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Background: Elevated lipoprotein(a) [Lp(a)] is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. We examined its potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease (ASCVD). Methods: Lp(a) levels measured in youth 9 to 24 years of age were linked to adult ASCVD and carotid intima-media thickness in the YFS (Cardiovascular Risk in Young Finns Study), in which 95 of the original 3596 participants (2.7%) recruited as children have been diagnosed with ASCVD at a median of 47 years of age. Results observed in YFS were replicated with the use of data for White participants from the BHS (Bogalusa Heart Study). In BHS, 587 White individuals had data on youth Lp(a) (measured at 8–17 years of age) and information on adult events, including 15 cases and 572 noncases. Analyses were performed with the use of Cox proportional hazard regression. Results: In YFS, those who had been exposed to high Lp(a) level in youth [defined as Lp(a) ≥30 mg/dL] had ≈2 times greater risk of developing adult ASCVD compared with nonexposed individuals (hazard ratio, 2.0 [95% CI, 1.4–2.6]). Youth risk factors, including Lp(a), low-density lipoprotein cholesterol, body mass index, and smoking, were all independently associated with higher risk. In BHS, in an age- and sex-adjusted model, White individuals who had been exposed to high Lp(a) had 2.5 times greater risk (95% CI, 0.9–6.8) of developing adult ASCVD compared with nonexposed individuals. When also adjusted for low-density lipoprotein cholesterol and body mass index, the risk associated with high Lp(a) remained unchanged (hazard ratio, 2.4 [95% CI, 0.8–7.3]). In a multivariable model for pooled data, individuals exposed to high Lp(a) had 2.0 times greater risk (95% CI, 1.0–3.7) of developing adult ASCVD compared with nonexposed individuals. No association was detected between youth Lp(a) and adult carotid artery thickness in either cohort or pooled data. Conclusions: Elevated Lp(a) level identified in youth is a risk factor for adult atherosclerotic cardiovascular outcomes but not for increased carotid intima-media thickness.

Context Aging varies between individuals, with profound consequences for chronic diseases and longevity. One hypothesis to explain the diversity is a genetically regulated molecular clock that runs differently between individuals. Large human studies with long enough follow-up to test the hypothesis are rare due to practical challenges, but statistical models of aging are built as proxies for the molecular clock by comparing young and old individuals cross-sectionally. These models remain untested against longitudinal data. Objective We applied novel methodology to test if cross-sectional modeling can distinguish slow vs accelerated aging in a human population. Methods We trained a machine learning model to predict age from 153 clinical and cardiometabolic traits. The model was tested against longitudinal data from another cohort. The training data came from cross-sectional surveys of the Finnish population (n = 9708; ages 25-74 years). The validation data included 3 time points across 10 years in the Young Finns Study (YFS; n = 1009; ages 24-49 years). Predicted metabolic age in 2007 was compared against observed aging rate from the 2001 visit to the 2011 visit in the YFS dataset and correlation between predicted vs observed metabolic aging was determined. Results The cross-sectional proxy failed to predict longitudinal observations (R2 = 0.018%, P = 0.67). Conclusion The finding is unexpected under the clock hypothesis that would produce a positive correlation between predicted and observed aging. Our results are better explained by a stratified model where aging rates per se are similar in adulthood but differences in starting points explain diverging metabolic fates.

Background: Observational findings for high-density lipoprotein (HDL)-mediated cholesterol efflux capacity (HDL-CEC) and coronary heart disease (CHD) appear inconsistent, and knowledge of the genetic architecture of HDL-CEC is limited. Objectives: A large-scale observational study on the associations of HDL-CEC and other HDL-related measures with CHD and the largest genome-wide association study (GWAS) of HDL-CEC. Participants/methods: Six independent cohorts were included with follow-up data for 14,438 participants to investigate the associations of HDL-related measures with incident CHD (1,570 events). The GWAS of HDL-CEC was carried out in 20,372 participants. Results: HDL-CEC did not associate with CHD when adjusted for traditional risk factors and HDL cholesterol (HDL-C). In contradiction, almost all HDL-related concentration measures associated consistently with CHD after corresponding adjustments. There were no genetic loci associated with HDL-CEC independent of HDL-C and triglycerides. Conclusion: HDL-CEC is not unequivocally associated with CHD in contrast to HDL-C, apolipoprotein A-I, and most of the HDL subclass particle concentrations. publishedVersion

The randomized controlled Special Turku Coronary Risk Factor Intervention Project (STRIP) has completed a 20-year infancy-onset dietary counselling intervention to reduce exposure to atherosclerotic cardiovascular disease risk factors via promotion of a heart-healthy diet. The counselling on, e.g., low intake of saturated fat and cholesterol and promotion of fruit, vegetable, and whole-grain consumption has affected the dietary characteristics of the intervention participants. By leveraging this unique cohort, we further investigated whether this long-term dietary intervention affected the gut microbiota bacterial profile six years after the intervention ceased. Our sub-study comprised 357 individuals aged 26 years (intervention

We studied whether repeatedly measured weight gain from birth up to age 2 years associated with cardiometabolic health in young adulthood.Using the data collected in the longitudinal Special Turku Coronary Risk Factor Intervention Project, we investigated in 454 healthy subjects how early weight gain in six age intervals (birth to 7 months, 7-13 months, 13-18 months, 18-24 months, and birth to 13 and 24 months) associated with measures of cardiometabolic health at age 20 years. Linear regression analyses were controlled for (1) child's sex, intervention/control group, gestational age, baseline weight and change in length for each interval, and (2) parents' education, mother's weight before pregnancy, height and weight gain during pregnancy, and father's body mass index at the 7-month visit.Weight gain after the first year of life associated directly, when adjusted for traits of the child and parents, with systolic blood pressure, waist circumference and body mass index at age 20 years. In the fully adjusted analyses, weight gain from birth to 1 year and to 2 years of age associated inversely with insulin and insulin resistance. We found no association between early growth and diastolic blood pressure or serum lipids.Early weight gain during first 2 years of life may predict later markers of cardiometabolic health.

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.

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.

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.

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 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.

Supplemental Digital Content is available in the text., Background: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia. Methods: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake. Results: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16–3.07] mg/dL per allele; P

This study quantifies the causal effect of birth weight on cardiovascular biomarkers in adulthood using the Cardiovascular Risk in Young Finns Study (YFS). We apply a multivariable Mendelian randomization (MVMR) method that provides a novel approach to improve inference in causal analysis based on a mediation framework. The results show that birth weight is linked to triglyceride levels (β = -0.294; 95% CI [-0.591, 0.003]) but not to low-density lipoprotein (LDL) cholesterol levels (β = 0.007; 95% CI [-0.168, 0.183]). The total effect of birth weight on triglyceride levels is partly offset by a mediation pathway linking birth weight to adult BMI (β = 0.111; 95% CI [-0.013, 0.234]). The negative total effect is consistent with the fetal programming hypothesis. The positive indirect effect via adult BMI highlights the persistence of body weight throughout a person's life and the adverse effects of high BMI on health. The results are consistent with previous findings that both low birth weight and weight gain increase health risks in adulthood.

Background Quantification of metabolic changes over the human life course is essential to understanding ageing processes. Yet longitudinal metabolomics data are rare and long gaps between visits can introduce biases that mask true trends. We introduce new ways to process quantitative time-series population data and elucidate metabolic ageing trends in two large cohorts. Methods Eligible participants included 1672 individuals from the Cardiovascular Risk in Young Finns Study and 3117 from the Northern Finland Birth Cohort 1966. Up to three time points (ages 24–49 years) were analysed by nuclear magnetic resonance metabolomics and clinical biochemistry (236 measures). Temporal trends were quantified as median change per decade. Sample quality was verified by consistency of shared biomarkers between metabolomics and clinical assays. Batch effects between visits were mitigated by a new algorithm introduced in this report. The results below satisfy multiple testing threshold of P Results Women gained more weight than men (+6.5% vs +5.0%) but showed milder metabolic changes overall. Temporal sex differences were observed for C-reactive protein (women +5.1%, men +21.1%), glycine (women +5.2%, men +1.9%) and phenylalanine (women +0.6%, men +3.5%). In 566 individuals with ≥+3% weight gain vs 561 with weight change ≤−3%, divergent patterns were observed for insulin (+24% vs −10%), very-low-density-lipoprotein triglycerides (+32% vs −6%), high-density-lipoprotein2 cholesterol (−6.5% vs +4.7%), isoleucine (+5.7% vs −6.0%) and C-reactive protein (+25% vs −22%). Conclusion We report absolute and proportional trends for 236 metabolic measures as new reference material for overall age-associated and specific weight-driven changes in real-world populations.

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.

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.

Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10(−6)) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

Coronary heart disease begins in childhood and warrants prevention strategies such as dietary modification. The objective was to determine the effect of the Special Turku Coronary Risk Factor Intervention Project (STRIP) dietary intervention on food consumption and nutrient intake over 20-year intervention period. The STRIP is a prospective, randomized trial conducted between 1990 and 2011. Enrolled 6-month-old infants (n = 1062) were randomized to an intervention group (n = 540) receiving dietary counseling biannually from age 7 months to 20 years or control group (n = 522) not receiving any intervention. Food and nutrient intake was assessed annually using 4-day food records. A food-based diet score was calculated. The intervention led to (1) higher consumption of low-fat unsweetened dairy (β = 177.76, 95% CI 157.36–198.16 g/day), vegetable-oil based fats (β = 6.00, 5.37–6.63 g/day), fish (β = 2.45, 1.44–3.45 g/day), fiber-rich grain products (β = 5.53, 3.17–7.89 g/day), fruits/berries (β = 9.93, 4.44–15.43 g/day), vegetables (β = 11.95, 7.74–16.16 g/day); (2) lower consumption of desserts (β = − 4.10, 95% CI − 6.50 to − 1.70 g/day); (3) lower intake of sucrose (β = − 1.61, 95% CI − 2.88 to − 0.35 g/day), and higher intake of fiber (β = 0.83, 0.55–1.11 g/day), folate (β = 11.14, 95% CI 8.23–14.05 μg/day), vitamin D (β = 0.52, 0.39–0.64 μg/day), C (β = 8.08, 4.79–11.38 mg/day), E (β = 0.93, 0.81–1.05 mg/day), iron (β = 0.31, 0.18–0.44 mg/day), zinc (β = 0.29, 0.17–0.40 mg/day), magnesium (β = 12.17, 9.02–15.33 mg/day), sodium (β = 55.00, 24.40–85.60 mg/day), potassium (β = 157.11, 107.24–206.98 mg/day). No effect was found on nut/seed, red/processed meat, sugar-sweetened beverage, salty snack consumption, or vitamin A and calcium intake. Intervention effect was more pronounced in boys. The STRIP intervention improved children’s diet quality over 20 years, indicating that beneficial dietary changes can be introduced and sustained in youth.

Background Genetic variants may modify the associations of adiposity measures with blood pressure (BP) and hypertension. The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene is an attractive candidate. Aims To examine interaction effects between I/D polymorphism and adiposity measures (BMI, waist circumference, waist-to-hip ratio, and skinfold thickness) during childhood and adulthood in relation to adult BP and hypertension. Methods Data were available for 4835 participants from three prospective cohort studies. Multivariable linear regression models for adult SBP and DBP, and multivariable logistic regression models for hypertension were fit that included interaction effects between child or adult adiposity and I/D polymorphism. Results Evidence for interaction effects on BP/hypertension were found across the three studies. Compared with childhood measures, the effect modification appeared to be more consistent when using adult adiposity. In particular, the adverse effects of greater adult waist circumference on increasing adult SBP and DBP appeared to be larger among carriers of ACE DD (or GG) [adjusted linear regression coefficients 0.26, 95% CI (0.21–0.31) and 0.28 (0.24–0.32) for SBP and DBP, respectively] and ID (or AG) genotypes [0.25 (0.21–0.29) and 0.25 (0.21–0.28), respectively], whereas those with II (or AA) genotypes had smaller effects [0.15 (0.09–0.21) and 0.19 (0.13–0.23)]. Conclusion ACE genetic variation may modify the effect of adult adiposity on increasing BP and risk of hypertension in adulthood. Individuals with ACE DD (or GG) and/or ID (or AG) genotypes, compared with those with II (or AA) genotype, appear more vulnerable to the impact of excess adiposity.

Background and aims: Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme associated with artery wall inflammation. Previous studies have verified correlation between IDO activity and early signs of atherosclerosis especially in females. We aimed to elucidate the relationship between an estimate of IDO activity and atherosclerotic risk factors related to non-alchohol-fatty liver (NAFLD) in a 6- and 10-year follow-up. Methods: Estimates of IDO activity along with complete risk factor data were measured from females (n = 506; age 24–39) and males (n = 421; age 24–39) in 2001. Risk factor measurements were conducted again in 2007 and 2011. Statistical examinations were carried out by Pearson correlation and risk ratio analysis. Results: In females, age-adjusted IDO correlated with body mass index (BMI) (p = 0.0008), waist (p = 0.0009), C-reactive protein (CRP) (p = 0.0014) and logarithmically modified triglycerides (p = 0.0488) in 2007. Correlation remained significant with BMI (p = 0.0007) and waist (p = 0.0063) in 2011. In males, age-adjusted IDO correlated with waist (p = 0.0367) and high-density lipoprotein cholesterol (HDL-C) (p = 0.0489) in 2007. Correlation remained significant with HDL-C (p = 0.0348) in 2011. In risk ratio analysis, relationship between IDO and obesity was confirmed in females after 10 years (RR = 1.026, p = 0.0147, 95% CI) and in males after 6 and 10 years (RR = 1.019, p = 0.0091, 95% CI and RR = 1.015, p = 0.0404, 95% CI, respectively) when the data was adjusted for age and BMI. Conclusions: IDO activity correlated with obesity and factors related to NAFLD, namely obesity of visceral type, hypertriglyceridemia and CRP (in females), well-characterized risk factors for diabetes and atherosclerosis in 6- and 10-year follow-up in males and premenopausal females. publishedVersion

Education and risky health behaviors are strongly negatively correlated. Education may affect health behaviors by enabling healthier choices through higher disposable income, increasing information about the harmful effects of risky health behaviors, or altering time preferences. Alternatively, the observed negative correlation may stem from reverse causality or unobserved confounders. Based on the data from the Cardiovascular Risk in Young Finns Study linked to register-based information on educational attainment and family background, this paper identifies the causal effect of education on risky health behaviors. To examine causal effects, we used a genetic score as an instrument for years of education. We found that individuals with higher education allocated more attention to healthy habits. In terms of health behaviors, highly educated people were less likely to smoke. Some model specifications also indicated that the highly educated consumed more fruit and vegetables, but the results were imprecise in this regard. No causal effect was found between education and abusive drinking. In brief, inference based on genetic instruments showed that higher education leads to better choices in some but not all dimensions of health behaviors. publishedVersion

Background: Osteoporosis and atherosclerosis are complex multifactorial diseases sharing common risk factors and pathophysiological mechanisms suggesting that these are comorbidities. Omics studies identifying joint molecular markers associated with these diseases are sparse. Subjects and methods: Using liquid chromatography-tandem mass spectrometry, we quantified 437 molecular lipid species from the Young Finns Study cohort (aged 30–45 years and 57% women) and performed lipidome-wide multivariate analysis of variance (MANOVA) with early markers for both diseases. Carotid intima-media thickness for atherosclerosis measured with ultrasound and bone mineral density from distal radius and tibia for osteoporosis measured with peripheral quantitative computed tomography were used as early markers of the diseases. Results: MANOVA adjusted with age, sex and body mass index, identified eight statistically significant (adjusted p-value (padj) < 0.05) and 15 suggestively significant (padj < 0.25) molecular lipid species associated with the studied markers. Similar analysis adjusted additionally for smoking habit, physical activity and alcohol consumption identified four significant and six suggestively significant molecular lipid species. These most significant lipid classes/species jointly associated with the studied markers were glycerolipid/TAG(18:0/18:0/18:1), glycerophospholipid/PC(40:3), sphingolipid/Gb3(d18:1/22:0), and sphingolipid/Gb3(d18:1/24:0). Conclusion: Our results support the osteoporosis-atherosclerosis comorbidity hypothesis and present potential new joint lipid biomarkers for these diseases. publishedVersion

BACKGROUND AND OBJECTIVES: Cardiovascular risk factors, such as obesity, blood pressure, and physical inactivity, have been identified as modifiable determinants of left ventricular (LV) diastolic function in adulthood. However, the links between childhood cardiovascular risk factor burden and adulthood LV diastolic function are unknown. To address this lack of knowledge, we aimed to identify childhood risk factors associated with LV diastolic function in the participants of the Cardiovascular Risk in Young Finns Study. METHODS: Study participants (N = 1871; 45.9% men; aged 34–49 years) were examined repeatedly between the years 1980 and 2011. We determined the cumulative risk exposure in childhood (age 6–18 years) as the area under the curve for systolic blood pressure, adiposity (defined by using skinfold and waist circumference measurements), physical activity, serum insulin, triglycerides, total cholesterol, and high- and low-density lipoprotein cholesterols. Adulthood LV diastolic function was defined by using E/é ratio. RESULTS: Elevated systolic blood pressure and increased adiposity in childhood were associated with worse adulthood LV diastolic function, whereas higher physical activity level in childhood was associated with better adulthood LV diastolic function (P < .001 for all). The associations of childhood adiposity and physical activity with adulthood LV diastolic function remained significant (both P < .05) but were diluted when the analyses were adjusted for adulthood systolic blood pressure, adiposity, and physical activity. The association between childhood systolic blood pressure and adult LV diastolic function was diluted to nonsignificant (P = .56). CONCLUSIONS: Adiposity status and the level of physical activity in childhood are independently associated with LV diastolic function in adulthood.

We examined whether success in achieving the key targets of an infancy-onset 20-year dietary intervention was associated with blood pressure (BP) from infancy to young adulthood. In the prospective randomized STRIP (Special Turku Coronary Risk Factor Intervention Project; n=877 children), dietary counseling was provided biannually based on the Nordic Nutrition Recommendations primarily to improve the quality of dietary fat in children’s diets and secondarily to promote intake of vegetables, fruits, and whole grains. Dietary data and BP were accrued annually from the age of 13 months to 20 years. The dietary targets for fat quality were defined as the ratio of saturated fatty acids to monounsaturated and polyunsaturated fatty acids P =0.03) and diastolic BP (mean [SE] diastolic BP, 60.4 [0.2], 60.5 [0.2], 59.9 [0.2], and 59.9 [0.3] mm Hg; P =0.02). When the lowest age-specific quintile of dietary cholesterol was added as an additional target, the association with systolic BP remained significant ( P =0.047), but the association with diastolic BP attenuated ( P =0.13). Achieving the key targets of an infancy-onset 20-year dietary intervention, reflecting dietary guidelines, was favorably albeit modestly associated with systolic and diastolic BP from infancy to young adulthood. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00223600.

Background Low socio-economic position (SEP) is a risk factor for multiple health outcomes, but its molecular imprints in the body remain unclear. Methods We examined SEP as a determinant of serum nuclear magnetic resonance metabolic profiles in ∼30 000 adults and 4000 children across 10 UK and Finnish cohort studies. Results In risk-factor-adjusted analysis of 233 metabolic measures, low educational attainment was associated with 37 measures including higher levels of triglycerides in small high-density lipoproteins (HDL) and lower levels of docosahexaenoic acid (DHA), omega-3 fatty acids, apolipoprotein A1, large and very large HDL particles (including levels of their respective lipid constituents) and cholesterol measures across different density lipoproteins. Among adults whose father worked in manual occupations, associations with apolipoprotein A1, large and very large HDL particles and HDL-2 cholesterol remained after adjustment for SEP in later life. Among manual workers, levels of glutamine were higher compared with non-manual workers. All three indicators of low SEP were associated with lower DHA, omega-3 fatty acids and HDL diameter. At all ages, children of manual workers had lower levels of DHA as a proportion of total fatty acids. Conclusions Our work indicates that social and economic factors have a measurable impact on human physiology. Lower SEP was independently associated with a generally unfavourable metabolic profile, consistent across ages and cohorts. The metabolites we found to be associated with SEP, including DHA, are known to predict cardiovascular disease and cognitive decline in later life and may contribute to health inequalities.

BackgroundIndividuals who are obese in childhood have an elevated risk of cardiometabolic disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independent of adult adiposity, is unclear.Methods and ResultsWe conducted a multivariable Mendelian randomization (MR) study to simultaneously evaluate the effects of childhood and adulthood body size on over 100 systemic molecular biomarkers representing multiple metabolic pathways. We first validated UK Biobank-derived genetic risk scores using data on body mass index (BMI) measured during childhood (n=2,427, age: 3-18 years) and adulthood (n= 1,762, age: 34-49 years) from the Young Finns Study (YFS). Results indicated that the childhood score is a stronger predictor of childhood BMI (0.74 vs 0.62 area under the curve (AUC) for the childhood and adult scores respectively), whereas the adult score was a stronger predictor of adulthood BMI (0.57 vs 0.62 AUC). Two-sample MR analyses in a univariable setting using summary genome-wide association study (GWAS) data in up to 24,925 adults provided evidence of an effect of childhood body size on 42 of the 123 metabolic markers assessed (based on P-04). Undertaking multivariable MR analyses suggested that the effects for the majority of these metabolic biomarkers (35/42) substantially attenuated when accounting for adult body size. In further analyses, the biomarkers with the strongest evidence of mediating a long-term effect of adiposity on coronary artery disease (CAD) risk were those related to triglyceride-rich very-low-density lipoprotein particles. In contrast, the biomarkers which showed the strongest evidence of being directly influenced by childhood body size (amino acids leucine, isoleucine and tyrosine) provided little evidence that they mediate this effect on adult disease risk.ConclusionsThe effects of childhood adiposity on the majority of biomarkers investigated in this study were greatly attenuated when accounting for adult body size. This suggests that the detrimental impact of genetically predicted childhood adiposity on systemic metabolism, as well as subsequent later life risk of CAD, can likely be mitigated through lifestyle modifications during adolescence and early adulthood.

Context The influence of dietary pattern trajectories from youth to adulthood on adult glucose metabolism is unknown. Objective To identify dietary pattern trajectories from youth to adulthood and examine their associations with adult impaired fasting glucose (IFG). Methods Thirty-one-year population-based cohort study among 1007 youths aged 3-18 years at baseline in Finland. Diet intake was assessed in 1980, 1986, 2001, 2007, and 2011. Group-based trajectory modelling was used to identify dietary pattern (identified by factor analysis) trajectories. Adult IFG was measured by the latest available data from 2001, 2007, and 2011. Results Among 1007 participants, 202 (20.1%) developed IFG and 27 (2.7%) developed type 2 diabetes in adulthood (mean follow-up of 30.7 years; mean [SD] age 40.5 [5.0] years). Three dietary patterns were identified at baseline and were retained in 1986 and 2001: “Traditional Finnish,” “High carbohydrate,” and “Vegetables and dairy products.” Three different patterns were identified in 2007, which remained similar in 2011: “Traditional Finnish and high carbohydrate,” “Red meat,” and “Healthy.” Trajectories of increased or stably medium “red meat” pattern scores from youth to adulthood were detrimentally associated with IFG (relative risk 1.46, 95% CI 1.12-1.90 for Medium (M)-stable/M-large increase vs low-stable trajectory) after adjusting for confounders. This association was slightly reduced after further adjusting for long-term dietary fiber intake. Conclusion Trajectories of an increased or stably moderate adherence to a “red meat” dietary pattern from youth to adulthood are associated with higher risk of adult IFG. This association is partly explained by low dietary fiber intake.

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18–26 nm) (−0.02 SD LDL defined by particle size; 95% CI: −0.10 to 0.05 for CETP versus −0.24 SD, 95% CI −0.30 to −0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18–1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies., Inhibition of cholesteryl ester transfer protein does not affect size-specific low-density lipoprotein cholesterol, but may lower coronary heart disease risk by lowering cholesterol concentrations in other apolipoprotein-B containing atherogenic lipoproteins, and by lowering triglyceride content of high-density lipoprotein particles.

BACKGROUND: The association of dietary fat distribution with markers of subclinical atherosclerosis during early life is unknown. We examined whether success in achieving the main target of an infancy-onset dietary intervention based on the distribution of dietary fat was associated with aortic and carotid intima-media thickness (IMT) and distensibility from childhood to young adulthood. METHODS: In the prospective randomized controlled Special Turku Coronary Risk Factor Intervention Project trial, personalized dietary counseling was given biannually to healthy children from infancy to young adulthood. The counseling was based on Nordic Nutrition Recommendations, with the main aim of improving the distribution of dietary fat in children’s diets. IMT and distensibility of the abdominal aorta and common carotid artery were measured repeatedly at ages 11 (n = 439), 13 (n = 499), 15 (n = 506), 17 (n = 477), and 19 years (n = 429). The targeted distribution of dietary fat was defined as a ratio of saturated fatty acids to monounsaturated and polyunsaturated fatty acids of RESULTS: Individuals who achieved the main intervention target had lower aortic IMT (age- and sex-adjusted mean difference 10.4 µm; 95% confidence interval: 0.3 to 20.5 µm) and better aortic distensibility (0.13% per 10 mm Hg; 95% confidence interval: 0.00% to 0.26% per10 mm Hg) compared with their peers who did not meet the target. CONCLUSIONS: Achieving the main target of an infancy-onset dietary intervention, reflecting dietary guidelines, was favorably associated with aortic IMT and distensibility during the early life course. These data support the recommendation of favoring unsaturated fat to enhance arterial health.

OBJECTIVE We examined whether success in achieving the key targets of an infancy-onset 20-year dietary intervention associated with insulin sensitivity and serum lipids from early childhood to young adulthood. RESEARCH DESIGN AND METHODS The sample comprised 941 children participating in the prospective, randomized Special Turku Coronary Risk Factor Intervention Project (STRIP). Dietary counseling was given biannually based on the Nordic Nutrition Recommendations with the main aim to improve the quality of dietary fat in children’s diets and the secondary aim to promote intake of vegetables, fruits, and whole-grain products. Food records and serum lipid profile were studied annually from 1 to 20 years of age, and HOMA of insulin resistance (HOMA-IR) was assessed between 7 and 20 years of age. Meeting the intervention targets for quality of dietary fat was defined as the ratio of saturated fatty acids (SAFA) to monounsaturated and polyunsaturated fatty acids (MUFA + PUFA) RESULTS Participants in the intervention group had a higher probability of meeting the targets of SAFA/(PUFA + MUFA) 3 g/MJ (RR 1.37 [95% CI 1.04–1.80]). Participants who achieved more targets had lower HOMA-IR, lower concentrations of fasting serum glucose, insulin, LDL cholesterol, and non-HDL cholesterol, and a lower ratio of apolipoprotein (Apo) B/ApoA1 (P values all ≤0.003). CONCLUSIONS Achieving the key targets of an infancy-onset 20-year dietary intervention was associated with better insulin sensitivity and serum lipid profile throughout the early life course.

Background Indoleamine 2,3-dioxygenase (IDO) is an intracellular enzyme that has an important immunomodulator function. Human inflammatory response promotes upregulation of IDO level in blood. This may lead to suppression of inflammation in atherosclerotic vessel wall and consequently may slow the progression of the disease. Previous studies have shown that IDO activity correlates with early signs of atherosclerosis especially in females but is not an atherosclerosis-specific marker. Materials and methods IDO levels were measured from females (n=544; age 24–39; weight 40.5–134.4 kg) in 2001 along with several risk factors for atherosclerosis. Follow-up risk factor measurements were performed in 2007 and 2011. Here we aimed to elucidate the relationship between IDO measurements from 2001 and several atherosclerotic risk factors from 2007 and 2011 by analyzing correlations and risk ratios from the Cardiovascular Risk in Young Finns Study patient cohort. Results After age standardization, IDO correlated significantly with BMI (p=0.0008), waist (p=0.0009) and logarithmically modified triglycerides (p=0.0488) and CRP (p=0.0014) in female samples (n=434) from 2007. When female samples (n=384) from 2011 were examined, statistically significant correlations were discovered in BMI and Waist in both unadjusted (p Conclusions It is concluded that IDO activity forecasts obesity – a well-characterized risk factor for diabetes and atherosclerosis – in premenopausal females.

Introduction: Physical activity (PA) is important in the prevention and treatment of impaired glucose metabolism. However, association of physical inactivity during the transition between childhood and adulthood with glucose metabolism is unknown. Therefore, we studied the association of persistent physical inactivity since childhood with glucose metabolism in adulthood. Methods: Data were drawn from the ongoing, Cardiovascular Risk in Young Finns Study with repeated follow-ups between 1980 and 2011 (baseline age, 3-18 yr; n = 3596). Impaired glucose metabolism was defined as having impaired fasting glucose (6.1-6.9 mmol·L-1) or type 2 diabetes in adulthood. Leisure-time PA habits were repeatedly collected with a standardized questionnaire and expressed as a PA Index. Using PA Index, four groups were formed (n = 2000): 1) persistently low PA, 2) decreasingly active, 3) increasingly active, and 4) persistently active subjects. Poisson regression model was used to examine the association between PA groups and impaired glucose metabolism. Results: The proportion of the sample with impaired glucose metabolism was 16.1% in individuals with persistently low PA, 14.5% in decreasingly active, 6.8% in increasingly active, and 11.1% in persistently active. Compared with individuals with persistently low PA, age and sex-adjusted risk for impaired glucose metabolism were lower in those who increased PA (relative risk [RR], 0.47; 95% confidence interval [CI], 0.29-0.76) and in those who were persistently active (RR, 0.70; 95% CI, 0.51-0.97), but similar in those who decreased PA (RR, 0.93; 95% CI, 0.66-1.36). Conclusions: Persistently physically inactive lifestyle from youth to adulthood is associated with increased risk of impaired glucose metabolism in adulthood. Importantly, a moderate increase in PA lowered the risk. The results highlight the importance of avoiding physically inactive lifestyle at all stages of life.

Background: Differences in health behaviors partly explain the socioeconomic gap in cardiovascular health. We prospectively examined the association between childhood socioeconomic status (SES) and lifestyle factors in adulthood, and the difference of lifestyle factors according to childhood SES in multiple time points from childhood to adulthood. Methods and results: The sample comprised 3453 participants aged 3-18 years at baseline (1980) from the longitudinal Young Finns Study. The participants were followed up for 31 years (N = 1675-1930). SES in childhood was characterized as reported annual family income and classified on an 8-point scale. Diet, smoking, alcohol intake and physical activity were used as adult and life course lifestyle factors. Higher childhood SES predicted a healthier diet in adulthood in terms of lower consumption of meat (beta +/- SE -3.6 +/- 0.99, p

Background: Data suggest that the prediction of adult cardiovascular disease using a model comprised entirely of adult nonlaboratory-based risk factors is equivalent to an approach that additionally incorporates adult lipid measures. We assessed and compared the utility of a risk model based solely on nonlaboratory risk factors in adolescence versus a lipid model based on nonlaboratory risk factors plus lipids for predicting high-risk carotid intima-media thickness (cIMT) in adulthood. Methods: The study comprised 2893 participants 12 to 18 years of age from 4 longitudinal cohort studies from the United States (Bogalusa Heart Study and the Insulin Study), Australia (Childhood Determinants of Adult Health Study), and Finland (The Cardiovascular Risk in Young Finns Study) and followed into adulthood when cIMT was measured (mean follow-up, 23.4 years). Overweight status was defined according to the Cole classification. Hypertension was defined according to the Fourth Report on High Blood Pressure in Children and Adolescents from the National High Blood Pressure Education Program. High-risk plasma lipid levels were defined according to the National Cholesterol Education Program Expert Panel on Cholesterol Levels in Children. High cIMT was defined as a study-specific value ≥90th percentile. Age and sex were included in each model. Results: In univariate models, all risk factors except for borderline high and high triglycerides in adolescence were associated with high cIMT in adulthood. In multivariable models (relative risk [95% confidence interval]), male sex (2.7 [2.0–2.6]), prehypertension (1.4 [1.0–1.9]), hypertension (1.9 [1.3–2.9]), overweight (2.0 [1.4–2.9]), obesity (3.7 [2.0–7.0]), borderline high low-density lipoprotein cholesterol (1.6 [1.2–2.2]), high low-density lipoprotein cholesterol (1.6 [1.1–2.1]), and borderline low high-density lipoprotein cholesterol (1.4 [1.0–1.8]) remained significant predictors of high cIMT ( P P =0.02). Conclusions: Nonlaboratory-based risk factors and lipids measured in adolescence independently predicted preclinical atherosclerosis in young adulthood. The addition of lipid measurements to traditional clinic-based risk factor assessment provided a statistically significant but clinically modest improvement on adolescent prediction of high cIMT in adulthood.

The aim of the present study was to examine whether pulse wave velocity (PWV) predicts the progression of blood pressure and the development of hypertension in young adults. In addition, we studied whether PWV improves the risk prediction of incident hypertension beyond traditional cardiovascular risk factors. Systolic and diastolic blood pressures were measured in 2007 and 2011 for 1449 Finnish adults (aged 30–45 years). In addition, PWV and other cardiovascular risk factors were measured in 2007. The association between PWV (in 2007) and blood pressure (in 2011) was studied in the whole population (n=1449) and in a normotensive subpopulation (n=1183). The ability of PWV measured in 2007 to predict incident hypertension in 2011 was investigated in the subpopulation (n=1183). PWV measured in 2007 was directly and independently associated with systolic and diastolic blood pressures measured in 2011 ( P P P =0.040), and the continuous net reclassification improvement 59.4% ( P

Sugar-sweetened beverages (SSBs) are a major dietary contributor to fructose intake. A molecular pathway involving the carbohydrate responsive element-binding protein (ChREBP) and the metabolic hormone fibroblast growth factor 21 (FGF21) may influence sugar metabolism and, thereby, contribute to fructose-induced metabolic disease. We hypothesise that common variants in 11 genes involved in fructose metabolism and the ChREBP-FGF21 pathway may interact with SSB intake to exacerbate positive associations between higher SSB intake and glycaemic traits. Data from 11 cohorts (six discovery and five replication) in the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium provided association and interaction results from 34,748 adults of European descent. SSB intake (soft drinks, fruit punches, lemonades or other fruit drinks) was derived from food-frequency questionnaires and food diaries. In fixed-effects meta-analyses, we quantified: (1) the associations between SSBs and glycaemic traits (fasting glucose and fasting insulin); and (2) the interactions between SSBs and 18 independent SNPs related to the ChREBP-FGF21 pathway. In our combined meta-analyses of discovery and replication cohorts, after adjustment for age, sex, energy intake, BMI and other dietary covariates, each additional serving of SSB intake was associated with higher fasting glucose (β ± SE 0.014 ± 0.004 [mmol/l], p = 1.5 × 10−3) and higher fasting insulin (0.030 ± 0.005 [log e pmol/l], p = 2.0 × 10−10). No significant interactions on glycaemic traits were observed between SSB intake and selected SNPs. While a suggestive interaction was observed in the discovery cohorts with a SNP (rs1542423) in the β-Klotho (KLB) locus on fasting insulin (0.030 ± 0.011 log e pmol/l, uncorrected p = 0.006), results in the replication cohorts and combined meta-analyses were non-significant. In this large meta-analysis, we observed that SSB intake was associated with higher fasting glucose and insulin. Although a suggestive interaction with a genetic variant in the ChREBP-FGF21 pathway was observed in the discovery cohorts, this observation was not confirmed in the replication analysis. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005121 (Framingham Offspring Study), NCT00005487 (Multi-Ethnic Study of Atherosclerosis) and NCT00005152 (Nurses’ Health Study).

Objectives: To determine whether vitamin D status in childhood and adolescence (herein collectively referred to as youth) and the long-term status from youth to adulthood is associated with risk of developing type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) in adulthood. Materials and methods: This was a 31-year follow-up study of 2300 participants aged 3–18 years. Multinomial logistic regression was used to assess the association of both (a) baseline 25-hydroxyvitamin D (25OHD) levels and (b) the mean of baseline and the latest follow-up 25OHD levels (continuous variable and quartiles) with incident T2DM and IFG (cut-off = 5.6 mmol/L) in adult life. Results: High serum 25OHD levels in youth and also mean values from youth to adulthood were associated with reduced risk of developing T2DM in adulthood (odds ratio, 95% confidence interval= 0.73, 0.57–0.95 and 0.65, 0.51–0.84, respectively, for each SD increment in 25OHD). Compared to Q1, a dose-dependent negative association was observed across other quartiles of youth 25OHD, while the strongest association was found in the Q3 for the mean 25OHD levels. Neither youth nor the mean 25OHD was associated with IFG. Conclusions: High serum 25OHD levels in youth, and from child to adult life, were associated with a reduced risk of developing T2DM in adulthood.Key MessagesHigh serum 25OHD levels in youth, and between youth and adulthood, were associated with a lower risk of T2DM in adulthood.Each SD (15.2 nmol/L) increment in youth serum 25OHD levels was associated with a 26% reduction in odds for T2DM, which was independent of a number of confounding variables and other risk factors for T2DM. A similar magnitude of association was observed for the long-term 25OHD levels between youth and adulthood.These findings suggest a potentially simple and cost-effective strategy for reducing adulthood risk of T2DM starting in an earlier stage of life – improving and maintaining vitamin D status throughout youth and early adulthood. High serum 25OHD levels in youth, and between youth and adulthood, were associated with a lower risk of T2DM in adulthood. Each SD (15.2 nmol/L) increment in youth serum 25OHD levels was associated with a 26% reduction in odds for T2DM, which was independent of a number of confounding variables and other risk factors for T2DM. A similar magnitude of association was observed for the long-term 25OHD levels between youth and adulthood. These findings suggest a potentially simple and cost-effective strategy for reducing adulthood risk of T2DM starting in an earlier stage of life – improving and maintaining vitamin D status throughout youth and early adulthood.

ObjectiveAortic sinus dilatation can lead to aortic valve regurgitation or even aortic dissection. Our objective was to examine the association between body surface area (BSA) measures from childhood to middle age and aortic sinus diameter in middle age. Understanding the relation of these two clarifies how aortic size is normally determined.MethodsCardiovascular Risk in Young Finns Study is a longitudinal study with follow-up of over 31 years (1980–2011). The study comprises information of body composition from multiple time points of 1950 subjects with cardiac ultrasound measurements made in 2011. The association between BSA in different ages and aortic sinus diameter in middle age was analysed by linear regression modelling adjusted with age, sex and diastolic blood pressure. Missing BSA values were derived for each life year (ages 3–33 years) from subject-specific curves for body weight and height estimated from longitudinal measurements using mixed model regression splines.ResultsBSA estimates in early 20s are most strongly associated with aortic sinus diameter in middle age. Top association was observed at age 23 years with one SD increase in estimated BSA corresponding to 1.04 mm (0.87–1.21 mm) increase in aortic diameter. Increase in body weight beyond early 20s does not associate with aortic sinus diameter, and the association between middle age BSA and aortic size is substantially weaker (0.74 mm increase (0.58–0.89 mm)). These results were confirmed in a subpopulation using only measured data.ConclusionThe association between aortic sinus diameter and BSA is stronger when considering BSA in young adulthood compared with BSA in middle age.

Increasing evidence supports the importance of socioeconomic factors in the development of atherosclerotic cardiovascular disease. However, the association of childhood socioeconomic status (SES) with arterial stiffness in adulthood has not been reported. Our aim was to determine whether higher childhood family-level SES is associated with lower arterial stiffness in adulthood. The analyses were performed using data gathered within the longitudinal Young Finns Study. The sample comprised 2566 participants who had data concerning family SES at ages 3 to 18 years in 1980 and arterial pulse wave velocity and carotid artery distensibility measured 21 or 27 years later in adulthood. Higher family SES in childhood was associated with lower arterial stiffness in adulthood; carotid artery distensibility being higher ( β value±SE, 0.029±0.0089%/10 mm Hg; P =0.001) and pulse wave velocity lower ( β value±SE, −0.062±0.022 m/s; P =0.006) among those with higher family SES in a multivariable analysis adjusted with age, sex, and conventional childhood cardiometabolic risk factors. The association remained significant after further adjustment for participant’s SES in adulthood ( β value±SE, 0.026±0.010%/10 mm Hg; P =0.01 for carotid artery distensibility and β value±SE, −0.048±0.023 m/s; P =0.04 for pulse wave velocity) but attenuated after adjustment for adulthood cardiometabolic risk factors ( β value±SE, 0.015±0.008%/10 mm Hg; P =0.08 for carotid artery distensibility and β value±SE, −0.019±0.02 m/s; P =0.38 for pulse wave velocity). In conclusion, we observed an association between higher family SES in childhood and lower arterial stiffness in adulthood. Our findings suggest that special attention could be paid to children from low SES families to prevent cardiometabolic diseases primordially.

Importance Elevated non–high-density lipoprotein cholesterol (non–HDL-C) is associated with the presence of coronary artery calcification (CAC), a marker of heart disease in adulthood. However, the relative importance of non–HDL-C levels at specific life stages for CAC remains unclear. Objective To identify the relative association of non–HDL-C measured at distinct life stages (adolescence, young adulthood, mid-adulthood) with the presence of CAC measured in mid-adulthood. Design, Setting, and Participants The Cardiovascular Risk in Young Finns Study is a population-based prospective cohort study that started in 1980 with follow-up over 28 years. Participants from 3 population centers (Kuopio, Tampere, and Turku in Finland) represent a convenience sample drawn from the 3 oldest cohorts at baseline (aged 12-18 years in 1980). Data were collected from September 1980 to August 2008. Analysis began February 2020. Exposures Non–HDL-C levels were measured at 3 life stages including adolescence (aged 12-18 years), young adulthood (aged 21-30 years), and mid-adulthood (aged 33-45 years). Main Outcomes and Measures In 2008, CAC was determined from computed tomography and dichotomized as 0 (no CAC, Agatston score = 0) and 1 (presence of CAC, Agatston score ≥1) for analysis. Using a bayesian relevant life course exposure model, the relative association was determined between non–HDL-C at each life stage and the presence of CAC in mid-adulthood. Results Of 589 participants, 327 (56%) were female. In a model adjusted for year of birth, sex, body mass index, systolic blood pressure, blood glucose level, smoking status, lipid-lowering and antihypertensive medication use, and family history of heart disease, cumulative exposure to non–HDL-C across all life stages was associated with CAC (odds ratio [OR], 1.50; 95% credible interval [CrI], 1.14-1.92). At each life stage, non–HDL-C was associated with CAC and exposure to non–HDL-C during adolescence had the strongest association (adolescence: OR, 1.16; 95% CrI, 1.01-1.46; young adulthood: OR, 1.14; 95% CrI, 1.01-1.43; mid-adulthood: OR, 1.12; 95% CrI, 1.01-1.34). Conclusions and Relevance These data suggest that elevated non–HDL-C levels at all life stages are associated with coronary atherosclerosis in mid-adulthood. However, adolescent non–HDL-C levels showed the strongest association with the presence of CAC in mid-adulthood, and greater awareness of the importance of elevated non–HDL-C in adolescence is needed.

Fatty liver is an expanding health concern associated with metabolic disturbances and increased risk of cardiovascular disease. Experimental studies in animals have shown associations between fatty liver and cardiorespiratory fitness but limited data exist in humans. The aim of this study was to analyze the links between cardiorespiratory fitness and fatty liver in a population-based sample of adults.Participants were 463 adults (48% men) from the Cardiovascular Risk in Young Finns Study. Cardiorespiratory fitness was measured with a cycle ergometer exercise test as peak oxygen uptake (V˙O2peak [mL·kg·min]) in 2008 to 2009. Hepatic ultrasonographic imaging was performed in 2011 to determine fatty liver.Cardiorespiratory fitness was associated with lower risk of fatty liver (1 mL·kg·min increase in V˙O2peak: risk ratio, 0.90; 95% confidence interval, 0.88-0.93, P0.0001; adjusted for age and sex). This association remained significant after further adjustments with physical activity, adiposity, smoking, alcohol consumption, serum lipids, insulin, glucose, and C-reactive protein. Participants who were obese (waist circumference,80 cm in women and94 cm in men) but fit (V˙O2peak in the upper age- and sex-specific median) had lower prevalence of fatty liver than participants who were obese and unfit (below median), (11.7% vs 34.8%, P = 0.0003).In a population-based sample of adults, cardiorespiratory fitness is strongly, inversely and independently related with the risk of fatty liver. Importantly, the association is evident also among obese.

Background The child-oriented dietary intervention given in the prospective Special Turku Coronary Risk Factor Intervention Project (STRIP) has decreased the intake of saturated fat and lowered serum cholesterol concentration in children from infancy until early adulthood. In this study, we investigated whether the uniquely long-term child-oriented intervention has affected also secondarily parental diet and cardio-metabolic risk factors. Methods The STRIP study is a longitudinal, randomized infancy-onset atherosclerosis prevention trial continued from the child's age of 8 months to 20 years. The main aim was to modify the child's diet towards reduced intake of saturated fat. Parental dietary intake assessed by a one-day food record and cardio-metabolic risk factors were analysed between the child's ages of 9-19 years. Results Saturated fat intake of parents in the intervention group was lower [mothers: 12.0 versus 13.9 daily energy (E%), p 0.0001; fathers: 12.5 versus 13.9 E%, p 0.0001] and polyunsaturated fat intake was higher (mothers: 6.1 versus 5.4 E%, p 0.0001; fathers: 6.3 versus 5.9 E%, p = 0.0003) compared with the control parents. Maternal total and low-density lipoprotein cholesterol concentrations were lower in the intervention compared with the control group (mean ± SE 5.02 ± 0.04 versus 5.14 ± 0.04 mmol/l, p = 0.04 and 3.19 ± 0.04 versus 3.30 ± 0.03 mmol/l, p = 0.03, respectively). Paternal cholesterol values did not differ between the intervention and control groups. Other cardio-metabolic risk factors were similar in the study groups. Conclusions Child-oriented dietary intervention shifted the dietary fat intakes of parents closer to the recommendations and tended to decrease total and low-density lipoprotein cholesterol in the intervention mothers. Dietary intervention directed to children benefits also parents.

Introduction: Type 2 diabetes is a public health concern, but psychosocial factors that may protect against the disease are unknown. This study examines whether a positive psychosocial environment in childhood is associated with lower risk for Type 2 diabetes in adulthood or healthier glucose trajectories over the life course, and whether BMI mediates the associations. Methods: A cohort of 3,596 Finnish children was followed into adulthood over 32 years. An overall positive psychosocial score, consisting of six subdomains, was measured at study baseline (1980). Relative risk ratios and multilevel growth curve modeling were used to examine associations of the psychosocial score with Type 2 diabetes (2012) and glucose trajectories (1986-2012). The mediating effect by BMI was examined using mediation analysis. The analyses were conducted between June 2015 and January 2016. Results: There was a 21% decrease in the rate of Type 2 diabetes (relative risk ratio, 0.79; 95% CI = 0.66, 0.94) for each 1-SD increase in the positive psychosocial score after adjustment for childhood cardiovascular risk factors and dietary behaviors. Adult BMI mediated 52% and weight gain mediated 25% of the association. The growth curve model showed healthier glucose trajectories (age X psychosocial score interaction, b = -0.01; p = 0.010) for participants with higher versus lower positive psychosocial score in childhood. Conclusions: Positive psychosocial environment in childhood seems to have beneficial influences on the risk for Type 2 diabetes over the life span. RCTs will be required to see if interventions directed at early-life circumstances are warranted. (C) 2017 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Background In adults, high blood pressure (BP), adverse serum lipids, and smoking associate with cognitive deficits. The effects of these risk factors from childhood on midlife cognitive performance are unknown. Objectives This study sought to investigate the associations between childhood/adolescence cardiovascular risk factors and midlife cognitive performance. Methods From 1980, a population-based cohort of 3,596 children (baseline age: 3 to 18 years) have been followed for 31 years in 3- to 9-year intervals. BP, serum lipids, body mass index, and smoking were assessed in all follow-ups. Cumulative exposure as the area under the curve for each risk factor was determined in childhood (6 to 12 years), adolescence (12 to 18 years), and young adulthood (18 to 24 years). In 2011, cognitive testing was performed in 2,026 participants aged 34 to 49 years. Results High systolic BP, elevated serum total-cholesterol, and smoking from childhood were independently associated with worse midlife cognitive performance, especially memory and learning. The number of early life risk factors, including high levels (extreme 75th percentile for cumulative risk exposure between ages 6 and 24 years) of systolic BP, total-cholesterol, and smoking associated inversely with midlife visual and episodic memory and visuospatial associative learning (–0.140 standard deviations per risk factor, p Conclusions Cumulative burden of cardiovascular risk factors from childhood/adolescence associate with worse midlife cognitive performance independent of adulthood exposure.

Background: Traditionally, a self-reported questionnaire has been a cost-effective method of gathering information about physical activity (PA). An objective measurement, such as the use of a pedometer, can be used to validate the findings of a PA questionnaire in a large population. Objective: The study objective was to determine the convergent validity of a PA questionnaire against objectively measured PA in adults obtained with the use of a pedometer. Methods: Data from the Cardiovascular Risk in Young Finns Study (YFS) were collected from 1853 participants aged 30 - 45 years. The participants completed a self-reported questionnaire that included items on leisure time, commuting and habitual PA. PA was expressed as leisure-time physical activity index (PAI) and metabolic equivalent hours/week (METh/wk). The participants wore a pedometer for seven consecutive days and used it to record their total daily and aerobic steps. Results: There was a low to moderate association between the self-reported questionnaire and pedometer measurements regarding both total steps and aerobic steps taken during leisure time and commuting PA. An association was not observed between pedometer data and habitual PA. Of the individual items in the questionnaire, questions that described the frequency of PA and the duration of vigorous PA correlated the most strongly with the pedometer values obtained for total and aerobic steps (r = 0.28 - 0.44, p ≤ 0.010). Conclusions: These findings suggest that the YFS PA questionnaire showed acceptable convergent validity in assessing, in particular, exercise-type PA in an adult population. peerReviewed