Smoking-related dysregulation of plasma circulating microRNAs: the Rotterdam study.

BACKGROUND: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Differential miRNA expression, which is widely shown to be associated with the pathogenesis of various diseases, can be influenced by lifestyle factors, including smoking. This study aimed to investigate the plasma miRNA signature of smoking habits, the potential effect of smoking cessation on miRNA levels, and relate the findings with lung cancer incidence. RESULTS: A targeted RNA-sequencing approach measured plasma miRNA levels in 2686 participants from the population-based Rotterdam study cohort. The association between cigarette smoking (current versus never) and 591 well-expressed miRNAs was assessed via adjusted linear regression models, identifying 41 smoking-associated miRNAs that passed the Bonferroni-corrected threshold (P < 0.05/591 = 8.46 × 10-5). Moreover, we found 42 miRNAs with a significant association (P < 8.46 × 10-5) between current (reference group) and former smokers. Then, we used adjusted linear regression models to explore the effect of smoking cessation time on miRNA expression levels. The expression levels of two miRNAs were significantly different within 5 years of cessation (P < 0.05/41 = 1.22 × 10-3) from current smokers, while for cessation time between 5 and 15 years we found 19 miRNAs to be significantly different from current smokers, and finally, 38 miRNAs were significantly different after more than 15 years of cessation time (P < 1.22 × 10-3). These results imply the reversibility of the smoking effect on plasma levels of at least 38 out of the 41 smoking-miRNAs following smoking cessation. Next, we found 8 out of the 41 smoking-related miRNAs to be nominally associated (P < 0.05) with the incidence of lung cancer. CONCLUSIONS: This study demonstrates smoking-related dysregulation of plasma miRNAs, which might have a potential for reversibility when comparing different smoking cessation groups. The identified miRNAs are involved in several cancer-related pathways and include 8 miRNAs associated with lung cancer incidence. Our results may lay the groundwork for further investigation of miRNAs as potential mechanism linking smoking, gene expression and cancer.

The Rotterdam Study. Design update and major findings between 2020 and 2024.

The Rotterdam Study is a population-based cohort study, started in 1990 in the district of Ommoord in the city of Rotterdam, the Netherlands, with the aim to describe the prevalence and incidence, unravel the etiology, and identify targets for prediction, prevention or intervention of multifactorial diseases in mid-life and elderly. The study currently includes 17,931 participants (overall response rate 65%), aged 40 years and over, who are examined in-person every 3 to 5 years in a dedicated research facility, and who are followed-up continuously through automated linkage with health care providers, both regionally and nationally. Research within the Rotterdam Study is carried out along two axes. First, research lines are oriented around diseases and clinical conditions, which are reflective of medical specializations. Second, cross-cutting research lines transverse these clinical demarcations allowing for inter- and multidisciplinary research. These research lines generally reflect subdomains within epidemiology. This paper describes recent methodological updates and main findings from each of these research lines. Also, future perspective for coming years highlighted.

Diet quality in relation to kidney function and its potential interaction with genetic risk of kidney disease among Dutch post-myocardial infarction patients.

PURPOSE: We examined the relation between diet quality, its components and kidney function decline in post-myocardial infarction (MI) patients, and we explored differences by genetic risk of chronic kidney disease (CKD). METHODS: We analysed 2169 patients from the Alpha Omega Cohort (aged 60-80 years, 81% male). Dietary intake was assessed at baseline (2002-2006) using a validated food-frequency questionnaire and diet quality was defined using the Dutch Healthy Diet Cardiovascular Disease (DHD-CVD) index. We calculated 40-months change in estimated glomerular filtration rate (eGFR, mL/min per 1.73m2). We constructed a weighted genetic risk score (GRS) for CKD using 88 single nucleotide polymorphisms previously linked to CKD. Betas with 95%-confidence intervals (CIs) were obtained using multivariable linear regression models for the association between DHD-CVD index and its components and eGFR change, by GRS. RESULTS: The average DHD-CVD index was 79 (SD 15) points and annual eGFR decline was 1.71 (SD 3.86) mL/min per 1.73 m2. The DHD-CVD index was not associated with annual eGFR change (per 1-SD increment in adherence score: -0.09 [95% CI -0.26,0.08]). Results for adherence to guidelines for red meat showed less annual eGFR decline (per 1-SD: 0.21 [0.04,0.38]), whereas more annual eGFR decline was found for legumes and dairy (per 1-SD: -0.20legumes [-0.37,-0.04] and - 0.18dairy [-0.34,-0.01]). Generally similar results were obtained in strata of GRS. CONCLUSION: The DHD-CVD index for overall adherence to Dutch dietary guidelines for CVD patients was not associated with kidney function decline after MI, irrespective of genetic CKD risk. The preferred dietary pattern for CKD prevention in CVD patients warrants further research.

Long-term air pollution exposure and the blood metabolome: The rotterdam study.

BACKGROUND: Air pollution is a well-established risk factor for several adverse health outcomes, but the specific molecular mechanisms, particularly those involving metabolic processes, remain incompletely understood. OBJECTIVE: To evaluate associations between long-term air pollutant exposure and circulating plasma metabolites in two sub-cohorts of the population-based Rotterdam Study. METHODS: We analyzed data from 1455 participants of sub-cohort I (mean age 76.9 years, 58% female, 2002-2004) and 1061 participants from sub-cohort III (mean age 62.6 years, 56% female, 2012-2014). Mean annual exposure to fine particulate matter (PM2.5), black carbon, nitrogen dioxide, and ozone (measured both annually and in warm seasons only) were estimated at residential addresses using land use regression models. Plasma metabolites were measured by Metabolon Inc., using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. Cross-sectional associations between each air pollutant and 940 metabolites were determined using linear regression models. Benjamini-Hochberg false discovery rate (FDR) was utilized to control for multiple testing. Enrichment analysis was performed on statistically significant associated metabolites to identify significant metabolic pathways (p-value <0.05). RESULTS: In sub-cohort I, PM2.5, black carbon, nitrogen dioxide, annual ozone and ozone in warm season were statistically significantly associated with, respectively, 63, 30, 20, 31, and 41 metabolites (FDR <0.05) mostly belonging to lipid and amino acid sub-classes, and unannotated metabolites. Sphinganine, X - 16576 and 2-pyrrolidinone displayed statistically significant associations across all five air pollutants. In sub-cohort III, black carbon, nitrogen dioxide and ozone in warm seasons were associated with a single unannotated metabolite (X - 24970), and annual ozone with two unannotated metabolites (X - 24970 and X - 24306). Enriched pathways identified in sub-cohort I included pyrimidine metabolism and steroid hormone biosynthesis. CONCLUSIONS: Our study revealed associations of long-term air pollutant exposure with several metabolites and enrichment of two pathways, which are known to be involved in the adrenal and reproductive system and cell metabolism.

The Beverage Quality Index and risk of cardiometabolic outcomes after a myocardial infarction: A prospective analysis in the Alpha Omega Cohort.

BACKGROUND AND AIMS: Individual beverages have varying associations with cardiometabolic outcomes, but little is known about overall beverage quality and cardiometabolic risk after myocardial infarction (MI). We created the Beverage Quality Index (BQI) to assess beverage quality and examined its association with cardiometabolic outcomes after MI. METHODS AND RESULTS: We included 4365 Dutch post-MI patients from the Alpha Omega Cohort, aged 60-80 years. Diet was assessed at baseline (2002-2006) with a 203-item FFQ. The BQI included eight components (coffee, tea, milk, juices, sugar-sweetened beverages, alcohol, added sugar to coffee and tea, and energy from beverages), and ranged from 0 to 80. Multivariable Cox models were used to estimate HRs for the BQI in relation to incident diabetes mellitus (DM), major adverse cardiovascular events (MACE), recurrent cardiovascular disease (CVD) and fatal CVD over 3.4 y of follow-up, with follow-up for fatal CVD extended through 2018 (12.4 y). The average BQI was 50.0 ± 12.5. During 3.4 y of follow-up, we identified 186 incident cases of DM, 601 of MACE, 310 of recurrent CVD and 140 of fatal CVD. In multivariable models, a higher BQI (T3 vs. T1) was associated with lower risk of MACE [HR: 0.73 (0.59-0.90)], and recurrent CVD [HR: 0.67 (0.50-0.91)], but not with DM or CVD mortality. After 12.4 y of follow-up, 903 CVD deaths occurred. A significant inverse association with CVD mortality during long-term follow-up was found [HR: 0.81 (0.68-0.96)]. CONCLUSION: Overall beverage intake quality, as assessed by the BQI, may represent an important target for the prevention of recurrent CVD.

Artificially sweetened beverage consumption and all-cause and cause-specific mortality: an updated systematic review and dose-response meta-analysis of prospective cohort studies.

BACKGROUND: Artificially sweetened beverages (ASB) are consumed globally, but their impact on overall health remains uncertain. We summarized published associations between ASB intake with all-cause and cause-specific mortality. METHODS: We searched Medline, Embase, Web of Science, and Cochrane CENTRAL databases until August 2023. Random effect meta-analysis was conducted to calculate pooled risk ratios (RRs) and 95% confidence intervals (95%CIs) for highest versus lowest categories of ASB consumption in relation to all-cause and cause-specific mortality. Linear and non-linear dose-response analyses were also performed. RESULTS: Our systematic review and meta-analysis included 11 prospective cohort studies. During a median/mean follow-up period of 7.0 to 28.9 years, 235,609 deaths occurred among 2,196,503 participants. Intake of ASB was associated with higher risk of all-cause and CVD mortality with pooled RRs (95%CIs) of highest vs. lowest intake categories of 1.13 (1.06, 1.21) (I2 = 66.3%) for all-cause mortality and 1.26 (1.10, 1.44) (I2 = 52.0%) for CVD mortality. Dose-response analysis revealed a non-linear association of ASB with all-cause mortality (pnon-linearity = 0.01), but a linear positive association with CVD mortality (pnon-linearity = 0.54). No significant association was observed for ASB intake and cancer mortality. Moreover, a secondary meta-analysis demonstrated that replacing 1 serving/day of sugary sweetened beverages (SSB) with ASB was associated with 4-6% lower risk of all-cause and CVD mortality. Per NutriGrade, the evidence quality for associations between ASB intake with all-cause and CVD mortality was moderate. CONCLUSIONS: Higher intake of ASB was associated with higher risk of all-cause and CVD mortality, albeit a lower risk than for SSB. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022365701.

Plasma MicroRNA Signature of Alcohol Consumption: The Rotterdam Study.

BACKGROUND: MicroRNAs (miRNAs) represent a class of noncoding RNAs that regulate gene expression and are implicated in the pathogenesis of different diseases. Alcohol consumption might affect the expression of miRNAs, which in turn could play a role in risk of diseases. OBJECTIVES: We investigated whether plasma concentrations of miRNAs are altered by alcohol consumption. Given the existing evidence showing the link between alcohol and liver diseases, we further explored the extent to which these associations are mediated by miRNAs. METHODS: Profiling of plasma miRNAs was conducted using the HTG EdgeSeq miRNA Whole Transcriptome Assay in 1933 participants of the Rotterdam Study. Linear regression was implemented to explore the link between alcohol consumption (glasses/d) and miRNA concentrations, adjusted for age, sex, cohort, BMI, and smoking. Sensitivity analysis for alcohol categories (nondrinkers, light drinkers, and heavy drinkers) was performed, where light drinkers corresponded to 0-2 glasses/d in men and 0-1 glasses/d in women, and heavy drinkers to >2 glasses/d in men and >1 glass/d in women. Moreover, we utilized the alcohol-associated miRNAs to explore their potential mediatory role between alcohol consumption and liver-related traits. Finally, we retrieved putative target genes of identified miRNAs to gain an understanding of the molecular pathways concerning alcohol consumption. RESULTS: Plasma concentrations of miR-193b-3p, miR-122-5p, miR-3937, and miR-4507 were significantly associated with alcohol consumption surpassing the Bonferroni-corrected P < 8.46 × 10-5. The top significant association was observed for miR-193b-3p (ß = 0.087, P = 2.90 × 10-5). Furthermore, a potential mediatory role of miR-3937 and miR-122-5p was observed between alcohol consumption and liver traits. Pathway analysis of putative target genes revealed involvement in biological regulation and cellular processes. CONCLUSIONS: This study indicates that alcohol consumption is associated with plasma concentrations of 4 miRNAs. We outline a potential mediatory role of 2 alcohol-associated miRNAs (miR-3937 and miR-122-5p), laying the groundwork for further exploration of miRNAs as potential mediators between lifestyle factors and disease development.

Dietary patterns, brain morphology and cognitive performance in children: Results from a prospective population-based study.

Dietary patterns in childhood have been associated with child neurodevelopment and cognitive performance, while the underlying neurobiological pathway is unclear. We aimed to examine associations of dietary patterns in infancy and mid-childhood with pre-adolescent brain morphology, and whether diet-related differences in brain morphology mediate the relation with cognition. We included 1888 and 2326 children with dietary data at age one or eight years, respectively, and structural neuroimaging at age 10 years in the Generation R Study. Measures of brain morphology were obtained using magnetic resonance imaging. Dietary intake was assessed using food-frequency questionnaires, from which we derived diet quality scores based on dietary guidelines and dietary patterns using principal component analyses. Full scale IQ was estimated using the Wechsler Intelligence Scale for Children-Fifth Edition at age 13 years. Children with higher adherence to a dietary pattern labeled as 'Snack, processed foods and sugar' at age one year had smaller cerebral white matter volume at age 10 (B = -4.3, 95%CI -6.9, -1.7). At age eight years, higher adherence to a 'Whole grains, soft fats and dairy' pattern was associated with a larger total brain (B = 8.9, 95%CI 4.5, 13.3), and larger cerebral gray matter volumes at age 10 (B = 5.2, 95%CI 2.9, 7.5). Children with higher diet quality and better adherence to a 'Whole grains, soft fats and dairy' dietary pattern at age eight showed greater brain gyrification and larger surface area, clustered primarily in the dorsolateral prefrontal cortex. These observed differences in brain morphology mediated associations between dietary patterns and IQ. In conclusion, dietary patterns in early- and mid-childhood are associated with differences in brain morphology which may explain the relation between dietary patterns and neurodevelopment in children.

Circulating lipoprotein (a) and all-cause and cause-specific mortality: a systematic review and dose-response meta-analysis.

AIMS: To investigate the association between circulating lipoprotein(a) (Lp(a)) and risk of all-cause and cause-specific mortality in the general population and in patients with chronic diseases, and to elucidate the dose-response relations. METHODS AND RESULTS: We searched literature to find prospective studies reporting adjusted risk estimates on the association of Lp(a) and mortality outcomes. Forty-three publications, reporting on 75 studies (957,253 participants), were included. The hazard ratios (HRs) and 95% confidence intervals (95%CI ) for the top versus bottom tertile of Lp(a) levels and risk of all-cause mortality were 1.09 (95%CI: 1.01-1.18, I2: 75.34%, n = 19) in the general population and 1.18 (95%CI: 1.04-1.34, I2: 52.5%, n = 12) in patients with cardiovascular diseases (CVD). The HRs for CVD mortality were 1.33 (95%CI: 1.11-1.58, I2: 82.8%, n = 31) in the general population, 1.25 (95%CI: 1.10-1.43, I2: 54.3%, n = 17) in patients with CVD and 2.53 (95%CI: 1.13-5.64, I2: 66%, n = 4) in patients with diabetes mellitus. Linear dose-response analyses revealed that each 50 mg/dL increase in Lp(a) levels was associated with 31% and 15% greater risk of CVD death in the general population and in patients with CVD. No non-linear dose-response association was observed between Lp(a) levels and risk of all-cause or CVD mortality in the general population or in patients with CVD (Pnonlinearity > 0.05). CONCLUSION: This study provides further evidence that higher Lp(a) levels are associated with higher risk of all-cause mortality and CVD-death in the general population and in patients with CVD. These findings support the ESC/EAS Guidelines that recommend Lp(a) should be measured at least once in each adult person's lifetime, since our study suggests those with higher Lp(a) might also have higher risk of mortality.

The long-term relation between physical activity and executive function in the Rotterdam Study.

BACKGROUND: Research on the association between physical inactivity and cognitive decline and dementia is dominated by studies with short-term follow-up, that might be biased by reverse causality. OBJECTIVE: Investigate the long-term association between physical activity, cognition, and the rate of age-associated cognitive decline. METHODS: We investigated the association between late-life physical activity and executive functioning and rate of decline of executive abilities during follow-up of up to 16 years, in 3553 participants of the prospective Rotterdam Study cohort. Measurement took place in 1997-1999, 2002-2004, 2009-2011, and 2014-2015. RESULTS: At baseline (age ± 72 years), higher levels of physical activity were associated with higher levels of executive functioning (adjusted mean difference = 0.03, 95% CI: 0.00 ; 0.06, p = 0.03). This difference remained intact up to 16 years of follow-up. The level of physical activity at baseline was unrelated to the rate of decline of executive abilities over time, in the whole group (adjusted mean difference in changetime*physical activity = 0.00, 95% CI: -0.00 ; 0.01, p = 0.31). However, stratification by APOE genotype showed that the accelerated decline of executive abilities observed in those with the ApoE-ε4 allele might be attenuated by higher levels of physical activity in late adulthood (ApoE-ε4 carriers: Btime*physical activity = 0.01, 95% CI: 0.00 ; 0.01, p = 0.03). CONCLUSION: Higher levels of physical activity in late adulthood are related to higher levels of executive functioning, up to 16 years of follow-up. Accelerated decline of executive abilities observed in those with the ApoE-ε4 allele might be mitigated by higher levels of physical activity.

The healthy beverage index is not associated with insulin resistance, prediabetes and type 2 diabetes risk in the Rotterdam Study.

PURPOSE: Whether beverage quality affects changes in glycaemic traits and type 2 diabetes (T2D) risk is unknown. We examined associations of a previously developed Healthy Beverage Index (HBI) with insulin resistance, and risk of prediabetes and T2D. METHODS: We included 6769 participants (59% female, 62.0 ± 7.8 years) from the Rotterdam Study cohort free of diabetes at baseline. Diet was assessed using food-frequency questionnaires at baseline. The HBI included 10 components (energy from beverages, meeting fluid requirements, water, coffee and tea, low-fat milk, diet drinks, juices, alcohol, full-fat milk, and sugar-sweetened beverages), with a total score ranging from 0 to 100. A higher score represents a healthier beverage pattern. Data on study outcomes were available from 1993 to 2015. Multivariable linear mixed models and Cox proportional-hazards regression models were used to examine associations of the HBI (per 10 points increment) with two measurements of HOMA-IR (a proxy for insulin resistance), and risk of prediabetes and T2D. RESULTS: During follow-up, we documented 1139 prediabetes and 784 T2D cases. Mean ± SD of the HBI was 66.8 ± 14.4. Higher HBI score was not associated with HOMA-IR (ß: 0.003; 95% CI - 0.007, 0.014), or with risk of prediabetes (HR: 1.01; 95% CI 0.97, 1.06), or T2D (HR: 1.01; 95% CI 0.96, 1.07). CONCLUSION: Our findings suggest no major role for overall beverage intake quality assessed with the HBI in insulin resistance, prediabetes and T2D incidence. The HBI may not be an adequate tool to assess beverage intake quality in our population.

MIND diet lowers risk of open-angle glaucoma: the Rotterdam Study.

PURPOSE: To assess the association between the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet and the incidence of open-angle glaucoma (iOAG), as well as the association between iOAG and two other well-established diets in the Netherlands, i.e., the Mediterranean diet and Dutch dietary guidelines. METHODS: In the Rotterdam Study, participants were followed for iOAG since 1991, with intervals of approximately 5 years. A total of 170 participants developed iOAG during follow-up. Participants with iOAG were matched with healthy controls on age and sex in a case:control ratio of 1:5. The associations between food frequency questionnaire-derived diet adherences (baseline) and iOAG were analyzed using multivariable conditional logistic regression analyses. The associations between the diet adherences and intraocular pressure (IOP; a risk factor for OAG) were assessed using multivariable linear regression analyses. RESULTS: Greater adherence to the MIND diet was associated with a decreased iOAG risk (odds ratio [95% confidence interval]: 0.80 [0.66 to 0.96], for each 10-percent increase in adherence). Food component analyses showed that, in particular a higher intake of green leafy vegetables, berries and fish tended to be protective for iOAG. No significant associations were observed between adherence to the Mediterranean diet or Dutch dietary guidelines and iOAG. Moreover, none of the three examined diets were associated with IOP. CONCLUSION: Adherence to the MIND diet was significantly associated with a lower incidence of OAG in contrast to adherence to the Mediterranean diet or the Dutch dietary guidelines. As this association was IOP-independent, the MIND diet may be particularly relevant for the prevention of neurodegeneration in the eye.

Plant-based dietary patterns and the risk of dementia: a population-based study.

BACKGROUND: Plant-based dietary patterns are increasingly popular in western countries and are supported by many governments and health organisations for their potential beneficial role in the prevention of chronic diseases. Yet, the potential role of plant-based dietary patterns in the development of dementia remains unclear. OBJECTIVE: To evaluate the association between plant-based dietary patterns and the risk of dementia. METHODS: Dietary intake was measured at baseline in 9,543 dementia-free participants (mean age 64 years, birth years 1897-1960, 58% women) of the prospective population-based Rotterdam Study, using food frequency questionnaires. Based on these questionnaires, we calculated an overall plant-based dietary index (PDI), healthy PDI (hPDI) and unhealthy PDI (uPDI), with higher scores reflecting higher consumption of (any, healthy and unhealthy, respectively) plant-based foods and lower consumption of animal-based foods. We analysed the association of the PDIs with incident dementia using Cox proportional hazard models. RESULTS: During a mean follow-up of 14.5 years, 1,472 participants developed dementia. Overall, the PDIs were not associated with the risk of dementia (hazard ratio [95% confidence interval] per 10-point increase: 0.99 [0.91-1.08] for PDI, 0.93 [0.86-1.01] for hPDI, 1.02 [0.94-1.10] for uPDI). However, among men and APOE ε4 carriers, a higher hPDI was linearly associated with a lower risk of dementia (0.86 [0.75-0.99] and 0.83 [0.73-0.95], respectively), while this association was U-shaped among APOE ε4 non-carriers (P value for non-linearity = 0.01). CONCLUSIONS: We found no strong evidence for an overall association between plant-based eating and the risk of dementia. Our findings in stratified analyses warranted further investigation.

Adherence to dietary guidelines and dental caries among children: a longitudinal cohort study.

BACKGROUND: Even though dietary sugars are the most important nutrient for caries development, the disease process is dependent on other dietary practices. The intake of individual nutrient components cannot be evaluated separately from the overall diet which includes other nutrients, foods and habits. Therefore, the aim of this study was to investigate the association between adherence to dietary guidelines and dental caries. METHODS: This study was embedded in the Generation R Study, conducted in Rotterdam, the Netherlands. In total, 2911 children were included in the present analyses. Dietary intake at the age of 8 years was assessed using food-frequency questionnaires. Diet quality scores were estimated, reflecting adherence to Dutch dietary guidelines. Dental caries was assessed at the age of 13 years using intra-oral photographs. Associations were estimated using multinomial logistic regression analyses, adjusted for sociodemographic characteristics and oral hygiene practices. RESULTS: The prevalence of dental caries at the age of 13 years was 33% (n = 969). Better diet quality was associated with a lower occurrence of severe dental caries after adjustments for sociodemographic factors [e.g. highest vs. lowest quartile of diet quality: odds ratio (OR) 0.62, 95% confidence interval (CI) 0.39-0.98]. After additional adjustments for oral hygiene practices, this association was not statistically significant (OR 0.65, 95% CI 0.41-1.03). CONCLUSION: Adherence to dietary guidelines has the potential to reduce dental caries in children; however, with proper oral hygiene practices, this relationship might be attenuated. To understand the role of dietary patterns and dental caries, the contributing role of daily eating occasions needs to be studied further.

Anti-tissue transglutaminase antibodies (TG2A) positivity and the risk of vitamin D deficiency among children - a cross-sectional study in the generation R cohort.

BACKGROUND: Suboptimal vitamin D status is common in people with celiac disease (CeD), a disease that can be characterized by the presence of serum anti-tissue transglutaminase antibodies (TG2A) (i.e., TG2A positivity). To date, it remains unclear whether childhood TG2A positivity is associated with vitamin D status and how this potential association can be explained by other factors than malabsorption only, since vitamin D is mainly derived from exposure to sunlight. The aim of our study was therefore to assess whether childhood TG2A positivity is associated with vitamin D concentrations, and if so, to what extent this association can be explained by sociodemographic and lifestyle factors. METHODS: This cross-sectional study was embedded in the Generation R Study, a population-based prospective cohort. We measured serum anti-tissue transglutaminase antibodies (TG2A) concentrations and serum 25-hydroxyvitamin D (25(OH)D) concentrations of 3994 children (median age of 5.9 years). Children with serum TG2A concentrations ≥ 7 U/mL were considered TG2A positive. To examine associations between TG2A positivity and 25(OH)D concentrations, we performed multivariable linear regression, adjusted for sociodemographic and lifestyle factors. RESULTS: Vitamin D deficiency (serum 25(OH)D < 50 nmol/L) was found in 17 out of 54 TG2A positive children (31.5%), as compared to 1182 out of 3940 TG2A negative children (30.0%). Furthermore, TG2A positivity was not associated with 25(OH)D concentrations (ß -2.20; 95% CI -9.72;5.33 for TG2A positive vs. TG2A negative children), and this did not change after adjustment for confounders (ß -1.73, 95% CI -8.31;4.85). CONCLUSIONS: Our findings suggest there is no association between TG2A positivity and suboptimal vitamin D status in the general pediatric population. However, the overall prevalence of vitamin D deficiency in both populations was high, suggesting that screening for vitamin D deficiency among children, regardless of TG2A positivity, would be beneficial to ensure early dietary intervention if needed.

Adiposity in the older population and the risk of dementia: The Rotterdam Study.

INTRODUCTION: We determined associations of total and regional adiposity with incident dementia among older adults. METHODS: Within the population-based Rotterdam Study, adiposity was measured as total, android, and gynoid fat mass using dual-energy X-ray absorptiometry in 3408 men and 4563 women, every 3 to 6 years between 2002 and 2016. Incident dementia was recorded until 2020. RESULTS: Higher adiposity measures were associated with a decreased risk of dementia in both sexes. After excluding the first 5 years of follow-up, only the association of gynoid fat among women remained significant (hazard ratio 0.85 [95% confidence interval 0.75-0.97] per standard deviation increase). No major differences in trajectories of adiposity measures were observed between dementia cases and dementia-free controls. DISCUSSION: Higher total and regional fat mass related to a decreased risk of dementia. These results may be explained by reverse causality, although a protective effect of adiposity cannot be excluded. HIGHLIGHTS: Total and regional adiposity were assessed using dual-energy X-ray absorptiometry scans in 7971 older adults. All adiposity measures were associated with a decreased risk of dementia. The results suggest a beneficial effect of gynoid fat on the risk of dementia in women. Reverse causation and competing risk may explain these inverse associations.

Objectively Measured Physical Activity Is Inversely Associated With Nonalcoholic Fatty Liver Disease: The Rotterdam Study.

INTRODUCTION: The disease burden of nonalcoholic fatty liver disease (NAFLD) increases rapidly, in line with the obesity pandemic. Physical activity has been linked to a lower risk of NAFLD. However, the impact of different intensities of activity and sedentary behavior and whether their effects on NAFLD are explained by metabolic health remain unclear. METHODS: We performed cross-sectional analyses within the population-based Rotterdam Study cohort. Abdominal ultrasound and accelerometry data were collected between 2009 and 2014. NAFLD was defined as hepatic steatosis diagnosed by ultrasound, in the absence of secondary causes for steatosis: viral hepatitis, steatogenic drugs, and excessive alcohol. We categorized accelerometry data into sedentary time and light, moderate, and vigorous physical activities. RESULTS: We included 667 participants (aged 63.3 ± 6.3 years, 53% female individuals), and 34.3% had NAFLD. Total physical activity was associated with lower NAFLD prevalence adjusted for demographic, lifestyle, and socioeconomic factors (odds ratio: 0.958 per 10 min/d, 95% confidence interval [CI]: 0.929-0.986). More intensive physical activity was more strongly associated with lower NAFLD prevalence: odds ratios for light, moderate, and vigorous physical activities were 0.931 (95% CI: 0.882-0.982), 0.891 (95% CI: 0.820-0.967), and 0.740 (95% CI: 0.600-0.906) per 10 min/d, respectively. These associations were explained by metabolic health, particularly homeostatic model assessment of insulin resistance (proportion mediated: 0.59, P < 0.001) and waist circumference (proportion mediated: 1.08, P < 0.001). Beyond this indirect effect, no direct effect could be demonstrated (P = 0.282-0.827). DISCUSSION: Physical activity at each intensity is inversely associated with NAFLD prevalence, with larger effects for higher intensities of physical activity. This association is mediated by better metabolic health, mainly lower insulin resistance and waist circumference. Physical activity should therefore be incorporated into NAFLD disease management and prevention programs.

Imaging-based body fat depots and new-onset atrial fibrillation in general population: a prospective cohort study.

BACKGROUND: Obesity is a well-established risk factor for atrial fibrillation (AF). Whether body fat depots differentially associate with AF development remains unknown. METHODS: In the prospective population-based Rotterdam Study, body composition was assessed using dual-energy X-ray absorptiometry (DXA) and liver and epicardial fat using computed tomography (CT). A body composition score was constructed by adding tertile scores of each fat depot. Principal component analysis was conducted to identify potential body fat distribution patterns. Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals (HR; 95% CI) per 1-standard deviation increase in corresponding fat depots to enable comparisons. RESULTS: Over a median follow-up of 9.6 and 8.6 years, 395 (11.4%) and 172 (8.0%) AF cases were ascertained in the DXA and the CT analyses, respectively. After adjustments for cardiovascular risk factors, absolute fat mass (HR; 95% CI 1.33; 1.05-1.68), gynoid fat mass (HR; 95% CI 1.36; 1.12-1.65), epicardial fat mass (HR; 95% CI 1.27; 1.09-1.48), and android-to-gynoid fat ratio (HR; 95% CI 0.81; 0.70-0.94) were independently associated with new-onset AF. After further adjustment for lean mass, associations between fat mass (HR; 95% CI 1.17; 1.04-1.32), gynoid fat mass (HR; 95% CI 1.21; 1.08-1.37), and android-to-gynoid fat ratio (HR; 95% CI 0.84; 0.72-0.97) remained statistically significant. Larger body fat score was associated with a higher AF risk (HR; 95% CI 1.10; 1.02-1.20). Borderline significant association was found between a subcutaneous fat predominant pattern with AF onset (HR; 95% CI 1.21; 0.98-1.49). CONCLUSIONS: Various body fat depots were associated with new-onset AF. Total fat mass and gynoid fat mass were independently associated with AF after adjustment for body size. The inverse association between android-to-gynoid fat ratio with AF presents a novel finding. A significant dose-response relationship between body fat accumulation and AF was observed. Our results underscore the predominant role of subcutaneous fat on AF development among a middle-aged and elderly population. Associations betw2een body fat depots, fat distribution and new-onset atrial fibrillation. ABBREVIATIONS: AF, atrial fibrillation.

Sex-specific patterns and lifetime risk of multimorbidity in the general population: a 23-year prospective cohort study.

BACKGROUND: Multimorbidity poses a major challenge for care coordination. However, data on what non-communicable diseases lead to multimorbidity, and whether the lifetime risk differs between men and women are lacking. We determined sex-specific differences in multimorbidity patterns and estimated sex-specific lifetime risk of multimorbidity in the general population. METHODS: We followed 6,094 participants from the Rotterdam Study aged 45 years and older for the occurrence of ten diseases (cancer, coronary heart disease, stroke, chronic obstructive pulmonary disease, depression, diabetes, dementia, asthma, heart failure, parkinsonism). We visualised participants' trajectories from a single disease to multimorbidity and the most frequent combinations of diseases. We calculated sex-specific lifetime risk of multimorbidity, considering multimorbidity involving only somatic diseases (1) affecting the same organ system, (2) affecting different organ systems, and (3) multimorbidity involving depression. RESULTS: Over the follow-up period (1993-2016, median years of follow-up 9.2), we observed 6334 disease events. Of the study population, 10.3% had three or more diseases, and 27.9% had two or more diseases. The most frequent pair of co-occurring diseases among men was COPD and cancer (12.5% of participants with multimorbidity), the most frequent pair of diseases among women was depression and dementia (14.9%). The lifetime risk of multimorbidity was similar among men (66.0%, 95% CI: 63.2-68.8%) and women (65.1%, 95% CI: 62.5-67.7%), yet the risk of multimorbidity with depression was higher for women (30.9%, 95% CI: 28.4-33.5%, vs. 17.5%, 95% CI: 15.2-20.1%). The risk of multimorbidity with two diseases affecting the same organ is relatively low for both sexes (4.2% (95% CI: 3.2-5.5%) for men and 4.5% (95% CI: 3.5-5.7%) for women). CONCLUSIONS: Two thirds of people over 45 will develop multimorbidity in their remaining lifetime, with women at nearly double the risk of multimorbidity involving depression than men. These findings call for programmes of integrated care to consider sex-specific differences to ensure men and women are served equally.

Plasma circulating microRNAs associated with obesity, body fat distribution, and fat mass: the Rotterdam Study.

BACKGROUND: MicroRNAs (miRNAs) represent a class of small non-coding RNAs that regulate gene expression post-transcriptionally and are implicated in the pathogenesis of different diseases. Limited studies have investigated the association of circulating miRNAs with obesity and body fat distribution and their link to obesity-related diseases using population-based data. METHODS: We conducted a genome-wide profile of circulating miRNAs in plasma, collected between 2002 and 2005, in 1208 participants from the population-based Rotterdam Study cohort. Obesity and body fat distribution were measured as body mass index (BMI), waist-to-hip ratio (WHR), android-fat to gynoid-fat ratio (AGR), and fat mass index (FMI) measured by anthropometrics and Dual X-ray Absorptiometry. Multivariable linear regression models were used to assess the association of 591 miRNAs well-expressed in plasma with these traits adjusted for potential covariates. We further sought for the association of identified miRNAs with cardiovascular and metabolic diseases in the Rotterdam study and previous publications. RESULTS: Plasma levels of 65 miRNAs were associated with BMI, 40 miRNAs with WHR, 65 miRNAs with FMI, and 15 miRNAs with AGR surpassing the Bonferroni-corrected P < 8.46 × 10-5. Of these, 12 miRNAs were significantly associated with all traits, while four miRNAs were associated only with WHR, three miRNAs only with FMI, and miR-378i was associated only with AGR. The most significant association among the overlapping miRNAs was with miR-193a-5p, which was shown to be associated with type 2 diabetes and hepatic steatosis in the Rotterdam Study. Moreover, five of the obesity-associated miRNAs and two of the body fat distribution miRNAs have been correlated previously to cardiovascular disease. CONCLUSIONS: This study indicates that plasma levels of several miRNAs are associated with obesity and body fat distribution which could help to better understand the underlying mechanisms and may have the biomarker potential for obesity-related diseases.