR]

The association between metabolic syndrome (MS) and bone health remains unclear. We aimed to study the association between MS and hip bone geometry (HBG), femoral neck bone mineral density (FN-BMD), and the risk of osteoporosis and incident fractures. Data of 2040 women and 1510 men participants in the third visit (1997–1999) of the Rotterdam Study (RSI-3), a prospective population based cohort, were available (mean follow-up 6.7 years). MS was defined according to the recent harmonized definition. HBG parameters were measured at the third round visit whereas FN-BMD was assessed at the third round and 5 years later. Incident fractures were identified from medical registry data. After correcting for age, body mass index (BMI), lifestyle factors and medication use, individuals with MS had lower bone width (β = -0.054, P = 0.003), lower cortical buckling ratio (β = -0.81, P = 0.003) and lower odds of having osteoporosis (odds ratio =0.56, P = 0.007) in women but not in men. Similarly, MS was associated with higher FN-BMD only in women (β = 0.028, P=0.001). In the analyses of MS components, the glucose component (unrelated to diabetes status) was positively associated with FN-BMD in both genders (β = 0.016, P = 0.01 for women and β = 0.022, P = 0.004 for men). In men, waist circumference was inversely associated with FN-BMD (β = -0.03, P = 0.004). No association was observed with fracture risk in either sex. In conclusion, women with MS had higher FN-BMD independent of BMI. The glucose component of MS was associated with high FN-BMD in both genders, highlighting the need to preserve glycemic control to prevent skeletal complications. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension is characterized by increased pulmonary artery pressure and carries an increased mortality. Population-based studies into pulmonary hypertension are scarce and little is known about its prevalence in the general population. We aimed to describe the distribution of echocardiographically-assessed pulmonary artery systolic pressure (ePASP) in the general population, to estimate the prevalence of pulmonary hypertension, and to identify associated factors. Methods: Participants (n = 3381, mean age 76.4 years, 59% women) from the Rotterdam Study, a population-based cohort, underwent echocardiography. Echocardiographic pulmonary hypertension was defined as ePASP>40 mmHg. Results: Mean ePASP was 26.3 mmHg (SD 7.0). Prevalence of echocardiographic pulmonary hypertension was 2.6% (95%CI: 2.0; 3.2). Prevalence was higher in older participants compared to younger ones (8.3% in those over 85 years versus 0.8% in those between 65 and 70), and in those with underlying disorders versus those without (5.9% in subjects with COPD versus 2.3%; 9.2% in those with left ventricular systolic dysfunction versus 2.3%; 23.1% in stages 3 or 4 left ventricular diastolic dysfunction versus 1.9% in normal or stage 1). Factors independently associated with higher ePASP were older age, higher BMI, left ventricular diastolic dysfunction, COPD and systemic hypertension. Conclusion: In this large population-based study, we show that pulmonary hypertension as measured by echocardiography has a low prevalence in the overall general population in the Netherlands, but estimates may be higher in specific subgroups, especially in those with underlying diseases. Increased pulmonary arterial pressure is likely to gain importance in the near future due to population aging and the accompanying prevalences of underlying disorders. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is the most common chronic arrhythmia and it increases the risk of cardiovascular morbidity and mortality. Still there is not a complete understanding of its etiology and underlying pathways. Vitamin D might regulate renin-angiotensin-aldosterone system and might be involved in inflammation, both implicated in the pathophysiology of AF. The objective of this work was to investigate the association between vitamin D status with the risk of AF in the elderly. This study was conducted within the Rotterdam Study, a community-based cohort of middle-aged and elderly participants in Rotterdam, The Netherlands. We had 3,395 participants who were free of AF diagnosis at the start of our study and who had vitamin D data available. We analyzed the association between serum 25-hydroxivitamin D (25(OH)D) and incidence of AF using Cox regression models. Vitamin D deficiency was defined as serum 25(OH)D concentrations <50nmol/l, insufficiency between 50nmol/l and 75nmol/l, while serum 25(OH)D concentrations equal to and above 75nmol/l were considered as adequate. After mean follow-up of 12.0 years 263 (7.7%) participants were diagnosed with incident AF. Vitamin D status was not associated with AF in any of the 3 multivariate models tested (model adjusted for socio-demographic factors and life-style factors: HR per 10 unit increment in serum 25(OH)D 0.96, 95% CI: 0.91-1.02; HR for insufficiency: 0.82, 95%CI: 0.60-1.11,and HR for adequate status: 0.76, 95%CI: 0.52-1.12 compared to deficiency). This prospective cohort study does not support the hypothesis that vitamin D status is associated with AF. [ABSTRACT FROM AUTHOR]

Objective: To examine the incremental predictive value of genetic risk scores of coronary heart disease (CHD) in the 10-year risk prediction of incident CHD. Methods: In 5899 subjects, we used 152 single nucleotide polymorphisms (SNPs) associated with coronary artery disease by the CARDIoGRAMplusC4D consortium to construct three weighted genetic risk scores: (i) GRSgws based on 49 genome-wide significant SNPs; (ii) GRSfdr based on 103 suggestively associated SNPs; and (iii) GRSall based on all 152 SNPs. We examined the changes in discrimination and reclassification of incident CHD when adding the genetic risk scores to models including traditional risk factors. We repeated the analysis for prevalent CHD. Results: The genetic risk scores were associated with incident CHD despite adjustment for traditional risk factors and family history: participants had a 13% higher rate of CHD per standard deviation increase in GRSall. GRSall improved the C-statistic by 0.006 [95% confidence interval (CI): 0.000, 0.013] beyond age and sex, 0.003 (95% CI: --0.001, 0.008) beyond traditional risk factors and 0.003 (95% CI:--0.001, 0.007) beyond traditional risk factors and family history. The genetic risk scores did not improve reclassification. GRSall strongly improved both discrimination and reclassification of prevalent CHD, even beyond traditional risk factors and family history, with a C-statistic improvement of 0.009 (0.003, 0.015). Conclusions: Although the genetic risk scores based on 152 SNPs were associated with incident CHD, they did not improve risk prediction. This discrepancy may be the result of SNP discovery for prevalent rather than incident CHD, since the SNPs do improve prediction for prevalent disease. [ABSTRACT FROM AUTHOR]

To investigate the prevalence of frailty in a Dutch elderly population and to identify adverse health outcomes associated with the frailty phenotype independent of the comorbidities. Cross-sectional and longitudinal analyses within the Rotterdam Study (the Netherlands), a prospective population-based cohort study in persons aged ≥55 years. Frailty was defined as meeting three or more of five established criteria for frailty, evaluating nutritional status, physical activity, mobility, grip strength and exhaustion. Intermediate frailty was defined as meeting one or two frailty criteria. Comorbidities were objectively measured. Health outcomes were assessed by means of questionnaires, physical examinations and continuous follow-up through general practitioners and municipal health authorities for mortality. Of 2,833 participants (median age 74.0 years, inter quartile range 9) with sufficiently evaluated frailty criteria, 163 (5.8 %) participants were frail and 1,454 (51.3 %) intermediate frail. Frail elderly were more likely to be older and female, to have an impaired quality of life and to have fallen or to have been hospitalized. 108 (72.0 %) frail participants had ≥2 comorbidities, compared to 777 (54.4 %) intermediate frail and 522 (44.8 %) non-frail participants. Adjusted for age, sex and comorbidities, frail elderly had a significantly increased risk of dying within 3 years (HR 3.4; 95 % CI 1.9-6.4), compared to the non-frail elderly. This study in a general Dutch population of community-dwelling elderly able to perform the frailty tests, demonstrates that frailty is common and that frail elderly are at increased risk of death independent of comorbidities. [ABSTRACT FROM AUTHOR]

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy ). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods. [ABSTRACT FROM AUTHOR]

Several studies have associated physical activity with the risk of dementia, but mostly did so during short follow-up. It remains unclear whether physical activity also affects dementia during longer follow-up. We examined the association between physical activity and risk of dementia during a follow-up period up to 14 years. From 1997 to 1999, physical activity was assessed using a validated questionnaire in 4,406 elderly persons (age range 61-97) from the prospective, population-based Rotterdam Study. Follow-up for dementia was complete until January 1, 2011. We used Cox proportional hazards models to assess the association between physical activity and incident dementia. Next, we stratified follow-up time using a cut-off of 4 years. We separately investigated dementia due to Alzheimer disease. During 38,631 person-years, 583 participants developed dementia. When adjusting for age and sex, we found a borderline significant association between higher physical activity and lower risk of dementia (HR 0.95; 95 % CI 0.87-1.04). This association was confined to follow-up up to 4 years (HR 0.82; 95 % CI 0.71-0.95), and not to follow-up of at least 4 years (HR 1.04; 95 % CI 0.93-1.16). Additional adjustments only slightly attenuated the associations. A similar pattern was present for Alzheimer disease. We found a higher level of physical activity to be associated with a lower risk of dementia. This association was confined to follow-up for up to 4 years and not to longer follow-up, suggesting either a role for reverse causality or only a short term effect of late-life physical activity in an elderly population. [ABSTRACT FROM AUTHOR]

Background: Inverse associations between dietary protein and hypertension have been reported, which may be attributed to specific amino acids. Objective: We examined whether the intake of glutamic acid, arginine, cysteine, lysine, or tyrosine was associated with blood pressure (BP) levels (n = 3086) and incident hypertension (n = 1810) in the Rotterdam Study. Design: We calculated BP levels in quartiles of amino acid intake as a percentage of total protein intake (% of protein) with adjustment for age, sex, BMI, smoking, alcohol intake, education, and dietary factors. Subsequently, we used Cox proportional models that included the same confounders to evaluate the associations between specific amino acid intake and hypertension incidence. Results: Glutamic acid contributed most to protein intake (21% of protein), whereas lysine provided 7%, arginine 5%, tyrosine 4%, and cysteine 1.5%. A higher intake of tyrosine (~0.3% of protein) was significantly related to a 2.4-mm Hg lower systolic BP (P-trend = 0.05) but not to diastolic BP (P = 0.35). The otherammo acids were not significantly associated with BP levels in a cross-sectional analysis. During 6 y of follow-up (7292 person-years), 873 cases of hypertension developed. None of the amino acids were significantly associated with incident hypertension (HR: 0.81-1.18; P-trend > 0.2). Conclusion: Our data do not suggest a major role for glutamic acid, arginine, lysine, tyrosine, or cysteine intake (as % of protein intake) in determining population BP or risk of hypertension. [ABSTRACT FROM AUTHOR]

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see ). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods. [ABSTRACT FROM AUTHOR]

Observational studies suggest that early onset of menopause is associated with increased risk of hypertension. Whether this association is causal or due to residual confounding and/or reverse causation remains undetermined. We aimed to evaluate the observational and causal association between age at natural menopause (ANM) and blood pressure traits in Caucasian women. A cross-sectional and one-sample Mendelian randomization (MR) study was conducted in 4451 postmenopausal women from the CoLaus and Rotterdam studies. Regression models were built with observational data to study the associations of ANM with systolic and diastolic blood pressure (SBP/DBP) and hypertension. One-sample MR analysis was performed by calculating a genetic risk score of 54 ANM-related variants, previously identified in a genome-wide association study (GWAS) on ANM. In the two-sample MR analysis we used the estimates from the ANM-GWAS and association estimates from 168,575 women of the UK Biobank to evaluate ANM-related variants and their causal association with SBP and DBP. Pooled analysis from both cohorts showed that a one-year delay in menopause onset was associated with 2% (95% CI 0; 4) increased odds of having hypertension, and that early menopause was associated with lower DBP (β = −1.31, 95% CI −2.43; −0.18). While one-sample MR did not show a causal association between ANM and blood pressure traits, the two-sample MR showed a positive causal association of ANM with SBP; the last was driven by genes related to DNA damage repair. The present study does not support the hypothesis that early onset of menopause is associated with higher blood pressure. Our results suggest different ANM-related genetic pathways could differently impact blood pressure. [ABSTRACT FROM AUTHOR]

Background Statins represent a key treatment for cardiovascular disease. Nevertheless, the direct effects of statin treatment on the composition of atherosclerotic plaques remain elusive. Objectives We aimed to investigate the association of statin treatment with the presence of different plaque components located in the carotid arteries within a population-based setting. Methods From the population-based Rotterdam Study, 1740 participants with carotid atherosclerosis (mean age 72.9 years, 46% women) underwent MRI of the carotid arteries to determine the presence of calcification, lipid core, and intraplaque hemorrhage. Information for the duration and dosage of statin use was obtained from pharmacy records for all participants. We used logistic regression models to study the association of statin use with the presence of plaque components. Results Statin treatment was associated with a higher presence of calcification (OR: 1.73 [95% CI: 1.22–2.44]). Longer duration of use strengthened this association (OR: 1.82 [95% CI: 1.00–3.33] for 10 to 48 months, and OR 1.74 [95% CI: 1.09–2.77] for >48 months, compared to OR: 1.65 [95% CI: 0.94–2.89] for ≤10 months). Current statin treatment was also associated with a lower presence of lipid core (OR: 0.66 [95% CI: 0.42–1.04]), but only when using statins for 10 months or less. Any dosage of statins was associated with a higher presence of calcification, whilst only high dosages (DDD > 1.33) were associated with a lower presence of lipid core. Conclusions Active, high-dosage statin use seems to beneficially influence the composition of carotid atherosclerosis by shifting the composition from vulnerable plaque with a lipid core to more stable calcified plaque. [ABSTRACT FROM AUTHOR]

Objectives: To design a frailty index (FI) and evaluate three methods to handle missing data. Furthermore, we evaluated its construct (i.e., skewed distribution, correlation with age and sub-maximum score) and criterion validity (based on mortality risk).Study Design: We included 11,539 participants (45± years) from a population-based cohort in the Netherlands. Frailty was measured with a FI, which we constructed based on the accumulation of 45 health-related variables, related to mood, cognition, functional status, diseases and conditions, biomarkers, and nutritional status. A total FI-score was calculated by averaging the scores of the deficits, resulting in a score between 0 and 1, with higher scores indicating increasing frailty. Mean imputation, single- and multiple imputation were applied.Main Outcome Measure: Mortality data were obtained by notification from the municipal administration. Median follow-up time was 9.5 years, during which 3902 (34%) participants died.Results: The median FI for the full population was 0.16 (IQR=0.11-0.23). The distribution of the FI was slightly right-skewed, the absolute maximum score was 0.78 and there was a strong correlation with age (Pearson correlation=0.52;95%CI=0.51-0.54). The adjusted HR per unit increase in FI-score on mortality was 1.05 (95%CI=1.05-1.06). Multiple imputation seemed to provide more robust results than mean imputation.Conclusion: Based on our results we advise to the use of at least 30 deficits from different health domains to construct a FI if data are not imputed. Future research should use the continuous nature of the FI to monitor trajectories in frailty and find preventive strategies. [ABSTRACT FROM AUTHOR]

Psoriasis has been suggested to be an independent risk factor for cardiovascular disease (CVD); however, available studies have shown inconsistent results. In this study, embedded within the population-based Rotterdam Study, we aimed to assess the association between psoriasis and cardiovascular outcomes. Adjusted means were calculated for subclinical atherosclerosis using general linear models. Using Cox regression, the hazards of cardiovascular events for psoriasis, as a time-dependent variable, were calculated. A total of 262 psoriasis (24% systemic/UV treatment) and 8,009 reference subjects were followed up for a mean of 11 years. Psoriasis patients were significantly younger, smoked more, and had higher diastolic blood pressure and body mass index levels. The adjusted carotid intima-media thickness was 1.02±0.18 mm for psoriasis and 1.02±0.16 mm for reference subjects. Similarly, crude and adjusted ankle-brachial index, pulse-wave velocity, and coronary artery calcium scores did not differ between the two groups. The risk of incident CVD was not increased in psoriasis (adjusted hazard ratio 0.73, 95% confidence interval 0.50-1.06). The results were similar when coronary heart disease, stroke, and heart failure were analyzed separately. Psoriasis patients with predominantly mild disease from the general population are as likely to develop atherosclerosis and cardiovascular events as subjects without psoriasis. [ABSTRACT FROM AUTHOR]