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Background— Adolescent metabolic syndrome (MetS) predicts type 2 diabetes mellitus and subclinical atherosclerosis in adulthood. Our aim was to establish the relationship between an infancy-onset dietary intervention and risk of having MetS between 15 and 20 years of age. Methods and Results— The Special Turku Coronary Risk Factor Intervention Project for Children (STRIP) study is a longitudinal, randomized atherosclerosis prevention trial in which repeated dietary counseling aiming at reducing intake of saturated fat took place from infancy to early adulthood. Participants who had complete data on the MetS components (waist circumference, blood pressure, triglycerides, glucose, high-density lipoprotein cholesterol) at 15 (n=512), 16 (n=485), 17 (n=475), 18 (n=459), 19 (n=439), and 20 (n=407) years of age were included in the study. Modified International Diabetes Foundation criteria with 80th/20th percentile cutoff points for the components were primarily applied in statistical analyses, and the results were replicated with the use of other pediatric MetS definitions. Between the ages of 15 and 20 years, the prevalence of MetS varied between 6.0% and 7.5% in participants in the intervention group and between 10% and 14% in the control group. The long-term relative risk of MetS was significantly lower in the intervention group (relative risk, 0.59; 95% confidence interval, 0.40–0.88; P =0.009). Of the individual MetS components, the intervention decreased risk of high blood pressure in both sexes (relative risk, 0.83; 95% confidence interval, 0.70–0.99) and high triglycerides in male subjects (relative risk, 0.71; 95% confidence interval, 0.52–0.98). A statistically nonsignificant reduction was seen in the risk of high waist circumference in the intervention individuals (relative risk, 0.78; 95% confidence interval, 0.59–1.03). Conclusion— Repeated infancy-onset dietary intervention is effective in the prevention of MetS in adolescence. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00223600.

BACKGROUND AND OBJECTIVES: Fasting insulin concentrations are increasingly being used as a surrogate for insulin resistance and risk for type 2 diabetes (T2DM), although associations with adult outcomes are unclear. Our objective was to determine whether fasting insulin concentrations in childhood associate with later T2DM. METHODS: Fasting insulin values were available from 2478 participants in the longitudinal Cardiovascular Risk in Young Finns Study at baseline age 3 to 18 years, along with data on adult T2DM (N = 84, mean age = 39.6 years). RESULTS: Among 3- to 6-year-olds, a 1-SD increase in fasting insulin was associated with a relative risk (RR) of 2.04 (95% confidence interval [CI], 1.54–2.70) for later T2DM, which remained significant after we adjusted for BMI and parental history of T2DM. For those aged 9 to 18 years, a 1-SD increase in insulin was associated with an RR of 1.32 (95% CI, 1.06–1.65) for T2DM, but this became nonsignificant after we adjusted for BMI and parental history of T2DM. In the latter age group, a 1-SD increase in BMI was associated with an RR of 1.45 (95% CI, 1.21–1.73) for T2DM, with adjustment for insulin and parental history of T2DM not improving this association. BMI in younger children was not associated with later T2DM. In life course analyses, those with T2DM had higher fasting insulin levels in early childhood and later adulthood but not in peripubertal years. CONCLUSIONS: Elevated fasting insulin concentrations in early childhood, but not adolescence, are independently associated with an elevated risk of T2DM in adulthood.

Aims We investigated associations of pre-clinical coronary heart disease (CHD), adolescence and adulthood CHD risk factors, and epicardial fat volume (EFV), which is thought to influence CHD pathology. Methods and results EFV and coronary calcium scores were quantified using computed tomography imaging for 557 subjects from the Cardiovascular Risk in Young Finns Study in 2007. CHD risk marker levels were assessed repeatedly from 1980 to 2007. Carotid intima-media thickness (cIMT), carotid distensibility, and brachial flow-mediated dilatation were measured by vascular ultrasound in 2007. Increased EFV was cross-sectionally associated with male sex, increased waist circumference, body-mass index (BMI), cIMT, metabolic syndrome prevalence, levels of apolipoprotein B, total cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein, blood pressure, insulin, and fasting glucose, as well as ever smoking, alcoholic intake, and lower high-density lipoprotein cholesterol (HDL-C), carotid distensibility and physical activity in adulthood. In BMI-adjusted analyses, only apolipoprotein B, ever smoking, alcohol intake and metabolic syndrome prevalence were independently associated with EFV. In adolescence, skinfold thickness, BMI, and insulin levels were higher and HDL-C lower with increasing EFV. Subjects in the lowest vs. highest quarter of EFV had consistently lower BMI across the early life-course. Conclusion Associations of CHD risk markers with EFV were attenuated after multivariable adjustment. We found no evidence of increased EFV being independently associated with pre-clinical atherosclerosis. EFV was most strongly associated with BMI and waist circumference. Subjects with higher EFV had consistently higher BMI from age 12 suggesting that life-long exposure to higher BMI influences the development of EFV.

Adenovirus-36 (Adv-36) infection is associated with exaggerated adipogenesis in cell culture and the development of obesity in animal models and humans, but a causal relationship remains unproven. Our objective was to determine whether serological evidence of Adv-36 infection in childhood and/or adulthood is associated with adult obesity.Paired plasma concentrations of Adv-36 antibodies were measured by a novel enzyme-linked immunosorbent assay in a subgroup (n=449) of the Cardiovascular Risk in Young Finns Study in childhood (mean age 11.9 years) and adulthood (mean age 41.3 years). The study group included (1) individuals who had maintained normal-weight status (2) those who became obese adults from a normal-weight status in childhood and (3) those that were overweight/obese as a child and obese as an adult.Mean (s.d.) time between baseline and follow-up was 29.4 (3.2) years (range 21-31 years). A total of 24.4% of individuals who were normal weight throughout life were seropositive for Adv-36 during child and/or adulthood as compared with 32.3% of those who became obese adults (P=0.11). Those who became obese in adulthood were more likely to be Adv-36 seropositive as adults compared with those who maintained normal weight (21.3% vs. 11.6%, P=0.02). This difference was mediated by a decline in Adv-36 seropositivity between child and adulthood in those maintaining normal weight. No differences were observed in body mass index across the life course, nor in waist circumference in adult life, between those who were Adv-36 seronegative or seropositive at any age.Individuals who gained weight across the life course were more likely to be Adv-36 seropositive in adult life than those who did not gain weight. However, analysis of change in weight status in relation to Adv-36 positivity did not support a causal role for Adv-36 in the development of obesity.

BACKGROUND The causal role of circulating sex hormone-binding globulin (SHBG) for type 2 diabetes is controversial. Information on the relations between SHBG and new biomarkers of cardiometabolic risk is scarce. METHODS We applied quantitative nuclear magnetic resonance metabolomics in three Finnish population-based cohorts to comprehensively profile circulating lipids and metabolites and study their associations with SHBG. Mendelian randomization was used to examine potential causality of SHBG on the metabolic measures and insulin resistance. Prospective associations and causal effect estimates of SHBG on type 2 diabetes were assessed via meta-analysis including summary statistics from the DIAGRAM consortium. RESULTS In cross-sectional analysis in 6475 young adults (mean age 31, 57% men), higher SHBG was linked with a more favourable cardiometabolic risk profile, including associations with lipoprotein subclasses, fatty acid composition, amino acids, ketone bodies and inflammation-linked glycoproteins. Prospective analysis of 1377 young adults with 6-year follow-up indicated that SHBG is also associated with future insulin resistance. Mendelian randomization suggested only minor, if any, causal effects of SHBG on lipid and metabolite measures and insulin resistance(n = 10,895).Causal effect estimates on type 2 diabetes for 41,439 cases and 103,870 controls indicated a causative protective role of SHBG (OR = 0.83 per 1-SD, 95% CI: 0.76, 0.91); however, effects were considerably weaker than observed in meta-analysis of prospective studies [hazard ratio (HR) = 0.47 per 1-SD, 95% CI: 0.41, 0.53]. CONCLUSION Circulating SHBG is strongly associated with systemic metabolism and predictive for insulin resistance and diabetes. The weaker causal estimates suggest that the observational associations are partly confounded rather than conferred directly via circulating SHBG.

Objective Most infections occur in pre-school children but the severity of the inflammatory response to common pathogens varies considerably. We examined the relationship between early childhood infections of sufficient severity to warrant hospitalisation, and markers of subclinical atherosclerosis in adulthood. Methods We investigated whether infection-related hospitalisation (IRH) in early childhood (0–5 years) was associated with adverse non-invasive phenotypes of atherosclerosis (carotid artery distensibility and intima-media thickness (IMT), and brachial artery flow-mediated dilation (FMD)) in adulthood in participants from the Cardiovascular Risk in Young Finns study. Analyses were adjusted for age, sex, and socioeconomic status and cardiovascular risk factors in childhood and adulthood. 1043 participants had lifetime IRH data with a mean age at adult follow-up of 33 years. Results Brachial FMD levels were significantly lower among individuals with early child IRH (mean ± SEM 8.15 ± 0.37 vs. 9.10 ± 0.16%, p = 0.03). These individuals had a 1.84% (95% CI 0.64–3.04, p = 0.002) greater decrease in FMD over a 6-year interval between two adult follow-ups at mean ages 27 and 33 years. Childhood IRH was associated with increased asymmetrical dimethylarginine (ADMA) in adulthood (0.62 ± 0.01 vs. 0.59 ± 0.01 μmol/l, p = 0.04), adjusted for age, sex, adult body mass index, and serum creatinine. Early childhood IRH was associated with lower carotid distensibility levels (1.95 ± 0.06 vs. 2.09 ± 0.02%/10 mmHg, p = 0.02), but not with carotid intima-media thickness (0.601 ± 0.006 vs. 0.596 ± 0.003 mm). All findings remained unchanged after adjustments for age, sex and conventional cardiovascular risk factors in childhood or adulthood. Conclusion Infection-related hospitalisation in the pre-school period was associated with adverse adult atherosclerotic phenotypes and increased ADMA. Infection may contribute to causal pathways leading to the development of endothelial dysfunction and early atherosclerosis.

Paraoxonase-1 (PON1) is suggested to have a role in the antioxidant activity of high-density lipoprotein (HDL). PON1 activity levels are strongly genetically determined by the rs662 polymorphism (PON1 Q192R). To clarify the role of PON1 in lipoprotein oxidation at the population level, we examined the relations between PON1 activity, the rs662 polymorphism and oxidized lipoprotein lipids in young adults.A population-based cross-sectional study of 1895 Finnish adults ages 24-39 years (872 males and 1023 females). PON1 activity was determined with paraoxon as the substrate. Analysis of oxidized lipids in isolated HDL (oxHDLlipids) and low-density lipoprotein (oxLDLlipids) was based on the determination of conjugated dienes. Oxidized LDL was also measured with a method based on antibodies against oxidized Apo-B (oxLDLprot). Serum lipids and apolipoproteins were measured. Genotyping was performed with the Illumina Bead Chip (Human 670 K).In multivariable models, PON1 activity associated inversely with oxLDLlipids (p = 0.0001, semi-partial R(2) = 0.09%), but it was not associated with oxHDLlipids (p = 0.93). There was a borderline significant association between PON1 activity and oxLDLprot (p = 0.08). PON1 rs662 polymorphism was strongly associated with PON1 activity (P-value0.0001), but not with oxidized lipoprotein lipids and oxLDLprot.Higher PON1 activity is associated with decreased oxLDLlipids levels, but not with oxHDLlipids in a population of young Finnish adults. These findings support the suggestion that PON1 activity may have a role in the oxidation of LDL lipids. There is a strong association between PON1 rs662 polymorphism and PON1 activity, but PON1 rs662 polymorphism is not associated with oxidized lipoprotein lipids and oxLDLprot.

Abstract— In adults, arterial distensibility decreases with age and relates to changes in cardiac left ventricular mass. Longitudinal data on changes in arterial distensibility from childhood to adulthood are lacking. Our aim was to study the effect of age and sex, and low-saturated fat dietary counseling on arterial distensibility from childhood to early adulthood. In addition, we assessed the association of arterial distensibility with left ventricular mass. Distensibility of the abdominal aorta and common carotid artery was measured repeatedly at ages 11, 13, 15, 17, and 19 years (n=395–472) in an atherosclerosis prevention trial (Special Turku Coronary Risk Factor Intervention Project [STRIP]). Aortic and carotid distensibility decreased with age (both P P P P P Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00223600.

Background— The association between passive smoking exposure in childhood and adverse cardiovascular health in adulthood is not well understood. Using a 26-year follow-up study, we examined whether childhood exposure to passive smoking was associated with carotid atherosclerotic plaque in young adults. Methods and Results— Participants were from the Cardiovascular Risk in Young Finns Study (n=2448). Information on childhood exposure to parental smoking was collected in 1980 and 1983. Carotid ultrasound data were collected in adulthood in 2001 or 2007. Childhood serum cotinine levels from 1980 were measured from frozen samples in 2014 (n=1578). The proportion of children with nondetectable cotinine levels was highest among households in which neither parent smoked (84%), was decreased in households in which 1 parent smoked (62%), and was lowest among households in which both parents smoked (43%). Regardless of adjustment for potential confounding and mediating variables, the relative risk of developing carotid plaque in adulthood increased among those children with 1 or both parents who smoked (relative risk, 1.7; 95% confidence interval, 1.0–2.8; P =0.04). Although children whose parents exercised good “smoking hygiene” (smoking parents whose children had nondetectable cotinine levels) had increased risk of carotid plaque compared with children with nonsmoking parents (relative risk, 1.6; 95% confidence interval, 0.6–4.0; P =0.34), children of smoking parents with poor smoking hygiene (smoking parents whose children had detectable serum cotinine levels) had substantially increased risk of plaque as adults (relative risk, 4.0; 95% confidence interval, 1.7–9.8; P =0.002). Conclusions— Children of parents who smoke have increased risk of developing carotid atherosclerotic plaque in adulthood. However, parents who exercise good smoking hygiene can lessen their child’s risk of developing plaque.

Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance., Author Summary Studies investigating the extent to which genetics influences human characteristics such as height have concentrated mainly on common variants of genes, where having one or two copies of a given variant influences the trait or risk of disease. This study explores whether a different type of genetic variant might also be important. We investigate the role of recessive genetic variants, where two identical copies of a variant are required to have an effect. By measuring genome-wide homozygosity—the phenomenon of inheriting two identical copies at a given point of the genome—in 35,000 individuals from 21 European populations, and by comparing this to individual height, we found that the more homozygous the genome, the shorter the individual. The offspring of first cousins (who have increased homozygosity) were predicted to be up to 3 cm shorter on average than the offspring of unrelated parents. Height is influenced by the combined effect of many recessive variants dispersed across the genome. This may also be true for other human characteristics and diseases, opening up a new way to understand how genetic variation influences our health.

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01–0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10−10, 6.0 × 10−5, and 2.9 × 10−3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders., Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.

Background and aims: Several genetic and environmental risk factors have been linked to chronic inflammatory bowel disease (IBD). The incidence of IBD has significantly increased in developed countries during last decades. The aim of the present study was to examine childhood risk factors for subsequent IBD diagnosis in a longitudinal cohort study of children and adolescents. Methods: A Finnish study population consisting of 3551 children and adolescents originally evaluated as part of the Cardiovascular Risk in Young Finns study in 1980. At baseline, participant BMI, insulin, lipid, C-reactive protein and blood pressure levels, socioeconomic position, dietary habits, and physical activity, were evaluated. In addition, information was gathered on rural residency, severe infections, breast feeding, parental smoking and birth weight. Subsequent IBD diagnosis status was evaluated based on nationwide registries on hospitalisations and drug imbursement decisions. Results: Altogether, 49 participants (1.4%) had IBD diagnosed during the 34 years of register follow-up, of which 31 had ulcerative colitis, 12 Crohn's disease and 6 undetermined colitis. In univariate analyses, significant correlations were observed between childhood HDL-cholesterol (risk ratio (95% CI) for 1-SD change (0.58 (0.42-0.79)) and CRP concentrations (1.20 (1.01-1.43)) with IBD. The inverse association between HDL-cholesterol and IBD remained significant (0.57 (0.39-0.82)) in a multivariable model including data on age, sex and CRP. In addition, a weighted genetic z-score of 71 single nucleotide polymorphisms associated with elevated HDL-cholesterol levels was significantly lower in IBD patients, p = 0.01). Conclusion: Low childhood HDL-cholesterol levels are associated with subsequent IBD diagnosis. In addition, a genetic risk score associated with low HDL-cholesterol levels predict later IBD suggesting that HDL-cholesterol metabolism might have a role in the pathogenesis of IBD. (C) 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background & aims: Gallstone disease is related to hypersecretion of cholesterol in bile, and low serum phytosterol levels. We examined how genetic polymorphisms of sterol transporters affect childhood cholesterol metabolism trait predicting adult gallstone disease. Patients and methods: In retrospective controlled study, we determined D19H polymorphism of ABCG8 gene, genetic variation at Niemann-Pick C1-like 1 (NPC1L1) gene locus (rs41279633, rs17655652, rs2072183, rs217434 and rs2073548), and serum cholesterol, noncholesterol sterols and lipids in children affected by gallstones decades later (n = 66) and controls (n = 126). Results: In childhood, phytosterols were lower (9.7%-23.4%) in carriers of risk allele 19H compared to 19D homozygotes. Lowest campesterol/cholesterol tertile consisted of 1.9-times more future gallstone subjects, and 3.7-times more 19H carriers than highest one. Campesterol/cholesterol-ratio was highest in 19D homozygote controls, but similar to 11% lower in gallstone 19D homozygotes and similar to 25% lower among gallstone and control carriers of 19H. Gallstone subjects with alleles CC of rs41279633 and TT of rs217434 of NPC1L1 had similar to 18% lower campesterol/cholesterol-ratio compared to mutation carriers. Conclusions: Risk trait of cholesterol metabolism (low phytosterols) in childhood favouring cholesterol gallstone disease later in adulthood is influenced by risk variant 19H of ABCG8 and obviously also other factors. NPC1L1 variants have minor influence on noncholesterol sterols. (c) 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

BACKGROUND AND OBJECTIVES: Youth with high BMI who become nonobese adults have the same cardiovascular risk factor burden as those who were never obese. However, the early-life BMI trajectories for overweight or obese youth who avoid becoming obese adults have not been described. We aimed to determine and compare the young-childhood BMI trajectories of participants according to their BMI status in youth and adulthood. METHODS: Bayesian hierarchical piecewise regression modeling was used to analyze the BMI trajectories of 2717 young adults who had up to 8 measures of BMI from childhood (ages 3–18 years) to adulthood (ages 34–49 years). RESULTS: Compared with those with persistently high BMI, those who resolved their high youth BMI by adulthood had lower average BMI at age 6 years and slower rates of BMI change from young childhood. In addition, their BMI levels started to plateau at 16 years old for females and 21 years old for males, whereas the BMI of those whose high BMI persisted did not stabilize until 25 years old for male subjects and 27 years for female subjects. Compared with those youth who were not overweight or obese and who remained nonobese in adulthood, those who developed obesity had a higher BMI rate of change from 6 years old, and their BMI continued to increase linearly until age 30 years. CONCLUSIONS: Efforts to alter BMI trajectories for adult obesity should ideally commence before age 6 years. The natural resolution of high BMI starts in adolescence for males and early adulthood for females, suggesting a critical window for secondary prevention.

Introducing nutritional principles of preventive cardiology to the care of young children may improve permanently adherence to a low-saturated-fat, low-cholesterol diet later in life. This approach has not been readily adapted because of worries of the possible effects of such a diet on the growth and development of children. In the STRIP baby project, 1062 infants were randomized at 7 months of age into an intervention group (n = 540) or a control group (n = 522). The counselling of the intervention children aimed at a fat intake of 30% of energy after the age of 1 year and to a 1:1:1 ratio in saturated:monounsaturated:polyunsaturated fat intake. Dietary intake, growth and serum lipid concentrations were monitored in the children regularly through the first years of life. The intake of total fat, saturated fat and cholesterol were lower and the intake of polyunsaturated fat and the ratio of polyunsaturated to saturated fat (P/S) in the diet were higher in the intervention children than in the controls. During the first 3 years of the trial, the serum cholesterol concentration was 3-6% lower in the intervention children than in the controls (95% CI for the mean difference between groups from -0.27 to-0.12 mmol/L). No differences in the growth of the children were observed between the groups. We conclude that repeated individualized counselling aiming at reduced consumption of saturated fat combined with regular follow-up is effective and does not restrict the growth of children.

The Cardiovascular Risk in Young Finns Study is a collaborative effort of all university departments of paediatrics and several other institutions in Finland to study the risk factors of coronary heart disease (CHD) and their determinants in children and adolescents in different parts of the country. The main cross-sectional study carried out in 1980 included 3596 3-18-year-old subjects. Follow-up studies have been performed in 1983, 1986, 1989 and 1992; in the last of these studies the subjects were 15-30 years old. The findings in anthropometry, obesity and blood pressure have been rather similar to reports from other countries in Europe. However, serum cholesterol and low-density lipoprotein cholesterol concentrations were higher than in other countries, 4.83 mmol/L and 3.09 mmol/L, respectively in 1980. By 1992 a decrease of 8% took place, probably as a result of dietary changes. Apolipoprotein phenotypes E4E4 or E4E3 were relatively frequent (34%) in the sample. Tracking and clustering have also been studied. Serum insulin levels predicted the clustering of the typical risk factor profile associated with insulin resistance syndrome. The dietary polyunsaturated to saturated fat (P/S) ratio increased from 0.26 in 1980 to 0.39 in 1992, with no significant changes in the total energy derived from fat. 'Hard-driving' was found to be the psychological risk factor most consistently related to the CHD risk factor level.

BACKGROUND Associations between dairy intake and body mass index (BMI) have been inconsistently observed in epidemiological studies, and the causal relationship remains ill defined. METHODS We performed Mendelian randomization (MR) analysis using an established dairy intake-associated genetic polymorphism located upstream of the lactase gene (LCT-13910 C/T, rs4988235) as an instrumental variable (IV). Linear regression models were fitted to analyze associations between (a) dairy intake and BMI, (b) rs4988235 and dairy intake, and (c) rs4988235 and BMI in each study. The causal effect of dairy intake on BMI was quantified by IV estimators among 184802 participants from 25 studies. RESULTS Higher dairy intake was associated with higher BMI (β = 0.03 kg/m2 per serving/day; 95% CI, 0.00–0.06; P = 0.04), whereas the LCT genotype with 1 or 2 T allele was significantly associated with 0.20 (95% CI, 0.14–0.25) serving/day higher dairy intake (P = 3.15 × 10−12) and 0.12 (95% CI, 0.06–0.17) kg/m2 higher BMI (P = 2.11 × 10−5). MR analysis showed that the genetically determined higher dairy intake was significantly associated with higher BMI (β = 0.60 kg/m2 per serving/day; 95% CI, 0.27–0.92; P = 3.0 × 10−4). CONCLUSIONS The present study provides strong evidence to support a causal effect of higher dairy intake on increased BMI among adults.

Background There is paucity of knowledge concerning the specific age in youth when the associations of metabolic syndrome (MetS) begin to be operative. Thus, we investigated the relation of age to the associations of childhood MetS with adult MetS, type 2 diabetes mellitus and high carotid intima‐media thickness. Methods and Results Five thousand eight‐hundred three participants were analyzed in 4 cohort studies (Cardiovascular Risk in Young Finns, Bogalusa Heart Study, Princeton Lipid Research Study, Insulin Study). International cutoffs and previously used 75th percentile cutoffs were used for children to define MetS and its components. Mean follow‐up period was 22.3 years. Logistic regression was used to calculate risk ratios and 95% confidence intervals. Childhood MetS and overweight were associated with over 2.4‐fold risk for adult MetS from the age of 5 years onward. Risk for type 2 diabetes mellitus was increased from the age of 8 (risk ratio, 2.6–4.1; 95% confidence interval, 1.35–6.76 and 1.12–7.24, respectively) onward for the 2 childhood MetS criteria based on international cut‐off values and for childhood overweight. Risk for high carotid intima‐media thickness was significant at ages 11 to 18 years in relation to childhood MetS or overweight (risk ratio, 2.44–4.22; 95% confidence interval, 1.55–3.55 and 2.55–5.66, respectively). Continuous childhood MetS score was associated with adult MetS from the age of 5, with type 2 diabetes mellitus from the age of 14 and with high carotid intima‐media thickness from the age of 11 years onward. Conclusions Adult MetS was predicted by MetS in childhood beginning at age 5. However, adult type 2 diabetes mellitus and subclinical atherosclerosis were not predicted by childhood data until after age 8. Body mass index measurement alone at the same age points provided similar findings.

Intergenerational continuity in parenting quality has been demonstrated but the mechanisms underlying this continuity are less understood. This study investigated whether the offspring personality and years of education mediate the continuity in qualities of the parent-child relationship and whether offspring personality moderates this association. The sample comprised 1308 Finnish offspring (G2; 62% female) and their mothers (G1). G1 (Mean age = 37.7) reported self-perceived qualities of the parent-child relationship in terms of emotional warmth and acceptance towards G2 aged 3-18 years in 1980. Thirty-two years later, once having become parents themselves, G2 (Mean age = 42.9) self-rated their own qualities of the parent-child relationship towards their children using the same scales. Between these follow-ups, G2 self-rated their personality (consisting of temperament and character traits) using the Temperament and Character Inventory and reported years of education. Results indicated that G2 character traits-Self-directedness and Cooperativeness-partially mediated the intergenerational continuity in self-perceived emotional warmth and explained 16% of this association. No mediating role of G2 temperament traits was found (all ps > .240). Character traits accounted for the indirect association better than education in a multiple mediator model. Moreover, no moderating role of either temperament or character traits was found (all psaEuroe.064). Study findings show that warm and accepting qualities of the parent-child relationship in childhood are related to offspring character traits that reflect personality maturity in adulthood, which in turn would predict their own positive parent-child relationship later in life.

Aim Children exposed to parental smoking are at increased long-term risk of subclinical atherosclerosis in adulthood. However, it has not been quantified if exposure to parental smoking in childhood is associated with adult systemic inflammation. This study aimed to determine if childhood exposure to parental smoking was associated with high-sensitivity C-reactive protein (hsCRP) in adulthood. Methods This longitudinal analysis of 2,511 participants used data from the Cardiovascular Risk in Young Finns Study, a prospective cohort of Finnish children. In 1980 or 1983, parents self-reported their smoking status and serum hsCRP was collected up to 31 years later in adulthood. Results Compared with children with non-smoking parents, the relative risk of developing high hsCRP (＞3 mg/L) in adulthood increased among those with 1 or both parents who smoked [relative risk (RR), 1.3; 95%confidence interval (CI), 1.0-1.8] after adjustment for socioeconomic status, cardiovascular risk factors, and smoking status in childhood and adulthood. Moreover, children exposed to mother smoking [RR, 2.4; 95% CI, 1.3-4.2] had highest risk of developing high hsCRP in adulthood compared with those exposed to father smoking [RR, 1.6; 95% CI, 1.2-2.3] and both parents smoking [RR, 1.4; 95% CI, 0.9-2.0]. Conclusion Our findings suggest that children exposed to parental smoking are at increased risk of having high hsCRP in adulthood. Limiting children's exposure to passive smoking may have long-term benefits on general low-grade inflammation.

We examined the intergenerational transmission of parent-child relationship qualities in a population-based Finnish sample of 1418 participants (G2) and their mothers (G1). At baseline, G1 (Mage=38) reported qualities of the parent-child relationship in terms of emotional warmth and acceptance towards G2 (age range 3-18). After 28years, G2 (Mage=39) rated the qualities of the parent-child relationship regarding their own children using the same questionnaire. Emotional warmth and acceptance were transmitted across generations even after controlling for demographic and family characteristics in both generations. The transmission was stronger for emotional warmth than acceptance. For emotional warmth, intergenerational transmission was stronger for men than women. The findings provide evidence for the long-term transmission of parenting quality across generations.

Increased left ventricular (LV) mass and diastolic dysfunction are associated with cardiovascular disease. Prospective data on effects of childhood socioeconomic status (SES) on measures of LV structure and function are lacking.To examine whether family SES in childhood was associated with LV mass and diastolic function after adjustment for conventional cardiovascular disease risk factors in childhood and adulthood.The analyses were performed in 2016 using data gathered in 1980 and 2011 within the longitudinal population-based Cardiovascular Risk in Young Finns Study. The sample comprised 1871 participants who reported family SES at ages 3 to 18 years and were evaluated for LV structure and function 31 years later.Socioeconomic status was characterized as annual income of the family and classified on a 3-point scale.Left ventricular mass indexed according to height at the allometric power of 2.7 and the E/e' ratio describing LV diastolic performance at ages 34 to 49 years.The participants were aged 3 to 18 years at baseline (mean [SD], 10.8 [5.0] years), and the length of follow-up was 31 years. Family SES was inversely associated with LV mass (mean [SD] LV mass index, 31.8 [6.7], 31.0 [6.6], and 30.1 [6.4] g/m2.7 in the low, medium, and high SES groups, respectively; differences [95% CI], 1.7 [0.6 to 2.8] for low vs high SES; 0.8 [-0.3 to 1.9] for low vs medium; and 0.9 [0.1 to 1.6] for medium vs high; overall P = .001) and E/e' ratio (mean [SD] E/e' ratio, 5.0 [1.0], 4.9 [1.0], and 4.7 [1.0] in the low, medium, and high SES groups, respectively; differences [95% CI], 0.3 [0.1 to 0.4] for low vs high SES; 0.1 [-0.1 to 0.3] for low vs medium; and 0.2 [0 to 0.3] for medium vs high; overall P.001) in adulthood. After adjustment for age, sex, and conventional cardiovascular disease risk factors in childhood and adulthood, and participants' own SES in adulthood, the relationship with LV mass (differences [95% CI], 1.5 [0.2 to 2.8] for low vs high SES; 1.3 [0 to 2.6] for low vs medium; and 0.2 [-0.6 to 1.0] for medium vs high; P = .03) and E/e' ratio (differences [95% CI], 0.2 [0 to 0.5] for low vs high SES; 0.1 [-0.1 to 0.4] for low vs medium; and 0.1 [0 to 0.3] for medium vs high; P = .02) remained significant.Low family SES was associated with increased LV mass and impaired diastolic performance more than 3 decades later. These findings emphasize that approaches of cardiovascular disease prevention must be directed also to the family environment of the developing child.

Background— Dyslipidemia is a major modifiable risk factor for cardiovascular disease. We examined whether the addition of novel single-nucleotide polymorphisms for blood lipid levels enhances the prediction of adult dyslipidemia in comparison to childhood lipid measures. Methods and Results— Two thousand four hundred and twenty-two participants of the Cardiovascular Risk in Young Finns Study who had participated in 2 surveys held during childhood (in 1980 when aged 3–18 years and in 1986) and at least once in a follow-up study in adulthood (2001, 2007, and 2011) were included. We examined whether inclusion of a lipid-specific weighted genetic risk score based on 58 single-nucleotide polymorphisms for low-density lipoprotein cholesterol, 71 single-nucleotide polymorphisms for high-density lipoprotein cholesterol, and 40 single-nucleotide polymorphisms for triglycerides improved the prediction of adult dyslipidemia compared with clinical childhood risk factors. Adjusting for age, sex, body mass index, physical activity, and smoking in childhood, childhood lipid levels, and weighted genetic risk scores were associated with an increased risk of adult dyslipidemia for all lipids. Risk assessment based on 2 childhood lipid measures and the lipid-specific weighted genetic risk scores improved the accuracy of predicting adult dyslipidemia compared with the approach using only childhood lipid measures for low-density lipoprotein cholesterol (area under the receiver-operating characteristic curve 0.806 versus 0.811; P =0.01) and triglycerides (area under the receiver-operating characteristic curve 0.740 versus area under the receiver-operating characteristic curve 0.758; P Conclusions— The inclusion of weighted genetic risk scores to lipid-screening programs in childhood could modestly improve the identification of those at highest risk of dyslipidemia in adulthood.

Scientific Reports 7: Article number: 45040; published online: 28 April 2017; updated: 26 May 2017 The original version of this Article contained a typographical error in the spelling of the author Martin H. de Borst, which was incorrectly given as Martin de Borst. This has now been corrected in both the PDF and HTML versions of the Article.

We examined associations between childhood temperamental activity, physical activity (PA), and television (TV) viewing over a 30-year period. The participants (1220 boys and 1237 girls) were aged 3, 6, 9, and 12 years in 1980 and were followed until 2011. Temperamental activity was evaluated by participants' mothers at baseline. The PA was assessed based on maternal ratings of the child from ages 3 to 6 and via self-report age from the age of 9 across all measurements. TV viewing was assessed using self-reports taken from 2001 to 2011. The associations between temperamental activity and the level and change of PA and TV viewing were determined using linear growth modeling stratified by gender and age group. High temperamental activity assessed from ages 9 to 12 was associated with high levels of childhood PA in both genders, but with a steeper decline in PA levels during the first 9 years of follow-up in boys. High temperamental activity assessed from ages 3 to 6 was associated with the decline of PA from childhood to youth in girls. High childhood temperamental activity was associated with decreased levels of PA in adulthood in men, but not in women. The associations between childhood temperamental activity and TV viewing during adulthood seemed to be positive but not consistently significant in all age and gender groups. High temperamental activity may contribute to the development of a physically inactive lifestyle. More evidence is needed with regard to gender differences among participants in similar study settings.

Children who are obese or have familial hypercholesterolemia have stiffer arteries compared with lean, healthy peers. Limited data are, however, available on the association of cardiometabolic risk markers and arterial distensibility in healthy children, particularly in a longitudinal setting. Therefore, we studied in the prospective STRIP (Special Turku Coronary Risk Factor Intervention Project) comprising healthy, predominantly normal weight participants the association of several cardiometabolic and dietary risk markers with arterial distensibility from childhood to early adulthood. Carotid and aortic distensibility (cdist, adist) was assessed repeatedly with ultrasonography at the age of 11, 13, 15, 17, and 19 years in the longitudinal atherosclerosis prevention study (n cdist =420–503, n adist =407–476). Data on cardiometabolic risk markers and diet were available since early childhood. In multivariable analyses, body mass index (β=−0.0019 [SE 0.0085]; P =0.037), systolic blood pressure (β=−0.0025 [SE 0.00065]; P =0.0001), low-density lipoprotein cholesterol (β=−0.026 [SE 0.012]; P =0.034), and homeostasis model of insulin resistance (β=−0.048 [SE 0.018]; P =0.0071) were independently associated with carotid distensibility. Systolic blood pressure (β=−0.0069 [SE 0.00097]; P P =0.031) associated independently with aortic distensibility. Dietary variables were not independently associated with arterial distensibility. Participants with low arterial distensibility had higher body mass index ( P cdist =0.0090, P adist =0.098) and higher systolic ( P cdist P adist P cdist P adist =0.0002) already from early childhood. Body mass index, blood pressure, low-density lipoprotein cholesterol, and homeostasis model of insulin resistance identified since childhood associate with arterial distensibility in healthy children and adolescents. These data support the relevance of these factors as part of primordial prevention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00223600.

Background Both hostile parenting and parental psychopathology have been shown to predict depression in the offspring. However, whether and how they interact in predicting the longitudinal course of depression from adolescence to adulthood remains unclear. Methods Participants were from the prospective Cardiovascular Risk in Young Finns study, aged 3–18 years at baseline in 1980. We used multilevel modeling for repeated measurements to examine the associations of hostile parenting (i.e., parental intolerance and emotional distance) and parental history of psychopathology with trajectories of depressive symptoms across five study phases from 1992 to 2012. Results On average, depressive symptoms decreased in a curvilinear pattern with age. A relatively steep decreasing trend was also observed among offspring of parents with a history of psychopathology but low intolerance. By contrast, among the offspring of parents with a history of psychopathology and high intolerance there was a rising trend in depressive symptoms starting from young adulthood. There was no similar interaction between parental history of psychopathology, emotional distance, and age. Limitations Non-standardized, parental self-report scales were used to measure hostile parenting. The observed effects were small, and the depressive symptoms scale applied in the study may not be used for measuring clinical depression. Conclusions Parental psychopathology might render individuals sensitive to the unfavorable characteristics of the caregiving environment. Intolerance towards the child can exacerbate the effects of parental psychopathology and have a long-term significance on the developmental trajectory of depressive symptoms over the life-course.

Elevated blood pressure (BP) in childhood has been associated with increased adult arterial stiffness, the independent predictor of cardiovascular and all-cause mortality. The favorable BP change from childhood to adulthood and the risk of high adult arterial stiffness has not been reported. We examined the effect of child and adult BP on pulse wave velocity (PWV) assessed in adulthood among 1540 white adults followed-up for 27 years since baseline (1980, aged 6–18 years). Childhood elevated BP was defined according to the tables from the National High Blood Pressure Education Program. In adulthood, BP was classified as elevated if systolic BP ≥120 mm Hg, diastolic BP ≥80 mm Hg, or self-reported use of antihypertensive medications. PWV was measured in 2007 by whole-body impedance cardiography, and high PWV was defined as values at or above the age-, sex-, and heart rate–specific 80th percentile. Individuals with persistently elevated BP and individuals with normal child but elevated adult BP had increased risk of high adult PWV (relative risk [95% confidence interval], 3.18 [2.22–4.55] and 2.64 [1.79–3.88], respectively) in comparison with individuals with normal (both child and adult) BP. In contrast, individuals with elevated BP in childhood but not in adulthood did not have significantly increased risk of high PWV (relative risk [95% confidence interval], 1.26[0.80–1.99]). The results were consistent when different definitions for child and adult elevated BP were applied. These findings highlight the importance of BP control in the primary prevention of cardiovascular diseases.

Background Prediabetes (PR) often occurs together with dyslipidaemia (D), which is paradoxically treated with statins predisposing to type 2 diabetes mellitus. We examined peripheral blood pathway profiles in prediabetic subjects with (PRD) and without dyslipidaemia (PR0) and compared these to non-prediabetic controls (C) without dyslipidaemia (C0). Methods The participants were from the Cardiovascular Risk in Young Finns Study, including 1,240 subjects aged 34-49 years. Genome-wide expression data of peripheral blood and gene set enrichment analysis were used to investigate the differentially expressed genes and enriched pathways between different subtypes of prediabetes. Results Pathways for cholesterol synthesis, interleukin-12 (IL12)-mediated signalling events and downstream signalling in naive CD8+ T cells were up-regulated in the PR0 group in comparison to controls (C0) and the up-regulation of these pathways was independent of waist circumference, blood pressure, smoking status and insulin. Adjustment for CRP left the CD8+ T cell signalling and IL12-mediated signalling event pathway up-regulated. The cholesterol synthesis pathway was also up-regulated when all prediabetic subjects (PR0 and PRD) were compared to the non-prediabetic control group. No pathways were up- or down-regulated when the PRD group was compared to the C0 group. Five genes in the PR0 group and one in the PRD group was significantly differentially expressed in comparison to the C0 group. Conclusions Blood cell gene expression profiles differ significantly between prediabetic subjects with and without dyslipidaemia. Whether this classification may be used in detection of prediabetic individuals at a high risk of cardiovascular complications remains to be examined.

Background Bayesian hierarchical piecewise regression (BHPR) modeling has not been previously formulated to detect and characterise the mechanism of trajectory divergence between groups of participants that have longitudinal responses with distinct developmental phases. These models are useful when participants in a prospective cohort study are grouped according to a distal dichotomous health outcome. Indeed, a refined understanding of how deleterious risk factor profiles develop across the life-course may help inform early-life interventions. Previous techniques to determine between-group differences in risk factors at each age may result in biased estimate of the age at divergence. Methods We demonstrate the use of Bayesian hierarchical piecewise regression (BHPR) to generate a point estimate and credible interval for the age at which trajectories diverge between groups for continuous outcome measures that exhibit non-linear within-person response profiles over time. We illustrate our approach by modeling the divergence in childhood-to-adulthood body mass index (BMI) trajectories between two groups of adults with/without type 2 diabetes mellitus (T2DM) in the Cardiovascular Risk in Young Finns Study (YFS). Results Using the proposed BHPR approach, we estimated the BMI profiles of participants with T2DM diverged from healthy participants at age 16 years for males (95% credible interval (CI):13.5–18 years) and 21 years for females (95% CI: 19.5–23 years). These data suggest that a critical window for weight management intervention in preventing T2DM might exist before the age when BMI growth rate is naturally expected to decrease. Simulation showed that when using pairwise comparison of least-square means from categorical mixed models, smaller sample sizes tended to conclude a later age of divergence. In contrast, the point estimate of the divergence time is not biased by sample size when using the proposed BHPR method. Conclusions BHPR is a powerful analytic tool to model long-term non-linear longitudinal outcomes, enabling the identification of the age at which risk factor trajectories diverge between groups of participants. The method is suitable for the analysis of unbalanced longitudinal data, with only a limited number of repeated measures per participants and where the time-related outcome is typically marked by transitional changes or by distinct phases of change over time. Electronic supplementary material The online version of this article (doi:10.1186/s12874-017-0358-9) contains supplementary material, which is available to authorized users.

Fatty liver may have different determinants in normal-weight and in obese individuals. We measured factors associated with fatty liver in 863 normal-weight (BMI25) and 1135 overweight/obese (BMI ≥ 25) young and middle-aged adults (45% male, age 34-49 years) in the population-based Cardiovascular Risk in Young Finns Study.The prevalence of fatty liver detected with ultrasound was 29% in overweight/obese and 5% in normal-weight participants. In overweight/obese, the independent correlates were waist circumference (odds ratio for 1 standard deviation increase = 3.78), alanine transaminase (2.11), BMI (2.00), male sex (1.74), triglycerides (1.44), systolic blood pressure (1.31), fasting insulin (1.23), and physical activity (0.76). In normal weight, the independent correlates included alanine transaminase (3.05), smoking (2.56), systolic blood pressure (1.54), and alcohol intake (1.41). In normal-weight participants, the associations with fatty liver were stronger for alcohol intake and smoking, and weaker for triglycerides, than in overweight/obese participants (P for interaction0.05).Prevalence of fatty liver was 29% in overweight/obese and 5% in normal-weight adults. Differences in factors associated with fatty liver were seen between these two groups: alcohol intake and smoking were more strongly and triglycerides more weakly associated in normal-weight than in overweight/obese participants.

Pregnancy conditions such as gestational diabetes (GDM) and macrosomia lead to an increased risk of diabetes and cardiovascular disease in the offspring, perpetuating a cycle of poor health. We hypothesized that (1) pre-pregnancy indicators of metabolism would be associated with GDM and birthweight; and (2) the lipid accumulation product (LAP; incorporating waist circumference and triglycerides) and visceral adiposity index (VAI; incorporating waist circumference, triglycerides, and HDL-c) would be better predictors of GDM and birthweight than other indicators. Data from the Cardiovascular Risk in Young Finns Study were linked to the Finnish birth registry for 349 women. BMI, triglycerides, waist circumference, insulin, HOMA-IR, LAP, and VAI at the visit prior to the pregnancy were examined as predictors of GDM and large-for-gestational-age (LGA) using logistic regression with adjustment for age, parity, and smoking. Waist circumference was the strongest predictor of GDM (adjusted odds ratio [aOR] 1.66, 95% confidence interval 1.16-2.38) and LGA (aOR 1.41, 1.00-1.99). For GDM, all markers had similar discrimination; for LGA, the area under the receiver operating curve for waist circumference was significantly higher than for BMI (p 0.01). This analysis suggests that pregnancy and even offspring health is affected by risk factors outside the immediate time period of pregnancy.

The American Psychiatric Association estimates that 3 to 7 per cent of all school aged children are diagnosed with attention deficit hyperactivity disorder (ADHD). Even after correcting for general cognitive ability, numerous studies report a negative association between ADHD and educational achievement. With polygenic scores we examined whether genetic variants that have a positive influence on educational attainment have a protective effect against ADHD. The effect sizes from a large GWA meta-analysis of educational attainment in adults were used to calculate polygenic scores in an independent sample of 12-year-old children from the Netherlands Twin Register. Linear mixed models showed that the polygenic scores significantly predicted educational achievement, school performance, ADHD symptoms and attention problems in children. These results confirm the genetic overlap between ADHD and educational achievement, indicating that one way to gain insight into genetic variants responsible for variation in ADHD is to include data on educational achievement, which are available at a larger scale. (C) 2014 Wiley Periodicals, Inc.

Objective— There is some evidence that people born with high birth weight may be at increased risk of cardiovascular disease in adulthood. Details of the underlying mechanisms remain unknown. We sought to determine whether people born large for gestational age have poor arterial health, increased adiposity, and a poor cardiovascular risk factor profile. Approach and Results— Carotid intima-media thickness, brachial flow–mediated dilatation, and cardiovascular risk factors were compared between young adults (24–45 years) born at term who were large for gestational age (birth weight >90th percentile; n=171), and a control group with normal birth weight (50–75th percentile; n=525), in the Cardiovascular Risk in Young Finns Study. Those born large for gestational age had higher body mass index throughout childhood, adolescence, and as young adults (26.4 kg/m 2 [SD 4.9], versus normal birth weight 25.1 kg/m 2 [SD 4.6]; P =0.002), and 2-fold greater risk of obesity. Other cardiovascular risk factors and arterial function did not differ; however, carotid intima-media thickness was increased in people born large for gestational age (0.60 mm [SD 0.09], versus normal birth weight 0.57 mm [SD 0.09]; P =0.003), independent of cardiovascular risk factors ( P =0.001 after adjustment). Both obesity and high birth weight were independently associated with carotid intima-media thickness in a graded and additive fashion. Conclusions— Young adults born large for gestational age are more likely to be obese, yet have an otherwise healthy cardiovascular risk profile. Nonetheless, they have increased carotid intima-media thickness, a marker of subclinical atherosclerosis, consistent with an increased risk of cardiovascular disease.

Aim Recent evidence suggests that the exposure of children to their parents' smoking adversely effects endothelial function in adulthood. We investigated whether the association was also present with carotid intima-media thickness (IMT) up to 25 years later. Methods and results The study comprised participants from the Cardiovascular Risk in Young Finns Study (YFS, n = 2401) and the Childhood Determinants of Adult Health (CDAH, n = 1375) study. Exposure to parental smoking (none, one, or both) was assessed at baseline by questionnaire. B-mode ultrasound of the carotid artery determined IMT in adulthood. Linear regression on a pooled dataset accounting for the hierarchical data and potential confounders including age, sex, parental education, participant smoking, education, and adult cardiovascular risk factors was conducted. Carotid IMT in adulthood was greater in those exposed to both parents smoking than in those whose parents did not smoke [adjusted marginal means: 0.647 mm ± 0.022 (mean ± SE) vs. 0.632 mm ± 0.021, P = 0.004]. Having both parents smoke was associated with vascular age 3.3 years greater at follow-up than having neither parent smoke. The effect was independent of participant smoking at baseline and follow-up and other confounders and was uniform across categories of age, sex, adult smoking status, and cohort. Conclusions These results show the pervasive effect of exposure to parental smoking on children's vascular health up to 25 years later. There must be continued efforts to reduce smoking among adults to protect young people and to reduce the burden of cardiovascular disease across the population.

MicroRNAs are involved in disease development and may be utilized as biomarkers. We investigated the association of blood miRNA levels and a) fatty liver (FL), b) lipoprotein and lipid pathways involved in liver lipid accumulation and c) levels of predicted mRNA targets in general population based cohort. Blood microRNA profiling (TaqMan OpenArray), genome-wide gene expression arrays and nuclear magnetic resonance metabolomics were performed for Young Finns Study participants aged 34–49 years (n = 871). Liver fat status was assessed ultrasonographically. Levels of hsa-miR-122-5p and -885-5p were up-regulated in individuals with FL (fold change (FC) = 1.55, p = 1.36 * 10−14 and FC = 1.25, p = 4.86 * 10−4, respectively). In regression model adjusted with age, sex and BMI, hsa-miR-122-5p and -885-5p predicted FL (OR = 2.07, p = 1.29 * 10−8 and OR = 1.41, p = 0.002, respectively). Together hsa-miR-122-5p and -885-5p slightly improved the detection of FL beyond established risk factors. These miRNAs may be associated with FL formation through the regulation of lipoprotein metabolism as hsa-miR-122-5p levels associated with small VLDL, IDL, and large LDL lipoprotein subclass components, while hsa-miR-885-5p levels associated inversely with XL HDL cholesterol levels. Hsa-miR-885-5p levels correlated inversely with oxysterol-binding protein 2 (OSBPL2) expression (r = −0.143, p = 1.00 * 10−4) and suppressing the expression of this lipid receptor and sterol transporter could link hsa-miR-885-5p with HDL cholesterol levels., published version, peerReviewed

IMPORTANCE Severe forms of common chronic oral infections or inflammations are associated with increased cardiovascular risk in adults. To date, the role of childhood oral infections in cardiovascular risk is not known because no long-term studies have been conducted. OBJECTIVE To investigate whether signs of oral infections in childhood are associated with cardiovascular risk factors and subclinical atherosclerosis in adulthood. DESIGN, SETTING, AND PARTICIPANTS The cohort study (n = 755) was derived from the Cardiovascular Risk in Young Finns Study, an ongoing prospective cohort study in Finland initiated in 1980. Participants underwent clinical oral examinations during childhood, when they were aged 6, 9, or 12 years and a clinical cardiovascular follow-up in adulthood in 2001 at age 27, 30, or 33 years and/or in 2007 at age 33, 36, or 39 years. Cardiovascular risk factors were measured at baseline and during the follow-up until the end of 2007. Final statistical analyses were completed on February 19, 2019. MAIN OUTCOMES AND MEASURES Four signs of oral infections (bleeding on probing, periodontal probing pocket depth, caries, and dental fillings) were documented. Cumulative lifetime exposure to 6 cardiovascular risk factors was calculated from dichotomized variables obtained by using the area-under-the-curve method. Subclinical atherosclerosis (ie, carotid artery intima-media thickness [IMT]) was quantified in 2001 (n = 468) and 2007 (n = 489). RESULTS This study included 755 participants, of whom 371 (49.1%) were male; the mean (SD) age at baseline examination was 8.07 (2.00) years. In this cohort, 33 children (4.5%) had no sign of oral infections, whereas 41 (5.6%) had 1 sign, 127 (17.4%) had 2 signs, 278 (38.3%) had 3 signs, and 248 (34.1%) had 4 signs. The cumulative exposure to risk factors increased with the increasing number of oral infections both in childhood and adulthood. In multiple linear regression models, childhood oral infections, including signs of either periodontal disease (R-2 = 0.018; P = .01), caries (R-2 = 0.022; P = .008), or both (R-2 = 0.024; P = .004), were associated with adulthood IMT. The presence of any sign of oral infection in childhood was associated with increased IMT (third tertile vs tertiles 1 and 2) with a relative risk of 1.87 (95% CI, 1.25-2.79), whereas the presence of all 4 signs produced a relative risk of 1.95 (95% CI, 1.28-3.00). The associations were more obvious in boys: if periodontal disease were present, the corresponding estimate was 1.69 (95% CI, 1.21-2.36); if caries, 1.46 (95% CI, 1.04-20.05); and if all 4 signs of oral infections, 2.25 (95% CI, 1.30-3.89). The associations were independent of cardiovascular risk factors. CONCLUSIONS AND RELEVANCE Oral infections in childhood appear to be associated with the subclinical carotid atherosclerosis seen in adulthood.

Background The American Heart Association recently defined ideal cardiovascular health by simultaneous presence of seven health behaviors and factors. The concept is associated with cardiovascular disease incidence, and cardiovascular disease and all-cause mortality. To effectively promote ideal cardiovascular health already early in life, childhood factors predicting future ideal cardiovascular health should be investigated. Our aim was thus to comprehensively explore childhood determinants of adult ideal cardiovascular health in population based cohorts from three continents.

Background: Berries are associated with health benefits. Little is known about the effect of baseline metabolome on the overall metabolic responses to berry intake. Objective: We studied the effects of berries on serum metabolome. Design: Eighty overweight women completed this randomized crossover study. During the interventions of 30 d, subjects consumed dried sea buckthorn berries (SBs), sea buckthorn oil (SBo), sea buckthorn phenolics ethanol extract mixed with maltodextrin (SBe+MD) (1:1), or frozen bilberries. Metabolic profiles were quantified from serum samples by using 1 H nuclear magnetic resonance spectroscopy. Results: All interventions induced a significant (P , 0.001‐0.003) effect on the overall metabolic profiles. The effect was observed both in participants who had a metabolic profile that reflected higher cardiometabolic risk at baseline (group B: P = 0.001‐0.008) and in participants who had a lower-risk profile (group A: P , 0.001‐ 0.009). Although most of the changes in individual metabolites were not statistically significant after correction for multiplicity, clear trends were observed. SB-induced effects were mainly on serum triglycerides and very-low-density lipoprotein (VLDL) and its subclasses, which decreased in metabolic group B. SBo induced a decreasing trend in the serum total, intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) cholesterol, and subfractions of IDL and LDL in group B. During the SBe+MD treatment, VLDL fractions and serum triglycerides increased. Bilberries caused beneficial changes on serum lipids and lipoproteins in group B, whereas the opposite was true in group A. Conclusion: Berry intake has overall metabolic effects, which depend on the cardio-metabolic risk profile at baseline. This trial was registered at clinicaltrials.gov as NCT01860547. Am J Clin Nutr doi: 10.3945/ajcn.113.060590.

OBJECTIVE We reported previously that low-saturated-fat dietary counseling started in infancy improves insulin sensitivity in healthy children 9 years of age. The aim of this study was to evaluate the effect of lifelong dietary counseling on insulin sensitivity in healthy adolescents between 15 and 20 years of age. In addition, we examined dietary fiber intake and the polyunsaturated fatty acid (PUFA) + monounsaturated (MUFA)-to-saturated fatty acid (SFA) ratio in the intervention and control adolescents and the association of these dietary factors with homeostasis model of insulin resistance (HOMA-IR). RESEARCH DESIGN AND METHODS The study comprised adolescents participating in the randomized, controlled Special Turku Coronary Risk Factor Intervention Project (STRIP) study, which aims to guide the study participants toward a diet beneficial for cardiovascular health. HOMA-IR was assessed annually between 15 and 20 years of age (n = 518; intervention, n = 245; control, n = 273), along with diet, BMI, pubertal status, serum cotinine concentrations, and physical activity. Dietary counseling was given biannually during the follow-up. RESULTS HOMA-IR was lower (7.5% on average) in the intervention group than in the control group between 15 and 20 years of age (P = 0.0051). The intervention effect was similar in girls and boys. The PUFA+MUFA-to-SFA ratio was higher (P < 0.0001) and the dietary fiber (g/MJ) intake was higher (P = 0.0058) in the intervention group compared with the control group. There was no association between the PUFA+MUFA-to-/SFA ratio and HOMA-IR, whereas dietary fiber intake (g/MJ) was associated with HOMA-IR in girls (P < 0.0001). CONCLUSIONS Dietary counseling initiated in infancy and maintained until 20 years of age was associated with improved insulin sensitivity in adolescents.

Background— Elevated blood pressure (BP) levels in childhood have been associated with subsequent atherosclerosis. However, it is uncertain whether this risk is attenuated in individuals who acquire normal BP by adulthood. The present study examined the effect of child and adult BP levels on carotid artery intima-media thickness (IMT) in adulthood. Methods and Results— The cohort consisted of 4210 participants from 4 prospective studies (mean follow-up, 23 years). Childhood elevated BP was defined according to the tables from the National High Blood Pressure Education Program. In adulthood, BP was classified as elevated for individuals with systolic BP ≥120 mm Hg, diastolic BP ≥80 mm Hg or with self-reported use of antihypertensive medications. Carotid artery IMT was measured in the left common carotid artery. High IMT was defined as an IMT ≥90th percentile according to age-, sex-, race-, and cohort-specific levels. Individuals with persistently elevated BP and individuals with normal childhood BP, but elevated adult BP had increased risk of high carotid artery IMT (relative risk [95% confidence interval]) 1.82[1.47–2.38] and 1.57[1.22–2.02], respectively) in comparison with individuals with normal child and adult BP. In contrast, individuals with elevated BP as children but not as adults did not have significantly increased risk (1.24[0.92–1.67]). In addition, these individuals had a lower risk of increased carotid artery IMT (0.66[0.50–0.88]) in compared with those with persistently elevated BP. The results were consistent when controlling for age, sex, and adiposity and when different BP definitions were applied. Conclusions— Individuals with persistently elevated BP from childhood to adulthood had increased risk of carotid atherosclerosis. This risk was reduced if elevated BP during childhood resolved by adulthood.

Background Low back pain (LBP) is a prevalent problem and tends to be socio-economically patterned. Relatively little is known about life-course socio-economic circumstances as determinants of different types of LBP. Our aim was to examine whether childhood and adult socio-economic position and social mobility are associated with radiating and non-specific LBP and sciatica. Method Data were derived from the Young Finns Study (n = 2231). Childhood socio-economic position was based on parental education, occupational class and family income at baseline in 1980. Data on own education and LBP outcomes were collected at the end of follow-up in 2007. Social mobility was based on parental and own education. Covariates were composed of age, parental body mass index and smoking. Results Both childhood and own socio-economic position remained associated with radiating LBP and sciatica after adjustments. However, the associations varied by socio-economic indicator and gender. Stable lower socio-economic position and downward mobility were associated with radiating LBP. Conclusion Childhood socio-economic circumstances affect the risk of radiating LBP and sciatica in adulthood. To prevent low back disorders, early socio-economic circumstances need to be considered alongside own socio-economic position.

Childhood nutrition may play a role in the development of cardiovascular disease risk in adulthood. We examined the links between childhood dietary fatty acid quality and adult subclinical atherosclerosis in a cohort of 374 males and 449 females, aged 3-18 y at baseline in 1980, followed for 27 y. Serum cholesterol ester fatty acid (CEFA) percentages were analyzed as markers of dietary fatty acid intake. Adulthood carotid artery intima media thickness (cIMT, μm), adjusted for childhood and adulthood lipid and nonlipid risk markers, was used as the outcome. In women, after adjustment for age and childhood nonlipid risk markers, the childhood saturated CEFA (B = 11.3; P = 0.011), monounsaturated CEFA (B = 2.5; P = 0.025), and n3 (ω3) polyunsaturated CEFA (B = 16.2; P = 0.035) percentages were directly associated with adult cIMT. In contrast, the n6 (ω6) polyunsaturated CEFA percentage was negatively associated with cIMT (B = -2.3; P = 0.008). Similar relationships were observed between childhood dietary intake data and adult cIMT. In men, these associations were generally weak and nonsignificant (P > 0.05) after controlling for confounders. These longitudinal data suggest that fat quality as reflected in the serum cholesterol ester fraction in childhood is associated with adult cIMT in women.

OBJECTIVE Branched-chain and aromatic amino acids are associated with the risk for future type 2 diabetes; however, the underlying mechanisms remain elusive. We tested whether amino acids predict insulin resistance index in healthy young adults. RESEARCH DESIGN AND METHODS Circulating isoleucine, leucine, valine, phenylalanine, tyrosine, and six additional amino acids were quantified in 1,680 individuals from the population-based Cardiovascular Risk in Young Finns Study (baseline age 32 ± 5 years; 54% women). Insulin resistance was estimated by homeostasis model assessment (HOMA) at baseline and 6-year follow-up. Amino acid associations with HOMA of insulin resistance (HOMA-IR) and glucose were assessed using regression models adjusted for established risk factors. We further examined whether amino acid profiling could augment risk assessment of insulin resistance (defined as 6-year HOMA-IR >90th percentile) in early adulthood. RESULTS Isoleucine, leucine, valine, phenylalanine, and tyrosine were associated with HOMA-IR at baseline and for men at 6-year follow-up, while for women only leucine, valine, and phenylalanine predicted 6-year HOMA-IR (P < 0.05). None of the other amino acids were prospectively associated with HOMA-IR. The sum of branched-chain and aromatic amino acid concentrations was associated with 6-year insulin resistance for men (odds ratio 2.09 [95% CI 1.38–3.17]; P = 0.0005); however, including the amino acid score in prediction models did not improve risk discrimination. CONCLUSIONS Branched-chain and aromatic amino acids are markers of the development of insulin resistance in young, normoglycemic adults, with most pronounced associations for men. These findings suggest that the association of branched-chain and aromatic amino acids with the risk for future diabetes is at least partly mediated through insulin resistance.

To provide a comprehensive overview on the main findings from the Cardiovascular Risk in Young Finns Study. This prospective multicenter study initiated in 1980 (N = 3596, baseline age 3-18 years) has followed up study participants over 30 years to investigate childhood risk factors for cardiometabolic outcomes in adulthood.Childhood BMI, socioeconomic status, parental risk factor status, as well as genetic polymorphisms are independent predictors of adult obesity, hypertension, and dyslipidemia. Results from the Young Finns Study and other follow-up studies have shown that conventional childhood risk factors, such as dyslipidemia, obesity, elevated blood pressure and smoking, are predictive of subclinical atherosclerosis in young adults. Recent findings suggest that childhood lifestyle (diet, physical activity) is associated with subclinical atherosclerosis and its progression in adulthood. Concerning the timing of risk factor measurements, they seem to be predictive of adult atherosclerosis from the age of 9 onwards. From a clinical point of view, a recent observation suggesting that the adverse cardiometabolic effects of childhood overweight/obesity are reversed among those who become nonobese adults, provides optimism during the days of obesity epidemic.Current data suggest that childhood risk factors are associated with higher risk of subclinical atherosclerosis in adulthood. Future studies among aging cohorts followed since childhood will provide data on their influence on clinical cardiovascular outcomes.

Background— Long-term physical inactivity seems to cause many health problems. We studied whether persistent physical activity compared with inactivity has a global effect on serum metabolome toward reduced cardiometabolic disease risk. Methods and Results— Sixteen same-sex twin pairs (mean age, 60 years) were selected from a cohort of twin pairs on the basis of their >30-year discordance for physical activity. Persistently (≥5 years) active and inactive groups in 3 population-based cohorts (mean ages, 31–52 years) were also studied (1037 age- and sex-matched pairs). Serum metabolome was quantified by nuclear magnetic resonance spectroscopy. We used permutation analysis to estimate the significance of the multivariate effect combined across all metabolic measures; univariate effects were estimated by paired testing in twins and in matched pairs in the cohorts, and by meta-analysis over all substudies. Persistent physical activity was associated with the multivariate metabolic profile in the twins ( P =0.003), and a similar pattern was observed in all 3 population cohorts with differing mean ages. Isoleucine, α1-acid glycoprotein, and glucose were lower in the physically active than in the inactive individuals ( P P P Conclusions— The numerous differences found between persistently physically active and inactive individuals in the circulating metabolome together indicate better metabolic health in the physically active than in inactive individuals.