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Funder: Nederlandse Organisatie voor Wetenschappelijk Onderzoek; doi: http://dx.doi.org/10.13039/501100003246, Funder: ZonMw; doi: http://dx.doi.org/10.13039/501100001826, Funder: Research Institute for Diseases in the Elderly, Funder: Ministerie van Onderwijs, Cultuur en Wetenschap; doi: http://dx.doi.org/10.13039/501100003245, Funder: Health Promotion Administration, Ministry of Health and Welfare; doi: http://dx.doi.org/10.13039/100013227, Funder: Municipality of Rotterdam, Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

Importance: Uncertainty currently exists about whether the same genetic variants are associated with susceptibility to low myopia (LM) and high myopia (HM) and to myopia and hyperopia. Addressing this question is fundamental to understanding the genetics of refractive error and has clinical relevance for genotype-based prediction of children at risk for HM and for identification of new therapeutic targets. Objective: To assess whether a common set of genetic variants are associated with susceptibility to HM, LM, and hyperopia. Design, Setting, and Participants: This genetic association study assessed unrelated UK Biobank participants 40 to 69 years of age of European and Asian ancestry. Participants 40 to 69 years of age living in the United Kingdom were recruited from January 1, 2006, to October 31, 2010. Of the total sample of 502682 participants, 117279 (23.3%) underwent an ophthalmic assessment. Data analysis was performed from December 12, 2019, to June 23, 2020. Exposures: Four refractive error groups were defined: HM, -6.00 diopters (D) or less; LM, -3.00 to -1.00 D; hyperopia, +2.00 D or greater; and emmetropia, 0.00 to +1.00 D. Four genome-wide association study (GWAS) analyses were performed in participants of European ancestry: (1) HM vs emmetropia, (2) LM vs emmetropia, (3) hyperopia vs emmetropia, and (4) LM vs hyperopia. Polygenic risk scores were generated from GWAS summary statistics, yielding 4 sets of polygenic risk scores. Performance was assessed in independent replication samples of European and Asian ancestry. Main Outcomes and Measures: Odds ratios (ORs) of polygenic risk scores in replication samples. Results: A total of 51841 unrelated individuals of European ancestry and 2165 unrelated individuals of Asian ancestry were assigned to a specific refractive error group and included in our analyses. Polygenic risk scores derived from all 4 GWAS analyses were predictive of all categories of refractive error in both European and Asian replication samples. For example, the polygenic risk score derived from the HM vs emmetropia GWAS was predictive in the European sample of HM vs emmetropia (OR, 1.58; 95% CI, 1.41-1.77; P = 1.54 × 10-15) as well as LM vs emmetropia (OR, 1.15; 95% CI, 1.07-1.23; P = 8.14 × 10-5), hyperopia vs emmetropia (OR, 0.83; 95% CI, 0.77-0.89; P = 4.18 × 10-7), and LM vs hyperopia (OR, 1.45; 95% CI, 1.33-1.59; P = 1.43 × 10-16). Conclusions and Relevance: Genetic risk variants were shared across HM, LM, and hyperopia and across European and Asian samples. Individuals with HM inherited a higher number of variants from among the same set of myopia-predisposing alleles and not different risk alleles compared with individuals with LM. These findings suggest that treatment interventions targeting common genetic risk variants associated with refractive error could be effective against both LM and HM..

BACKGROUND The links between fatty acids (FAs) and cardiometabolic outcomes are topics of debate. OBJECTIVE Our aim was to investigate the associations between serum standardized FA percentages and cardiometabolic outcomes. METHODS We used cross-sectional (n = 2187-2200 subjects, age 24-39 y, women 54%) and 10-year prospective data (n = 975-1414 subjects) from the Young Finns Study. Outcomes included prevalent and incident obesity, insulin resistance (HOMA-IR index in the upper quintile), elevated blood pressure (BP; taking medication, or diastolic or systolic BP in the upper quintile), and incident nonalcoholic fatty liver. Logistic regression models were used to calculate ORs per SD increase in fatty acids (FAs). The models were adjusted for age and sex, and additionally for other potential confounders. RESULTS Several cross-sectional findings were also statistically significant in prospective models (Bonferroni corrected P

Background Secure attachment is important in maintaining an individual’s health and well-being. Attachment disturbances increase the risk for developing psychiatric disorders such as affective disorders. Yet, the neurobiological correlates of human attachment are poorly understood at the neurotransmitter level. We investigated whether adult attachment style is linked to functioning of the opioid and serotonergic systems in the human brain. Methods We used positron emission tomography with radioligands [11C]carfentanil and [11C]MADAM to quantify mu opioid receptor (n = 39) and serotonin transporter (n = 37) availability in volunteers with no current psychiatric disorders. Attachment style was determined according to the Dynamic-Maturational Model of Attachment and Adaptation with the structured Adult Attachment Interview. Results Secure attachment was associated with higher mu opioid receptor availability in the hippocampus, amygdala, thalamus, and prefrontal cortex when compared with insecure (i.e., avoidant or ambivalent groups combined) attachment. In contrast, attachment style was not associated with serotonin transporter availability. Conclusions Our results provide preliminary in vivo evidence that the opioid system may be involved in the neurocircuits associated with individual differences in adult attachment behavior. The results suggest that variation in mu opioid receptor availability may be linked with the individuals’ social relationships and psychosocial well-being and thus contributes to risk for psychiatric morbidity.

Background Individuals who are obese in childhood have an elevated risk of disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independently of adult adiposity, is unclear. In this study, we have simultaneously evaluated the effects of childhood and adulthood body size on 123 systemic molecular biomarkers representing multiple metabolic pathways. Methods Two-sample Mendelian randomization (MR) was conducted to estimate the causal effect of childhood body size on a total of 123 nuclear magnetic resonance-based metabolic markers using summary genome-wide association study (GWAS) data from up to 24 925 adults. Multivariable MR was then applied to evaluate the direct effects of childhood body size on these metabolic markers whilst accounting for adult body size. Further MR analyses were undertaken to estimate the potential mediating effects of these circulating metabolites on the risk of coronary artery disease (CAD) in adulthood using a sample of 60 801 cases and 123 504 controls. Results Univariable analyses provided evidence that childhood body size has an effect on 42 of the 123 metabolic markers assessed (based on P Conclusions Our findings suggest that childhood adiposity predominantly exerts its detrimental effect on adult systemic metabolism along a pathway that involves adulthood body size.

OBJECTIVES Heart disease is the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD). Emerging data have shown that NAFLD may affect subclinical myocardial remodeling, mainly left ventricular hypertrophy; however, evidence from the prospective studies is still lacking. METHODS Prospective analyses were performed to investigate the association of fatty liver index (FLI) with left ventricular mass (LVM) among 1962 participants from the Bogalusa Heart Study (BHS, 1995-2010) and 1547 participants from the Cardiovascular Risk in Young Finns Study (YFS, 2001-2011) free of cardiovascular diseases (CVD) at baseline. LVM was assessed by two-dimensional guided M-mode echocardiography and indexed (LVMI) to body height (m2.7). Multivariable regression models were applied after adjustment for traditional CVD risk factors. RESULTS In both cohorts, we observed significant and positive associations between FLI and LVM (BHS: β=0.59, P

Purpose This study aimed to investigate the tracking and changes of steps per day in adults and their determinants over 13 yr. Methods A total of 2195 subjects (1236 women) 30-45 yr of age were randomly recruited from the ongoing Cardiovascular Risk in Young Finns Study in 2007 and were followed up in 2020. Steps per day, including both total and aerobic steps per day, were monitored for seven consecutive days with a pedometer in 2007-2008 and 2011-2012 and with an accelerometer in 2018-2020. Tracking was analyzed using Spearman's correlation. Stability and changes of steps per day over time in both low-active and high-active groups (based on median values) were described by percentage agreements, kappa statistics, and logistic regression. Associations of sex, age, and body mass index with the initial number and changes in steps per day were analyzed using linear growth curve modeling. Results Tracking correlations of total steps per day at 4-, 9-, and 13-yr intervals were 0.45-0.66, 0.33-0.70, and 0.29-0.60, while corresponding correlations for aerobic steps per day were 0.28-0.55, 0.23-0.52, and 0.08-0.55, respectively. Percentage agreements were higher than 54%, and kappa statistics ranged from slight to fair over time. Compared with the low-active group, the high-active group at baseline had a higher probability of being active later in adulthood. Female sex and higher age were associated directly with the initial number of steps per day and inversely with changes in the number of steps per day. Body mass index was inversely associated with the initial number of steps per day and changes in the number of total steps per day. Conclusion The 13-yr tracking of steps per day in adulthood was found to be low to moderately high. Daily ambulatory activity is essential to maintaining an active lifestyle throughout adulthood. Changes in the amount of adult steps per day vary by sex, age, and BMI. publishedVersion

BACKGROUND AND AIMS Our objective was to study relationships between the new biomarker of vascular health, carotid artery longitudinal wall motion (CALM) and metabolic syndrome (MetS). METHODS Carotid ultrasound and assessment of MetS and its components were performed with 281 subjects aged 30-45 years. In the longitudinal motion analysis, the amplitude of motion and the antegrade-oriented and retrograde-oriented components of motion between the intima-media complex and adventitial layer of the common carotid artery wall were assessed. RESULTS Metabolic syndrome, according to the harmonized criteria, was detected in 53 subjects (19%). MetS was significantly associated with increased antegrade and decreased retrograde longitudinal motion in the carotid artery wall. Augmented antegrade amplitude of longitudinal motion was associated with obesity (β = 0.149, p

Background Increased left ventricular mass (LVM) predicts cardiovascular events and mortality. The objective of this study was to determine whether early-life exposures to body mass index (BMI) and systolic blood pressure (SPB) affects the left ventricular structure in adulthood. Methods We used longitudinal data from a 31-year follow-up to examine the associations between early-life (between ages 6-18) BMI and SPB on LVM in an adult population (N = 1864, aged 34-49). The burden of early-life BMI and SBP was defined as area under the curve. Results After accounting for contemporary adult determinants of LVM, early-life BMI burden associated significantly with LVM (3.61 g/SD increase in early-life BMI; [1.94 - 5.28], p 25 kg/m(2)) associated with 4.7% (2.5-6.9%, p 30kg/m(2)) resulted in a 21% (17.3-32.9%, p

OBJECTIVE To examine childhood BMI, fasting glucose, and insulin in relation to incident adult type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS We used data from the International Childhood Cardiovascular Cohort (i3C) Consortium. Data included childhood (age 3–19 years) measurements obtained during the 1970s–1990s; a health questionnaire, including self-report of adult T2DM (occurrence age, medication use) obtained at mean age 40 years; and a medical diagnosis registry (Finland). RESULTS The sample included 6,738 participants. Of these, 436 (6.5%) reported onset of T2DM between ages 20 and 59 (mean 40.8) years, and 86% of them reported use of a confirmed antidiabetic medication. BMI and glucose (age and sex standardized) were associated with incident T2DM after adjustment for cohort, country, sex, race, age, and calendar year of measurement. Increasing levels of childhood BMI and glucose were related to an incrementally increased risk of T2DM beginning at age 30 years, beginning at cut points CONCLUSIONS Childhood BMI and glucose are predictors of adult T2DM at levels previously considered to be within the normal range. These easy-to-apply measurements are appealing from a clinical perspective. Fasting insulin has the potential to be an additional predictor.

To study whether systemic hemodynamics, especially systemic vascular resistance, predicts the development of hypertension and improves the risk prediction of incident hypertension beyond common risk factors in the risk models in young adults.Typical risk factors for hypertension in the risk prediction models (systolic and diastolic blood pressure, parental history of hypertension, age, sex, body-mass index, smoking), laboratory values (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, C-reactive protein), heart rate (HR), stroke index (SI), and systemic vascular resistance index (SVRI) calculated by whole-body impedance cardiography were evaluated in 2007 and blood pressure in 2011 in 1293 Finnish adults (aged 30-45 years; females 56%;Of hemodynamic variables, SVRI and HR evaluated in 2007 were independently associated with systolic blood pressure (These findings suggest that systemic vascular resistance index predicts the incidence of hypertension in young adults and that the evaluation of systemic hemodynamics could provide an additional tool for hypertension risk prediction.

Chronic oral infection/inflammation is cross-sectionally associated with metabolic syndrome (MetS) in adults, but there are few longitudinal studies and studies on childhood oral infections and adult MetS risk. We investigated whether childhood clinical parameters indicative of oral infection/inflammation were associated with adulthood MetS and its components. A total of 755 children aged 6, 9, and 12 y underwent a clinical oral examination in 1980 as part of the Cardiovascular Risk in Young Finns Study. Oral health measures included bleeding on probing (BOP), periodontal probing pocket depth, caries, fillings, and visible plaque. Metabolic parameters were determined at baseline and during follow-up. MetS was diagnosed ( n = 588, 77.9%) in the adulthood at 21 y (in 2001), 27 y (in 2007), and 31 y (in 2011) after the oral assessment, when the participants were 27 to 43 y old. Regression analyses were adjusted for childhood age, sex, body mass index, and family income, as well as adulthood smoking and education level. In adulthood, MetS was diagnosed in 11.9% (2001), 18.7% (2007), and 20.7% (2011) of participants at the 3 follow-ups. Childhood caries and fillings were associated with increased risk of adult MetS (risk ratio [95% CI], 1.25 [0.90 to 2.45] and 1.27 [1.02 to 1.99]) and with increased systolic blood pressure (1.78 [1.01 to 4.26] and 2.48 [1.11 to 4.12]) and waist circumference (2.25 [1.02 to 4.99] and 1.56 [1.01 to 3.25]), whereas BOP and visible plaque were associated with plasma glucose (1.97 [1.08 to 3.60] and 1.88 [1.00 to 3.53]). Severity of BOP ( P = 0.015) and caries ( P = 0.005) and teeth with plaque ( P = 0.027) were associated with number of MetS components. No such trends were seen with probing pocket depth. Childhood oral infection/inflammation was associated with adverse metabolic parameters and MetS in adulthood.

Summary Background Primordial and primary prevention is the cornerstone for cardiometabolic health. In the randomised, controlled Special Turku Coronary Risk Factor Intervention Project (STRIP; n=1116), a 20-year dietary counselling intervention was given to children biannually from infancy, and cardiometabolic health benefits had been observed among the participants in the intervention group. Here, we report on the key results of the first follow-up done 6 years after the end of the intervention, at age 26 years. Methods The randomised controlled STRIP study recruited children at age 5 months from well-baby clinics in Turku, Finland, and randomly assigned them to either an intervention or control group; group allocation was unmasked. The intervention introduced participants to a heart-healthy diet, characterised by low proportional intake of saturated fat and cholesterol, by dietary counselling and nutrition education sessions to parents and children from the age of 7 months to 20 years. Children in the control group received only the basic health education given at Finnish well-baby clinics and school health care. We assessed diet, lifestyle, and cardiometabolic risk factor data, including blood pressure, anthropometry, serum biochemistry (lipids, apolipoproteins, glucose, and insulin), and homoeostatic model assessment of insulin resistance (HOMA-IR) in the participants at age 26 years. Findings 1116 children were included in the original STRIP study, of whom 551 provided data at the age 26 years follow-up, and data for 507 participants were analysed (243 in the intervention group and 264 in the control group). At follow-up, those who had been in the intervention group had slightly lower mean intake of saturated fat as a proportion of total energy intake than the control group (13·0% [SD 3·3] vs 13·7% [3·6], p=0·049). A higher proportion of participants in the intervention group achieved the targeted monounsaturated and polyunsaturated fat to saturated fat ratio of more than 2:1 than the control group (78 [39%] of 200 vs 70 [30%] of 235; risk ratio [RR] 1·16 [95% CI 1·01–1·33]; p=0·035). A higher proportion of intervention group participants met the ideal total cholesterol concentration of less than 5·17 mmol/L (194 [81%] of 240 vs 187 [72%] of 261; RR 1·45 [1·05–2·01], p=0·024) and optimal LDL cholesterol concentration of less than 3·0 mmol/L (166 [69%] of 240 vs 158 [61%] of 251; RR 1·30 [1·03–1·66], p=0·031). Those who received the intervention had lower glucose (5·00 mmol/L [SD 0·43] vs 5·07 mmol/L [0·46], p=0·040) and HOMA-IR (median 1·44 [IQR 1·09–1·91] vs 1·62 [1·22–2·09], p=0·037) than the participants in the control group. Interpretation Previously observed intervention effects during the 20-year counselling were largely maintained into adulthood 6 years after the withdrawal of the intervention. Dietary counselling introduced in infancy thus provided a sustained benefit to diet quality and cardiometabolic risk factor levels. Funding Academy of Finland, Juho Vainio Foundation, Finnish Foundation for Cardiovascular Research, Finnish Ministry of Education and Culture, Finnish Cultural Foundation, Sigrid Juselius Foundation, Special Governmental grants for Health Sciences Research (Turku University Hospital), Yrjo Jahnsson Foundation, Finnish Medical Foundation, and Turku University Foundation.

Purpose: High pulse wave velocity (PWV), a marker of increased arterial stiffness, and an exaggerated exercise blood pressure (EEBP) response during an exercise test have both been related to an in...

We studied whether exposure to parental smoking in childhood/adolescence is associated with midlife cognitive function, leveraging data from the Cardiovascular Risk in Young Finns Study. A population-based cohort of 3,596 children/adolescents aged 3–18 years was followed between 1980 and 2011. In 2011, cognitive testing was performed on 2,026 participants aged 34–49 years using computerized testing. Measures of secondhand smoke exposure in childhood/adolescence consisted of parental self-reports of smoking and participants’ serum cotinine levels. Participants were classified into 3 exposure groups: 1) no exposure (nonsmoking parents, cotinine

The association between socioeconomic disadvantage and increased risk of depressive symptoms in adulthood is well established. We tested 1) the contribution of early exposure to neighborhood socioeconomic disadvantage to later depressive symptoms throughout life, 2) the persistence of the potential association between early exposure and depressive symptoms, and 3) the contributions of other known risk factors to the association. Data were collected from the Young Finns Study, a prospective, population-based 32-year follow-up study that included participants aged 3–18 years at baseline in 1980. Participants were followed up with repeated measurements of depressive symptoms between 1992 and 2012 (n = 2,788) and linked to national grid data on neighborhood disadvantage via residential addresses. We examined the associations in mixed models separately for the 5-, 10-, 15-, and 20-year follow-ups. Living in a disadvantaged neighborhood during childhood and adolescence was associated with a higher level of depressive symptoms in adulthood during all follow-up periods (β = 0.07, P = 0.001) than living in a nondisadvantaged area. Individual adulthood socioeconomic status mediated the associations. These findings suggest that living in a socioeconomically disadvantaged area during childhood and adolescence has a long-lasting negative association with mental health irrespective of family-related risks, partially due to socioeconomic adversity later in life.

Background This study investigated (i) whether compassion is associated with blood pressure or hypertension in adulthood and (ii) whether familial risk for hypertension modifies these associations. Method The participants (N = 1112–1293) came from the prospective Young Finns Study. Parental hypertension was assessed in 1983–2007; participants’ blood pressure in 2001, 2007, and 2011; hypertension in 2007 and 2011 (participants were aged 30–49 years in 2007–2011); and compassion in 2001. Results High compassion predicted lower levels of diastolic and systolic blood pressure in adulthood. Additionally, high compassion was related to lower risk for hypertension in adulthood among individuals with no familial risk for hypertension (independently of age, sex, participants’ and their parents’ socioeconomic factors, and participants’ health behaviors). Compassion was not related to hypertension in adulthood among individuals with familial risk for hypertension. Conclusion High compassion predicts lower diastolic and systolic blood pressure in adulthood. Moreover, high compassion may protect against hypertension among individuals without familial risk for hypertension. As our sample consisted of comparatively young participants, our findings provide novel implications for especially early-onset hypertension.

Objective The Systolic Blood Pressure Intervention Trial (SPRINT) reported that lowering SBP to below 120 mmHg (intensive treatment) reduced cardiovascular morbidity and mortality among adults with hypertension but increased the incidence of adverse events, particularly acute kidney injury (AKI). The goal of this study was to develop an accurate risk estimation tool for comparing the risk of cardiovascular events and adverse kidney-related outcomes between standard and intensive antihypertensive treatment strategies. Methods By applying Lasso regression on the baseline characteristics and health outcomes of 8760 participants with complete baseline information in the SPRINT trial, we developed predictive models for primary cardiovascular disease (CVD) outcome and incidence of AKI. Both models were validated against an independent test set of the SPRINT trial (one third of data not used for model building) and externally against the cardiovascular and renal outcomes available in Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial, consisting of 4733 participants with type 2 diabetes mellitus. Results Lasso regression identified a subset of variables that accurately predicted the primary CVD outcome and the incidence of AKI (areas under receiver-operating characteristic curves 0.70 and 0.77, respectively). Based on the validated risk models, an easy-to-use risk assessment tool was developed and made available as an easy-to-use online tool. Conclusion By predicting the risks of CVD and AKI at baseline, the developed tool can be used to weigh the benefits of intensive versus standard blood pressure control and to identify those who are likely to benefit most from intensive treatment.

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1

Background and aims Carotid plaque is a specific sign of atherosclerosis and adults with carotid plaque are at increased risk for cardiovascular outcomes. Atherosclerosis has roots in childhood and pediatric guidelines provide cut-off values for cardiovascular risk factors. However, it is unknown whether these cut-offs predict adulthood advanced atherosclerosis. Methods The Cardiovascular Risk in Young Finns Study is a follow-up of children that begun in 1980 when 2653 participants with data for the present analyses were aged 3–18 years. In 2001 and 2007 follow-ups, in addition to adulthood cardiovascular risk factors, carotid ultrasound data was collected. Long-term burden, as the area under the curve, was evaluated for childhood (6–18 years) risk factors. To study the associations of guideline-based cut-offs with carotid plaque, both childhood and adult risk factors were classified according to clinical practice guidelines. Results Carotid plaque, defined as a focal structure of the arterial wall protruding into lumen >50% compared to adjacent intima-media thickness, was present in 88 (3.3%) participants. Relative risk for carotid plaque, when adjusted for age and sex, was 3.03 (95% CI, 1.76–5.21) for childhood dyslipidemia, 1.51 (95% CI, 0.99–2.32) for childhood elevated systolic blood pressure, and 1.93 (95% CI, 1.26–2.94) for childhood smoking. Childhood dyslipidemia and smoking remained independent predictors of carotid plaque in models additionally adjusted for adult risk factors and family history of coronary heart disease. Carotid plaque was present in less than 1% of adults with no childhood risk factors. Conclusions Findings reinforce childhood prevention efforts and demonstrate the utility of guideline-based cut-offs in identifying children at increased risk for adulthood atherosclerosis.

Substantial genetic correlations have been reported across psychiatric disorders and numerous cross-disorder genetic variants have been detected. To identify the genetic variants underlying general psychopathology in childhood, we performed a genome-wide association study using a total psychiatric problem score. We analyzed 6,844,199 common SNPs in 38,418 school-aged children from 20 population-based cohorts participating in the EAGLE consortium. The SNP heritability of total psychiatric problems was 5.4% (SE = 0.01) and two loci reached genome-wide significance: rs10767094 and rs202005905. We also observed an association of SBF2, a gene associated with neuroticism in previous GWAS, with total psychiatric problems. The genetic effects underlying the total score were shared with common psychiatric disorders only (attention-deficit/hyperactivity disorder, anxiety, depression, insomnia) (rG > 0.49), but not with autism or the less common adult disorders (schizophrenia, bipolar disorder, or eating disorders) (rG < 0.01). Importantly, the total psychiatric problem score also showed at least a moderate genetic correlation with intelligence, educational attainment, wellbeing, smoking, and body fat (rG > 0.29). The results suggest that many common genetic variants are associated with childhood psychiatric symptoms and related phenotypes in general instead of with specific symptoms. Further research is needed to establish causality and pleiotropic mechanisms between related traits. The work of H. Tiemeier is further supported by a European Union’s Horizon 2020 research and innovation program (Contract grant number: 633595, DynaHealth) and a NWO-VICI grant (NWO-ZonMW: 016.VICI.170.200). https://www.nwo.nl/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Fatty liver is a preventable cause of liver failure, but early risk factors for adulthood fatty liver are poorly understood. We examined the association of childhood socioeconomic disadvantage with adulthood fatty liver and tested adulthood risk factors of fatty liver as possible mediators of this link. The study population comprised 2,042 participants aged 3-18 years at baseline (1980) from the longitudinal Cardiovascular Risk in Young Finns Study. Follow-up with repeated clinical examinations was 31 years. Childhood socioeconomic disadvantage was assessed using data from parents' socioeconomic position and socioeconomic circumstances in participants' residential neighborhoods, categorized as high versus low socioeconomic disadvantage. Fatty liver was determined by ultrasound during the last follow-up (2011) at ages 34-49 years. Childhood and adulthood risk factors, including metabolic biomarkers and lifestyle variables, were assessed in clinical examinations. A total of 18.9% of the participants had fatty liver in adulthood. High childhood socioeconomic disadvantage was associated with an increased risk of fatty liver (risk ratio [95% confidence interval], 1.42 [1.18-1.70]; P = 0.0002). This association was robust to adjustment for age, sex, and childhood risk factors of fatty liver, including high body mass index, elevated insulin, and low birth weight (1.33 [1.09-1.62]; P = 0.005). High childhood socioeconomic disadvantage was also associated with the development of risk factors of fatty liver in adulthood. Adulthood risk factors linking childhood socioeconomic disadvantage with fatty liver included waist circumference (proportion mediated of the total effect of childhood socioeconomic disadvantage, 45%), body mass index (40%), systolic blood pressure (29%), insulin (20%), physical activity (15%), triglycerides (14%), and red meat consumption (7%). Conclusion: Childhood socioeconomic disadvantage was associated with multiple risk factors of fatty liver and increased likelihood of fatty liver in adulthood.

Introduction: This study used causal mediation analysis to assess the life-course associations of a favorable childhood psychosocial environment with left ventricular mass and diastolic function in adulthood and the extent to which adult health behaviors mediate these associations. Methods: The sample included 880 participants (56% women) from the Young Finns Study with data on the childhood environment from 1980, adult health behaviors (smoking, physical activity, diet, and BMI) from 2001 and an echocardiographic assessment of the left ventricular mass (g/m(2.7)) and diastolic function (E/e' ratio; higher values indicating a lower diastolic function) from 2011. The associations of the childhood environment with the left ventricular mass and E/e' ratio and mediation pathways through health behaviors were assessed using marginal structural models that were controlled for age, sex, and time-dependent confounding by adult socioeconomic position (measured as educational attainment) via inverse probability weighting. The data were analyzed in 2018-2019. Results: The mean age in 2011 was 41 (range 34-49) years. Those above versus below the median childhood score had a 1.28 g/m(2.7) lower left ventricular mass (95% CI = -2.63, 0.07) and a 0.18 lower E/e' ratio (95% CI = -0.39, 0.03). There was no evidence for indirect effects from childhood environments to left ventricular outcomes through adult health behaviors after controlling for time-dependent confounding by the adult socioeconomic position (indirect effect beta = -0.30, 95% CI = -1.22, 0.63 for left ventricular mass; beta = -0.04, 95% CI = -0.18, 0.11 for E/e' ratio). The results after multiple imputation were similar. Conclusions: A favorable childhood environment is associated with more optimal cardiac structure and function in adulthood. After accounting for socioeconomic positions, adult health behaviors explain little of the associations. (C) 2019 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Background In high-income countries, cancer is the leading cause of death among middle-aged adults. Prospective data on the effects of childhood risk exposures on subsequent cancer mortality are scarce. Methods We examined whether childhood body mass index (BMI), blood pressure, glucose and lipid levels were associated with adult cancer mortality, using data from 21,012 children enrolled aged 3–19 years in seven prospective cohort studies from the U.S., Australia, and Finland that have followed participants from childhood into adulthood. Cancer mortality (cancer as a primary or secondary cause of death) was captured using registries. Results 354 cancer deaths occurred over the follow-up. In age-, sex, and cohort-adjusted analyses, childhood BMI (Hazard ratio [HR], 1.13; 95% confidence interval [CI] 1.03–1.24 per 1-SD increase) and childhood glucose (HR 1.22; 95%CI 1.01–1.47 per 1-SD increase), were associated with subsequent cancer mortality. In a multivariable analysis adjusted for age, sex, cohort, and childhood measures of fasting glucose, total cholesterol, triglycerides, and systolic blood pressure, childhood BMI remained as an independent predictor of subsequent cancer mortality (HR, 1.24; 95%CI, 1.03–1.49). The association of childhood BMI and subsequent cancer mortality persisted after adjustment for adulthood BMI (HR for childhood BMI, 1.35; 95%CI 1.12–1.63). Conclusions Higher childhood BMI was independently associated with increased overall cancer mortality.

Introduction Small or large birth weight for gestational age has been linked with later cardiovascular disease risk. However, cardiovascular risk markers from childhood to adulthood according to birth weight in diverse longitudinal settings globally have not been extensively studied. Objectives To examine the relationship between birth weight and cardiovascular risk profile from childhood until young adulthood in two geographically and socioeconomically distinct cohorts. Methods Data were derived from two longitudinal birth cohort studies; one from southern Finland (Special Turku Coronary Risk Factor Intervention Project, STRIP) and one from northern Australia comprising Indigenous Australians (Aboriginal Birth Cohort, ABC). The sample included 747 Finnish participants and 541 Indigenous Australians with data on birth weight, gestational age and cardiovascular risk factors (body mass index [BMI]), waist-to-height ratio [WHtR], lipid profile, blood pressure) collected at ages 11, 18 and 25 or 26 years. Carotid intima-media thickness (cIMT) was assessed at age 18 or 19 years. Participants were categorised according to birth weight for gestational age (small [SGA], appropriate [AGA] or large [LGA]). Associations between birth weight category and cardiovascular risk markers were studied using a repeated measures ANOVA. Results Higher birth weight category was associated with higher BMI later in life in both cohorts (p=.003 for STRIP and p

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization (QRS duration) and repolarization (JT interval). Abnormalities of the QT interval are associated with potentially fatal ventricular arrhythmia. We conducted genome-wide multi-ancestry analyses in >250,000 individuals and identified 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identified associations with Mendelian disease genes. Enrichments were observed in established pathways for QT and JT, with new genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast, connective tissue components and processes for cell growth and extracellular matrix interactions were significantly enriched for QRS. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlighted potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

The prevalence of ideal cardiovascular health (CVH) among adults in the United States is low and decreases with age. Our objective was to identify specific age windows when the loss of CVH accelerates, to ascertain preventive opportunities for intervention. Data were pooled from 5 longitudinal cohorts (Project Heartbeat!, Cardiovascular Risk in Young Finns Study, The Bogalusa Heart Study, Coronary Artery Risk Development in Young Adults, Special Turku Coronary Risk Factor Intervention Project) from the United States and Finland from 1973 to 2012. Individuals with clinical CVH factors (i.e., body mass index, blood pressure, cholesterol, blood glucose) measured from ages 8 to 55 years were included. These factors were categorized and summed into a clinical CVH score ranging from 0 (worst) to 8 (best). Adjusted, segmented, linear mixed models were used to estimate the change in CVH over time. Among the 18,343 participants, 9,461 (52%) were female and 12,346 (67%) were White. The baseline mean (standard deviation) clinical CVH score was 6.9 (1.2) at an average age of 17.6 (8.1) years. Two inflection points were estimated: at 16.9 years (95% confidence interval: 16.4, 17.4) and at 37.2 years (95% confidence interval: 32.4, 41.9). Late adolescence and early middle age appear to be influential periods during which the loss of CVH accelerates.

Publisher Copyright: © 2021 European Sleep Research Society We analysed (A) the association of short-term as well as long-term cumulative exposure to natural light, and (B) the association of detailed temporal patterns of natural light exposure history with three indicators of sleep: sleep duration, sleep problems, and diurnal preference. Data (N = 1,962; 55% women; mean age 41.4 years) were from the prospective Young Finns Study, which we linked to daily meteorological data on each participant’s neighbourhood natural light exposure using residential postal codes. Sleep outcomes were self-reported in 2011. We first examined associations of the sleep outcomes with cumulative light exposure of 5-year, 2-year, 1-year, and 2-month periods prior to the sleep assessment using linear and Poisson regression models adjusting for potential confounders. We then used a data-driven time series approach to detect clusters of participants with different light exposure histories and assessed the associations of these clusters with the sleep outcomes using linear and Poisson regression analyses. A greater cumulative light exposure over ≥1 year was associated with a shorter sleep duration (β = −0.10, 95% confidence interval [CI] −0.15 to −0.04), more sleep problems (incident rate ratio [IRR] 1.04, 95% CI 1.0–1.07) and diurnal preference towards eveningness (β = −0.09, 95% CI −0.14 to −0.03). The data-driven exposure pattern of “slowly increasing” light exposure was associated with fewer overall sleep problems (IRR 0.93, 95% CI 0.88–0.98) compared to a “recently declining” light exposure group representing the “average-exposure” group. These findings suggest that living in an area with relatively more intense light exposure for a longer period of time influences sleep.

Background and aims: Ceramides have been identified as novel biomarkers for cardiovascular disease (CVD) related events and mortality but their role in etiology of subclinical atherosclerosis is unknown. We aimed to assess association between plasma ceramides and carotid intima-media thickness (CIMT) and evaluate predictive value of the ceramides for high CIMT over traditional CVD risk factors. Methods: Association between plasma ceramides and CIMT in the Young Finns Study participants was analyzed with CIMT as outcome and ceramides along with traditional risk factors as predictors with regression model. Predictive value of the ceramides and related coronary event risk test (CERT) score for high CIMT as surrogate marker of subclinical atherosclerosis was assessed by comparing logistic regression-based prediction models including, i) traditional risk factors and ceramides, ii) traditional risk factors and CERT score, iii) age, sex and ceramides or alternatively CERT score with a reference model including only traditional risk factors. The prediction models were fitted to training data (70% data) and tested on test data (30% data). The predictive models were assessed with area under the receiver operating curve (AUC). The variance of AUC was estimated by repeating the model fitting and testing for 1000 bootstraps of the original data. Results: Predictive models with plasma ceramides or alternatively with CERT score in addition to age and sex variables were able to predict high CIMT with AUC 0.726 and 0.720 respectively. However, the ceramides and CERT score did not have statistically significant added predictive value for high CIMT over traditional risk factors. Conclusions: The new systemic biomarkers, high-risk plasma ceramides and CERT score, showed promising predictive performance for high CIMT with only age and sex as additional variables. This may help in predicting subclinical atherosclerosis for primary prevention. publishedVersion

Objective: To evaluate the impact of the 2017 American Academy of Pediatrics hypertension Clinical Practice Guideline (CPG), compared with the previous guideline (“Fourth Report”), on the frequency of hypertensive blood pressure (BP) measurements in childhood and associations with hypertension in adulthood using data from the International Childhood Cardiovascular Cohort Consortium. Study design: Childhood BPs were categorized in normal, prehypertensive/elevated, and hypertensive (stage 1 and 2) ranges using the Fourth Report and the CPG. Participants were contacted in adulthood to assess self-reported hypertension. The associations between childhood hypertensive range BPs and self-reported adult hypertension were evaluated. Results: Data were available for 34 014 youth (10.4 ± 3.1 years, 50.6% female) with 92 751 BP assessments. Compared with the Fourth Report, the CPG increased hypertensive readings from 7.6% to 13.5% and from 1.3% to 2.5% for stage 1 and 2 hypertensive range, respectively (P < .0001). Of 12 761 adults (48.8 ± 7.9 years, 43% male), 3839 (30.1%) had self-reported hypertension. The sensitivity for predicting adult hypertension among those with hypertensive range BPs at any point in childhood, as defined by the Fourth Report and the CPG, respectively, was 13.4% and 22.4% (specificity 92.3% and 85.9%, P < .001), with no significant impact on positive and negative predictive values. Associations with self-reported adult hypertension were similar and weak (c-statistic range 0.61-0.68) for hypertensive range BPs as defined by the Fourth Report and CPG. Conclusions: The CPG significantly increased the prevalence of childhood BPs in hypertensive ranges and improved the sensitivity, without an overall strengthened association, of predicting self-reported adult hypertension.

Objective: To determine the association of number of siblings on cardiovascular risk factors in childhood and in adulthood. Study design: In total, 3554 participants (51% female) from the Cardiovascular Risk in Young Finns Study with cardiovascular disease risk factor data at baseline 1980 (age 3-18 years) and 2491 participants with longitudinal risk factor data at the 2011 follow-up. Participants were categorized by number of siblings at baseline (0, 1, or more than 1). Risk factors (body mass index, physical activity, hypertension, dyslipidemia, and overweight, and metabolic syndrome) in childhood and in adulthood were used as outcomes. Analyses were adjusted for age and sex. Results: In childhood, participants without siblings had higher body mass index (18.2 kg/m2, 95% CI 18.0-18.3) than those with 1 sibling (17.9 kg/m2, 95% CI 17.8-18.0) or more than 1 sibling (17.8 kg/m2, 95% CI 17.7-17.9). Childhood physical activity index was lower among participants without siblings (SD -0.08, 95% CI -0.16-0.00) compared with participants with 1 sibling (SD 0.06, 95%CI 0.01-0.11) or more than 1 sibling (SD -0.02, 95% CI -0.07-0.03). OR for adulthood hypertension was lower among participants with 1 sibling (OR 0.73, 95% CI 0.54-0.98) and more than 1 sibling (OR 0.71, 95% CI 0.52-0.97) compared with participants with no siblings. OR for obesity was lower among participants with 1 sibling (OR 0.72, 95% CI 0.54-0.95) and more than 1 sibling (OR 0.75, 95% CI 0.56-1.01) compared with those with no siblings. Conclusions: Children without siblings had poorer cardiovascular risk factor levels in childhood and in adulthood. The number of siblings could help identify individuals at increased risk that might benefit from early intervention. publishedVersion

Purpose The longitudinal influence of parental leisure-time physical activity (LTPA) on their offspring's LTPA is poorly understood. This study examined the longitudinal associations between parental LTPA and offspring's LTPA at two-time intervals. Method Child (offspring) participants (N=3596) were enrolled from the Cardiovascular Risk in Young Finns Study in 1980. Their LTPA was self-rated through nine phases from baseline to 2018 and categorized by year into youth (1980-1986) and adult (1992-2018) LTPA. Parental LTPA was assessed with a single self-reported question at three phases from 1980 to 1986. Latent growth curve modeling stratified by gender was fitted to estimate the potential pathways between parental LTPA and offspring's youth and adult LTPA. Results Higher initial levels of paternal and maternal LTPA were independently associated with greater initial levels of youth and adult LTPA of offspring in both genders respectively, except maternal LTPA that did not associate with male offspring's adult LTPA. The initial levels of paternal LTPA were directly related to changes in male offspring's youth LTPA after adjusting for age, residential place, paternal education and occupation, having siblings, and offspring's body mass index. Conclusion Our study demonstrates that the initial levels of parental LTPA are directly linked to the initial levels of offspring's LTPA during youth and adulthood, while changes in parental LTPA are unrelated to changes in offspring's youth and adult LTPA for either gender over time. These results imply that higher initial levels of LTPA in parents may serve as a predictor of offspring's LTPA across life stages.

Background Atherosclerosis develops silently for decades before adult cardiovascular disease (aCVD) occurs. There is currently no evidence directly linking childhood risk factors to aCVD outcomes. Methods i3C is an international consortium of 7 cohorts involving 40,709 participants enrolled between 1970-95 in childhood (age 3-19) who underwent measurement for BMI, SBP, total cholesterol, and triglycerides, and smoking (the last mostly in adolescence). Participants were followed by direct contact and review of medical records or death registry ascertainment through adulthood in 2014-19. 20,560 participants were found and interviewed or had died in the approximately 40 years since enrollment; 738 had a CVD event, confirmed by medical record review (n = 449) or death certificate ICD code (n = 289). Results Estimated hazard ratios (HRs) for childhood risk factors and their confidence intervals are displayed in the table below. The CIs excluded 1.0 for all these variables in the univariable analysis and, although the HRs were reduced in multivariable analysis which included all of these risk factors, the CIs still excluded 1.0. Conclusion Exposure to CVD risk factors in youth predicts adult CVD with implications for primordial CVD prevention. Key messages Intervention to reduce CVD risk factors in childhood is likely to reduce risk of adult CVD

Background: Within-visit SBP variability is associated with age and SBP, but its long-term clinical significance is unknown. We examined the association between child, adult, and life-time within-visit SBP variability with markers of end-organ damage using data from a 31-year longitudinal study. Methods: Within-visit SBP variability was calculated as the standard deviation of three sitting SBP readings among up to 3010 participants aged 6–18 years (childhood) who were re-measured up to seven times to mid-adulthood. Markers of cardiovascular end-organ damage in adulthood were carotid intima--media thickness, brachial flow-mediated dilatation, carotid distensibility, pulse wave velocity, left ventricular mass index, carotid plaque, and coronary artery calcification. Results: The mean (standard deviation) cumulative within-visit SBP variability was 2.7 (1.5) mmHg in childhood, 3.9 (1.9) mmHg in adulthood and 3.7 (1.5) mmHg across the observed life-time. Childhood within-visit SBP variability was not correlated with its subsequent values measured from 3 to 31 years later. With adjustment for age, sex, cumulative SBP, BMI and serum lipids, neither child, adult, or life-time cumulative within-visit SBP variability associated with markers of cardiovascular end-organ damage. However, higher child, adult, and life-time cumulative SBP significantly associated with higher carotid intima--media thickness, higher pulse wave velocity, lower brachial flow-mediated dilatation, lower carotid distensibility in adulthood. Conclusion: Within-visit SBP variability from childhood to adulthood does not provide additional predictive utility over SBP over the same period of the life course.

Objectives In the general population, increased afamin concentrations are associated with the prevalence and incidence of metabolic syndrome as well as type 2 diabetes. Although metabolic syndrome is commonly associated with nonalcoholic fatty liver disease (NAFLD), there exist no information on afamin and NAFLD. Methods Afamin concentrations were cross-sectionally measured in 146 Austrian patients with NAFLD, in 45 patients without NAFLD, and in 292 age- and sex-matched healthy controls. Furthermore, the feasibility of afamin to predict incident NAFLD was evaluated in 1,434 adult participants in the population-based Cardiovascular Risk in Young Finns Study during a 10-year follow-up. Results Median afamin concentrations were significantly higher in NAFLD patients (83.6 mg/L) than in patients without NAFLD (61.6 mg/L, p Conclusions Afamin concentrations are increased in patients with NAFLD and independently predict the development of NAFLD in a population-based cohort.

Objectives To understand if pregnancy unmasks previously silent cardiovascular (CV) adverse factors, or initiates lasting injury. Methods Pre-pregnancy and during pregnancy CV risk factors (blood pressure, fasting lipids, and glucose) from 296 women belonging to studies in the International Childhood Cardiovascular Cohort (i3C) Consortium, a group of studies assessing the relationship between child and adolescent CV risk factors and adult outcomes, were used. Correlation coefficients between the pre- and during pregnancy measures were calculated, and the mean difference between the measures was modeled with adjustment for age, body mass index, race, smoking, and study. Results Measures were strongly correlated at pre- and during-pregnancy visits (p Conclusions Pre- and during-pregnancy CV risk factors are moderately well correlated. This may indicate that susceptible women enter pregnancy with higher risk rather than pregnancy inducing new vascular or metabolic effects.

Background Temperament is associated with circulating inflammatory biomarkers, such as C-reactive protein (CRP), which has been associated with various health conditions, including depression. This study aims to investigate whether genetic disposition for increased circulating CRP concentration may influence temperament over the life-course. Methods Using a longitudinal cohort that began in 1980—the Cardiovascular Risk in Young Finns Study (YFS)—we included 920 participants (59.8% female) aged 3–12 years old at baseline (childhood), and the same participants again at ages 30–39 years old (adulthood) in this study. We used both ordinary least-squares regression (OLS linear regression) and instrumental variable (IV) regression to assess associations between CRP concentration and temperament dimensions (negative emotionality, activity, and sociability). To represent genetically determined risk for increase in circulating CRP concentration, we calculated a weighted genetic risk score (GRS) which reflects risk for increased circulating CRP concentration. Results In OLS linear regression analyses, we found that increased circulating CRP concentration in childhood was associated with slightly higher scores for sociability in childhood (19% increase, CI ​= ​7–32%) and adulthood (13% increase, CI ​= ​2–27%), and lower activity scores in adulthood (15% decrease, CI ​= ​3–25%). For all IV regressions, there were no apparent associations between GRS and temperament in either childhood or adulthood (all p>0.3). The Durbin-Wu-Hausman test for endogeneity produced p-values (all>0.05) that suggest there is no evidence for disagreement between the OLS and IV estimates. Conclusions We found no clear evidence for an association of GRS for elevated CRP with childhood or adulthood emotionality, activity, or sociability, although circulating CRP was associated with some of these traits.

Normal weight is associated with a favorable cardiometabolic risk profile and low risk of type 2 diabetes and cardiovascular disease. However, some normal-weight individuals-the "metabolically obese normal weight" (MONW)-show a cardiometabolic risk profile similar to the obese. Previous studies have shown that older age, central body fat distribution, and unfavorable lifestyle increase the risk of MONW. However, the role of early-life factors in MONW remains unknown. We examined the associations of early-life factors with adult MONW in 1178 individuals from the Cardiovascular Risk in Young Finns study who were followed up from childhood to adulthood. The strongest early predictor for adult MONW was an increase in BMI from childhood to adulthood (p = 3.1 × 10-11); each 1 SD increase in BMI z-score from childhood to adulthood led to a 2.56-fold increase in the risk of adult MONW (CI 95% = 1.94-3.38). Other significant predictors of adult MONW were male sex (OR = 2.38, 95% = 1.63-3.47, p = 7.0 × 10-6), higher childhood LDL cholesterol (OR = 1.41 per 1 SD increase in LDL cholesterol, CI 95% = 1.14-1.73, p = 0.001), and lower HDL cholesterol (OR = 1.51 per 1 SD decrease in HDL cholesterol, CI 95% = 1.23-1.85, p = 5.4 × 10-5). Our results suggest that an increase in adiposity from childhood to adulthood is detrimental to cardiometabolic health, even among individuals remaining normal weight.

Background: Mendelian randomization studies in adults suggest that abdominal adiposity is causally associated with increased risk of type 2 diabetes and coronary artery disease in adults, but its causal effect on cardiometabolic risk in children remains unclear.Objective: We aimed to study the causal relation of abdominal adiposity with cardiometabolic risk factors in children by applying Mendelian randomization.Methods: We constructed a genetic risk score (GRS) using variants previously associated with waist-to-hip ratio adjusted for BMI (WHRadjBMI) and examined its associations with cardiometabolic factors by linear regression and Mendelian randomization in a meta-analysis of 6 cohorts, including 9895 European children and adolescents aged 3-17 y.Results: WHRadjBMI GRS was associated with higher WHRadjBMI (β = 0.021 SD/allele; 95% CI: 0.016, 0.026 SD/allele; P = 3 × 10-15) and with unfavorable concentrations of blood lipids (higher LDL cholesterol: β = 0.006 SD/allele; 95% CI: 0.001, 0.011 SD/allele; P = 0.025; lower HDL cholesterol: β = -0.007 SD/allele; 95% CI: -0.012, -0.002 SD/allele; P = 0.009; higher triglycerides: β = 0.007 SD/allele; 95% CI: 0.002, 0.012 SD/allele; P = 0.006). No differences were detected between prepubertal and pubertal/postpubertal children. The WHRadjBMI GRS had a stronger association with fasting insulin in children and adolescents with overweight/obesity (β = 0.016 SD/allele; 95% CI: 0.001, 0.032 SD/allele; P = 0.037) than in those with normal weight (β = -0.002 SD/allele; 95% CI: -0.010, 0.006 SD/allele; P = 0.605) (P for difference = 0.034). In a 2-stage least-squares regression analysis, each genetically instrumented 1-SD increase in WHRadjBMI increased circulating triglycerides by 0.17 mmol/L (0.35 SD, P = 0.040), suggesting that the relation between abdominal adiposity and circulating triglycerides may be causal.Conclusions: Abdominal adiposity may have a causal, unfavorable effect on plasma triglycerides and potentially other cardiometabolic risk factors starting in childhood. The results highlight the importance of early weight management through healthy dietary habits and physically active lifestyle among children with a tendency for abdominal adiposity.

Background and Objectives: Adult class II/III obesity (BMI ≥ 35 kg/m2) has significant adverse health outcomes. Early prevention and treatment are critical, but prospective childhood risk estimates are lacking. This study aimed to define the prospective risk of adult class II/III obesity, using childhood BMI. Methods: Children ages 3–19 years enrolled in cohorts of The International Childhood Cardiovascular Cohort (i3C) Consortium with measured BMI assessments in childhood and adulthood were included. Prospective risk of adult class II/III obesity was modeled based on childhood age, sex, race and BMI. Results: 12 142 individuals (44% male, 85% white) were assessed at median age 14 [Interquartile range, IQR: 11, 16] and 33 [28, 39] years. Class II/III adult obesity developed in 6% of children with normal weight; 29% of children with overweight; 56% of children with obesity; and 80% of children with severe obesity. However, 38% of the 1 440 adults with class II/III obesity (553/1440) were normal weight as children. Prospective risk of adult class II/III obesity varied by age, sex and race within childhood weight status classifications, and is notably higher for girls, black participants, and those in the United States. The risk of class II/III obesity increased with older adult age. Conclusions: Children with obesity or severe obesity have a substantial risk of adult class II/III obesity, and observed prospective risk estimates are now presented by age, sex, race and childhood BMI. Clinical monitoring of children’s BMI for adult class II/III obesity risk may be especially important for females and black Americans., Table of Contents Summary This study developed prospective risk estimates of adult class II/III obesity using childhood BMI, childhood age, sex and race, using longitudinal international data.

apoE, a key regulator of plasma lipids, mediates altered functionalities in lipoprotein metabolism and thus affects the risk of coronary artery disease (CAD). The significance of different apoE polymorphisms remains unclear; although the ε4 allele is clearly associated with increased cholesterol levels (which inform CAD risk), direct studies about apoE polymorphisms on CAD risk and development have yielded controversial results. Furthermore, certain species of ceramides—complex lipids abundant in plasma LDL—are markers of increased risk of myocardial infarction and cardiovascular death. Using a high-throughput MS approach, we quantified 30 molecular plasma ceramide species from a cohort of 2,160 apoE-genotyped (rs7412, rs429358) young adults enrolled in the population-based Cardiovascular Risk in Young Finns Study. We then searched this lipidome data set to identify new indications of pathways influenced by apoE polymorphisms and possibly related to CAD risk. This approach revealed a previously unreported association between apoE polymorphism and a consistently documented high-risk CAD marker, Cer(d18:1/16:0). Compared with the apoE ε3/3 reference group, plasma levels of apoE ε4 were elevated and those of apoE ε2 were lowered in all subjects without evidence of apoE-by-sex interactions. apoE associated with seven ceramides that are connected to atherogenically potent macrophages and/or lipoprotein particles; these associations could indicate a plausible linkage between apoE polymorphism and ceramide metabolism, leading to adverse plasma LDL metabolism and atherogenesis. In conclusion, new evidence from plasma ceramides links apoE polymorphism with an increased risk of CAD and extends our understanding of the role of apoE in health and disease.

Objective To determine the association between cumulative exposure to parent-reported childhood adversities and self-reported adulthood suboptimal sleep. Methods Participants (n = 1,038; 57.4% women) were drawn from the prospective population-based Young Finns Study. Childhood adversities were assessed in 1980 among 3- to- 18-year-olds, while components of suboptimal sleep were measured 27 years later. Cumulative childhood adversities included factors from four domains: stressful life events, adverse parental health behaviors, adverse emotional environment, and low socioeconomic status. Logistic, linear, and ordinal regression analyses were conducted to examine associations between cumulative exposure and self-reported sleep duration, sleep deficiency, and sleep problems, respectively. Multiple imputations were applied to correct for participants lost to follow-up and for missing values (resulting in n = 3,559) and the aforementioned analyses were rerun. Results More adverse parental health behaviors (OR = 1.19, CI 95% [1.02-1.38], p = .03) and combined childhood adversities (OR = 1.10, CI 95% [1.02-1.19], p = .02) were associated with sleeping less than six hours. Neither association withstood adjustment for adulthood health or socioeconomic status or both, nor for attrition bias. No associations were found between adverse childhood environments and sleep deficiency or problems. Conclusions The accumulation of more typical childhood adversities might not persistently affect self-reported sleep duration, sleep deficiency or sleep problems in adulthood. However, this study is among the first to assess the effects of the accumulation of everyday stressors on sleep and therefore, more research is warranted on everyday adversities for more definitive conclusions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Blood pressure (BP) tracking (maintaining a BP percentile) across life is not well defined but is important in predicting which children will become hypertensive adults. We computed BP tracking in subjects with BP measured in childhood and adulthood and performed logistic regression to determine the ability of childhood BP to predict adult hypertension (N=5035, 46.7 years, 74.2% white, 17.7% black; 39.6% male). Prevalence of hypertension was 29%. Correlations between systolic BP for child and adolescent were r =0.48; for adolescent and young adult were r =0.40, and for child and young adult were r =0.24 (all P P P 2

Background Promoting ideal cardiovascular health behaviors is an objective of the American Heart Association 2020 goals. We hypothesized that ideal health behaviors of parents are associated with health behaviors of their adult offspring, and that higher socioeconomic position in either generation enhances intergenerational associations of ideal health behaviors. Design Prospective cohort study. Methods We included 1856 Young Finns Study participants who had repeated measurements of socioeconomic position (education, income, occupation), smoking status, body mass index, physical activity and diet from 2001, 2007 and 2011, and data on parental socioeconomic position and health behaviors from 1980. We calculated the total number of ideal behaviors in both generations using American Heart Association definitions. Intergenerational associations were examined using ordinal and linear multilevel regression with random intercepts, in which each participant contributed one, two or three measurements of adult health behaviors (2001, 2007, 2011). All analyses were adjusted for offspring sex, birth year, age, parental education and single parenthood. Results Overall, parental ideal health behaviors were associated with ideal behaviors among offspring (odds ratio (OR) 1.28, 95% confidence interval 1.17, 1.39). Furthermore, ORs for these intergenerational associations were greater among offspring whose parents or who themselves had higher educational attainment (OR 1.56 for high vs. OR 1.19 for low parental education; P = 0.01 for interaction, OR 1.32 for high vs. OR 1.04 for low offspring education; P = 0.02 for interaction). Similar trends were seen with parental income and offspring occupation. Results from linear regression analyses were similar. Conclusions These prospective data suggest higher socioeconomic position in parents or in their adult offspring strengthens the intergenerational continuum of ideal cardiovascular health behaviors.

Childhood blood pressure (BP) levels predict adult subclinical atherosclerosis. However, the best childhood BP component for prediction has not been determined. This study comprised 5925 participants aged 3 to 18 years from 6 cohorts who were followed into adulthood (mean follow-up 25.8±6.2 years). Childhood BP was measured by using a standard mercury sphygmomanometer in all cohorts. Study-specific carotid intima-media thickness ≥90th percentile was used to define subclinical atherosclerosis. Per SD change in the predictor, childhood systolic BP (SBP; age- and sex-adjusted odds ratio [95% CI], 1.24 [1.13–1.37]), mean arterial pressure (1.10 [1.07–1.13]), and pulse pressure (1.15 [1.05–1.27]) were associated with increased adulthood intima-media thickness. In age- and sex-adjusted analyses, area under the receiver operating characteristic curves for SBP ( C value [95% CI], 0.677 [0.657–0.704]) showed significantly improved prediction compared with diastolic BP (0.669 [0.646–0.693], P =0.006) or mean arterial pressure (0.674 [0.653–0.699], P =0.01). Pulse pressure provided a C value that was not different from SBP (0.676 [0.653–0.699], P =0.16). Combining different BP components did not improve prediction over SBP measurement alone. Based on the associations with adult carotid intima-media thickness, cut points for elevated SBP were 105 mm Hg for 3- to 6-year-old boys, 108 mm Hg for 3- to 6-year-old girls, 108 mm Hg for 7- to 12-year-old boys, 106 mm Hg for 7- to 12-year-old girls, 123 mm Hg for 13- to 18-year-old boys, and 115 mm Hg for 13- to 18-year-old girls. Our analyses suggest that several childhood BP measurement components are related to adulthood carotid intima-media thickness. Of these, SBP provided the best predictive ability.

Context To the best of our knowledge, no previous studies have examined the role of youth calcium intake in the development of impaired glucose metabolism, especially those with long-term high calcium intake. Objectives To examine whether youth and long-term (between youth and adulthood) dietary calcium intake is associated with adult impaired glucose metabolism and type 2 diabetes (T2D). Design, setting, and participants The Cardiovascular Risk in Young Finns Study is a 31-year prospective cohort study (n = 1134; age, 3 to 18 years at baseline). Exposures Dietary calcium intake was assessed at baseline (1980) and adult follow-up visits (2001, 2007, and 2011). Long-term (mean between youth and adulthood) dietary calcium intake was calculated. Main outcome measures Adult impaired fasting glucose (IFG) and T2D. Results We found no evidence for nonlinear associations between calcium intake and IFG or T2D among females and males (all P for nonlinearity > 0.05). Higher youth and long-term dietary calcium intake was not associated with the risk of IFG or T2D among females or males after adjustment for confounders, including youth and adult body mass index. Conclusions Youth or long-term dietary calcium intake is not associated with adult risk of developing impaired glucose metabolism or T2D.

Background and aims In the 1960s and 1970s, Finland, mortality due to coronary heart disease (CHD) was over 30% higher among Finns residing in the east of the country compared with those residing in the west. Today, CHD mortality remains 20% higher among eastern Finns. The higher incidence of CHD mortality among eastern Finns has largely been explained by higher risk factor levels. Using a unique longitudinal cohort, we aimed to determine if participants who resided in eastern Finland during childhood had higher CHD risk factors in adulthood and from childhood to adulthood. Methods The study population included 2063 participants of the Cardiovascular Risk in Young Finns Study, born during the period 1962–1977, with risk factor data available from baseline (1980) when participants were aged 3–18 years, and had risk factor data collected again in adulthood (2011) when aged 34–49 years. Results Adult CHD risk factor profile was similar for those who resided in eastern or western Finland in childhood. Over life-course from 1980 to 2011, those subjects with childhood residency in eastern Finland had, on average, higher systolic (p = 0.006) and diastolic (p = 0.0009) blood pressures, total (p = 0.01) and LDL-cholesterol (p = 0.01), triglycerides (p = 0.04), apoB (p = 0.02), and serum glucose (p Conclusions Our sample of adult Finns aged 34–49 years had a similar CHD risk factor profile irrespective of whether they resided in eastern or western Finland during their childhood. However, when considering participants risk factor profiles over a 31-year period, those who resided in eastern Finland in childhood were associated with a less favorable CHD risk factor profile than those who resided in western Finland in childhood. The observed differences suggest that future CHD mortality might remain higher in eastern Finland compared with western Finland.

The relationship between single measures of systolic blood pressure (SBP) in youth and adult levels is weak. We sought to define trajectories of SBP over childhood to determine ability to predict adult hypertension (HTN). In the International Childhood CV Cohort (i3C) Consortium, we constructed SBP trajectories in 11,482 participants (mean age 8.0 + 2.0 years at time of first measure, 47% male, 25% non-Caucasian) who had at least 3 SBPs in youth between the ages of 4 and

Background: Cardiovascular risk factors, such as high blood pressure, adverse serum lipids, and elevated body mass index in midlife, may harm cognitive performance. It is important to note that longitudinal accumulation of cardiovascular risk factors since childhood may be associated with cognitive performance already since childhood, but the previous evidence is scarce. We studied the associations of cardiovascular risk factors from childhood to midlife, their accumulation, and midlife cognitive performance. Methods: From 1980, a population-based cohort of 3596 children (3–18 years of age) have been repeatedly followed up for 31 years. Blood pressure, serum lipids, and body mass index were assessed in all follow-ups. Cardiovascular risk factor trajectories from childhood to midlife were identified using latent class growth mixture modeling. Cognitive testing was performed in 2026 participants 34 to 49 years of age using a computerized test. The associations of the cardiovascular risk factor trajectories and cognitive performance were studied for individual cardiovascular risk factors and cardiovascular risk factor accumulation. Results: Consistently high systolic blood pressure (β=–0.262 SD [95% CI, –0.520 to –0.005]) and serum total cholesterol (β=–0.214 SD [95% CI, –0.365 to –0.064]) were associated with worse midlife episodic memory and associative learning compared with consistently low values. Obesity since childhood was associated with worse visual processing and sustained attention (β=–0.407 SD [95% CI, –0.708 to –0.105]) compared with normal weight. An inverse association was observed for the cardiovascular risk factor accumulation with episodic memory and associative learning ( P for trend=0.008; 3 cardiovascular risk factors: β=–0.390 SD [95% CI, –0.691 to –0.088]), with visual processing and sustained attention ( P for trendP for trend=0.048; 2 cardiovascular risk factors: β=–0.164 SD [95% CI, –0.318 to –0.010]). Conclusions: Longitudinal elevated systolic blood pressure, high serum total cholesterol, and obesity from childhood to midlife were inversely associated with midlife cognitive performance. It is important to note that the higher the number of cardiovascular risk factors, the worse was the observed cognitive performance. Therefore, launching preventive strategies against cardiovascular risk factors beginning from childhood might benefit primordial promotion of cognitive health in adulthood.