Kaikki aineistot
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Abstract Apolipoprotein E (apoE) is the key regulator of plasma lipids, mediating altered functionalities in lipoprotein metabolism — affecting the risk of coronary artery (CAD) and Alzheimer’s diseases, as well as longevity. Searching pathways influenced by apoE prior to adverse manifestations, we utilized a metabolome dataset of 228 nuclear-magnetic-resonance-measured serum parameters with a 10-year follow-up from the population-based Young Finns Study cohort of 2,234 apoE-genotyped (rs7412, rs429358) adults, aged 24–39 at baseline. At the end of our follow-up, by limiting FDR-corrected p < 0.05, regression analyses revealed 180/228 apoE-polymorphism-related associations with the studied metabolites, in all subjects — without indications of apoE x sex interactions. Across all measured apoE- and apoB-containing lipoproteins, ε4 allele had consistently atherogenic and ε2 protective effect on particle concentrations of free/esterified cholesterol, triglycerides, phospholipids and total lipids. As novel findings, ε4 associated with glycoprotein acetyls, LDL-diameter and isoleucine — all reported biomarkers of CAD-risk, inflammation, diabetes and total mortality. ApoE-subgroup differences persisted through our 10-year follow-up, although some variation of individual metabolite levels was noticed. In conclusion, apoE polymorphism associate with a complex metabolic change, including aberrations in multiple novel biomarkers related to elevated cardiometabolic and all-cause mortality risk, extending our understanding about the role of apoE in health and disease.
Abstract Background: Low education, low cognitive abilities, and certain cognitive styles are suggested to predispose to social intolerance and prejudices. Evidence is, however, restricted by comparatively small samples, neglect of confounding variables and genetic factors, and a narrow focus on a single sort of prejudice. We investigated the relationships of education, polygenic cognitive potential, cognitive performance, and cognitive styles with social intolerance in adulthood over a 15-year follow-up. Methods: We used data from the prospective population-based Young Finns Study (n = 960‒1679). Social intolerance was evaluated with the Social Intolerance Scale in 1997, 2001, and 2011; cognitive performance with the Cambridge Neuropsychological Test Automated Battery in 2011; cognitive styles in 1997; and socioeconomic factors in 1980 (childhood) and 2011 (adulthood); and polygenic cognitive potential was calculated based on genome-wide association studies. Results: We found that nonrational thinking, polygenic cognitive potential, cognitive performance, or socioeconomic factors were not related to social intolerance. Regarding cognitive styles, low flexibility (B = –0.759, p < .001), high perseverance (B = 1.245, p < .001), and low persistence (B = –0.329, p < .001) predicted higher social intolerance consistently in the analyses. Discussion: When developing prejudice-reduction interventions, it should be considered that educational level or cognitive performance may not be crucial for development of social intolerance. Adopting certain cognitive styles may play more important roles in development of social intolerance.
Abstract High L-homoarginine (hArg) levels are directly associated with several risk factors for cardiometabolic diseases whereas low levels predict increased mortality in prospective studies. The biomarker role of hArg in young adults remains unknown. To study the predictive value of hArg in the development of cardiometabolic risk factors and diseases, we utilized data on high-pressure liquid chromatography-measured hArg, cardiovascular risk factors, ultrasound markers of preclinical atherosclerosis and type 2 diabetes from the population-based Young Finns Study involving 2,106 young adults (54.6% females, aged 24–39). We used a Mendelian randomization approach involving tens to hundreds of thousands of individuals to test causal associations. In our 10-year follow-up analysis, hArg served as an independent predictor for future hyperglycaemia (OR 1.31, 95% CI 1.06–1.63) and abdominal obesity (OR 1.60, 95% 1.14–2.30) in men and type 2 diabetes in women (OR 1.55, 95% CI 1.02–2.41). The MR analysis revealed no evidence of causal associations between serum hArg and any of the studied cardiometabolic outcomes. In conclusion, lifetime exposure to higher levels of circulating hArg does not seem to alter cardiometabolic disease risk. Whether hArg could be used as a biomarker for identification of individuals at risk developing cardiometabolic abnormalities merits further investigation.
Abstract Preterm birth (PTB) is associated with increased risk of type 2 diabetes and neurocognitive impairment later in life. We analyzed for the first time the associations of PTB with blood miRNA levels in adulthood. We also investigated the relationship of PTB associated miRNAs and adulthood phenotypes previously linked with premature birth. Blood MicroRNA profiling, genome-wide gene expression analysis, computer-based cognitive testing battery (CANTAB) and serum NMR metabolomics were performed for Young Finns Study subjects (aged 34–49 years, full-term n = 682, preterm n = 84). Preterm birth (vs. full-term) was associated with adulthood levels of hsa-miR-29b-3p in a fully adjusted regression model (p = 1.90 × 10–4, FDR = 0.046). The levels of hsa-miR-29b-3p were down-regulated in subjects with PTB with appropriate birthweight for gestational age (p = 0.002, fold change [FC] = − 1.20) and specifically in PTB subjects with small birthweight for gestational age (p = 0.095, FC = − 1.39) in comparison to individuals born full term. Hsa-miR-29b-3p levels correlated with the expressions of its target-mRNAs BCL11A and CS and the gene set analysis results indicated a target-mRNA driven association between hsa-miR-29b-3p levels and Alzheimer’s disease, Parkinson’s disease, Insulin signaling and Regulation of Actin Cytoskeleton pathway expression. The level of hsa-miR-29b-3p was directly associated with visual processing and sustained attention in CANTAB test and inversely associated with serum levels of VLDL subclass component and triglyceride levels. In conlcusion, adult blood levels of hsa-miR-29b-3p were lower in subjects born preterm. Hsa-miR-29b-3p associated with cognitive function and may be linked with adulthood morbidities in subjects born preterm, possibly through regulation of gene sets related to neurodegenerative diseases and insulin signaling as well as VLDL and triglyceride metabolism.
Abstract The atherogenic process begins already in childhood and progresses to symptomatic condition with age. We investigated the association of cholesterol efflux capacity (CEC) and vascular markers of subclinical atherosclerosis in healthy, young adults. CEC was determined in 2282 participants of the Young Finns study using cAMP treated 3H-cholesterol-labeled J774 cells. The CEC was correlated to baseline and 6-year follow-up data of cardiovascular risk factors and ultrasound measurements of arterial structure and function. CEC was higher in women, correlated with total cholesterol, HDL-C, and apolipoprotein A-I, but not with LDL-C or apolipoprotein B. Compared to the lowest CEC quartile, the highest CEC quartile was significantly associated with high CRP levels and inversely associated with adiponectin. At baseline, high CEC was associated with decreased flow-mediated dilation (FMD) and carotid artery distensibility, as well as an increased Young’s modulus of elasticity, indicating adverse changes in arterial structure, and function. The association reversed with follow-up FMD data, indicating the interaction of preclinical parameters over time. A higher CEC was directly associated with a lower risk of subclinical atherosclerosis at follow-up. In young and healthy subjects, CEC was associated with important lipid risk parameters at baseline, as in older patients and CAD patients, but inversely with early risk markers for subclinical atherosclerosis.
Abstract 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.
Abstract Background: Increased left ventricular mass (LVM) predicts cardiovascular events and mortality. The objective of this study was to determine whether early-life exposures to body mass index (BMI) and systolic blood pressure (SPB) affects the left ventricular structure in adulthood. Methods: We used longitudinal data from a 31-year follow-up to examine the associations between early-life (between ages 6–18) BMI and SPB on LVM in an adult population (N = 1864, aged 34–49). The burden of early-life BMI and SBP was defined as area under the curve. Results: After accounting for contemporary adult determinants of LVM, early-life BMI burden associated significantly with LVM (3.61 g/SD increase in early-life BMI; [1.94 − 5.28], p < 0.001). Overweight in early-life (age- and sex-specific BMI values corresponding to adult BMI > 25 kg/m2) associated with 4.7% (2.5–6.9%, p < 0.0001) higher LVM regardless of BMI status in adulthood. Overweight in early-life combined with obesity in adulthood (BMI > 30kg/m2) resulted in a 21% (17.3–32.9%, p < 0.0001) increase in LVM. Higher early-life BMI was associated with a risk of developing eccentric hypertrophy. The burden of early-life SPB was not associated with adult LVM or left ventricular remodeling. Conclusions: High BMI in early-life confers a sustained effect on LVM and the risk for eccentric hypertrophy independently of adulthood risk factors.
Abstract Background & Aims: We aimed to determine how childhood body mass index and metabolic health, along with the change in body mass index between childhood and adulthood, determine the risk of adult non‐alcoholic fatty liver disease. Methods: Data from 2020 participants aged 3–18 years at baseline, followed up 31 years later, were examined to assess the utility of four childhood metabolic phenotypes (Metabolic Groups I: normal body mass index, no metabolic disturbances; II: normal body mass index, one or more metabolic disturbances; III: overweight/obese, no metabolic disturbances; IV: overweight/obese, one or more metabolic disturbances) and four life‐course adiposity phenotypes (Adiposity Group 1: normal child and adult body mass index; 2, high child, normal adult body mass index; 3, normal child body mass index, high adult body mass index; 4, high child and adult body mass index) in predicting adult non‐alcoholic fatty liver disease. Results: The risk for adult non‐alcoholic fatty liver disease was similar across all four groups after adjustment for age, sex, lifestyle factors and adult body mass index. Risk of adult non‐alcoholic fatty liver disease was not increased among individuals overweight/obese in childhood but non‐obese in adulthood. In contrast, overweight or obese adults, irrespective of their youth body mass index status, had ~eight‐fold to 10‐fold increased risk (P < 0.001). Conclusions: Childhood overweight/obesity, not metabolic health, is associated with increased risk for adult non‐alcoholic fatty liver disease. However, the increased risk associated with childhood overweight/obesity can be largely removed by obtaining a normal body mass index by adulthood.
Abstract Aims: To investigate the association between overweight/obesity and fatty liver index (FLI) on the odds of incident prediabetes/type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) in 2020 participants after 10 years follow up. Methods: At baseline (in 2001) 2020 participants, males and females, aged 24–39 years, were stratified according to body mass index (BMI), normal weight (<25 kg/m2), overweight (≥25–<30 kg/m2), or obese (≥30 kg/m2) and FLI (as high FLI ≥60 or low FLI <60). We examined the incidence of prediabetes/type 2 diabetes and NAFLD (ultrasound assessed) over 10 years to 2011 to determine the relative impact of FLI and BMI. Results: 514 and 52 individuals developed prediabetes and type 2 diabetes during follow-up. Such individuals were older, with higher BMI, serum glucose, insulin, alanine aminotransferase (ALT) and triglyceride (TG) concentrations than those who did not develop prediabetes or type 2 diabetes (n = 1454). The additional presence of high FLI significantly increased the risk of developing prediabetes and type 2 diabetes above the risk of being overweight/obese. Compared with normal weight, low FLI participants, the odds of prediabetes were ∼2-fold higher and the odds of type 2 diabetes were 9–10-fold higher respectively in the overweight/obese, high FLI group. No difference was observed between normal weight, low FLI and overweight/obese and low FLI groups. Conclusions: An increased FLI significantly increases the odds of incident prediabetes, type 2 diabetes and NAFLD in individuals with overweight/obese highlighting the contributory role of liver fat accumulation in the pathophysiology of prediabetes/type 2 diabetes.
Abstract Background: Childhood exposure to dyslipidemia is associated with adult atherosclerosis, but it is unclear whether the long‐term risk associated with dyslipidemia is attenuated on its resolution by adulthood. We aimed to address this question by examining the links between childhood and adult dyslipidemia on carotid atherosclerotic plaques in adulthood. Methods and Results: The Cardiovascular Risk in Young Finns Study is a prospective follow‐up of children that began in 1980. Since then, follow‐up studies have been conducted regularly. In 2001 and 2007, carotid ultrasounds were performed on 2643 participants at the mean age of 36 years to identify carotid plaques and plaque areas. For childhood lipids, we exploited several risk factor measurements to determine the individual cumulative burden for each lipid during childhood. Participants were categorized into the following 4 groups based on their childhood and adult dyslipidemia status: no dyslipidemia (reference), incident, resolved, and persistent. Among individuals with carotid plaque, linear regression models were used to study the association of serum lipids with plaque area. The prevalence of plaque was 3.3% (N=88). In models adjusted for age, sex, and nonlipid cardiovascular risk factors, the relative risk for carotid plaque was 2.34 (95% CI, 0.91–6.00) for incident adult dyslipidemia, 3.00 (95% CI, 1.42–6.34) for dyslipidemia resolved by adulthood, and 5.23 (95% CI, 2.57–10.66) for persistent dyslipidemia. Carotid plaque area correlated with childhood total, low‐density lipoprotein, and non–high‐density lipoprotein cholesterol levels. Conclusions: Childhood dyslipidemia, even if resolved by adulthood, is a risk factor for adult carotid plaque. Furthermore, among individuals with carotid plaque, childhood lipids associate with plaque size. These findings highlight the importance of primordial prevention of dyslipidemia in childhood to reduce atherosclerosis development.
Abstract Background and Objectives: Serum creatinine is typically used to assess kidney function. Impaired kidney function and thus high serum creatinine increase the risk of poor cognitive performance. However, serum creatinine might have a nonlinear association because low serum creatinine has been linked to cardiovascular risk and impaired cognitive performance. We studied the longitudinal association between serum creatinine and cognitive performance in midlife. Methods: Since 2001, participants from the Cardiovascular Risk in Young Finns Study were followed up for 10 years. Serum creatinine was measured repeatedly in 2001, 2007, and 2011. Sex-specific longitudinal trajectories for serum creatinine among participants without kidney disease were identified with latent class growth mixture modeling. Overall cognitive function and 4 specific domains—working memory, episodic memory and associative learning, reaction time, and information processing—were assessed with a computerized cognitive test. Results: Four serum creatinine trajectory groups with clinically normal serum creatinine were identified for both men (n = 973) and women (n = 1,204). After 10 years of follow-up, cognitive testing was performed for 2,026 participants 34 to 49 years of age (mean age 41.8 years). In men and women, consistently low serum creatinine was associated with poor childhood school performance, low adulthood education, low adulthood annual income, low physical activity, and smoking. Compared to the men in the low serum creatinine trajectory group, those in the high serum creatinine group had better overall cognitive performance (β = 0.353 SD, 95% CI 0.022–0.684) and working memory (β = 0.351 SD, 95% CI 0.034–0.668), while those in the moderate (β = 0.247 SD, 95% CI 0.026–0.468) or normal (β = 0.244 SD, 95% CI 0.008–0.481) serum creatinine groups had better episodic memory and associative learning. No associations were found for women. Discussion: Our results indicate that in men, compared to low serum creatinine levels, consistently high levels may be associated with better memory and learning function in midlife.
Abstract Objective: To determine the association of number of siblings on cardiovascular risk factors in childhood and in adulthood. Study design: In total, 3554 participants (51% female) from the Cardiovascular Risk in Young Finns Study with cardiovascular disease risk factor data at baseline 1980 (age 3–18 years) and 2491 participants with longitudinal risk factor data at the 2011 follow-up. Participants were categorized by number of siblings at baseline (0, 1, or more than 1). Risk factors (body mass index, physical activity, hypertension, dyslipidemia, and overweight, and metabolic syndrome) in childhood and in adulthood were used as outcomes. Analyses were adjusted for age and sex. Results: In childhood, participants without siblings had higher body mass index (18.2 kg/m2, 95% CI 18.0-18.3) than those with 1 sibling (17.9 kg/m2, 95% CI 17.8-18.0) or more than 1 sibling (17.8 kg/m2, 95% CI 17.7-17.9). Childhood physical activity index was lower among participants without siblings (SD -0.08, 95% CI -0.16-0.00) compared with participants with 1 sibling (SD 0.06, 95%CI 0.01-0.11) or more than 1 sibling (SD -0.02, 95% CI -0.07-0.03). OR for adulthood hypertension was lower among participants with 1 sibling (OR 0.73, 95% CI 0.54-0.98) and more than 1 sibling (OR 0.71, 95% CI 0.52-0.97) compared with participants with no siblings. OR for obesity was lower among participants with 1 sibling (OR 0.72, 95% CI 0.54-0.95) and more than 1 sibling (OR 0.75, 95% CI 0.56-1.01) compared with those with no siblings. Conclusions: Children without siblings had poorer cardiovascular risk factor levels in childhood and in adulthood. The number of siblings could help identify individuals at increased risk that might benefit from early intervention.
Abstract We studied whether exposure to parental smoking in childhood/adolescence is associated with midlife cognitive function, leveraging data from the Cardiovascular Risk in Young Finns Study. A population-based cohort of 3,596 children/adolescents aged 3–18 years was followed between 1980 and 2011. In 2011, cognitive testing was performed on 2,026 participants aged 34–49 years using computerized testing. Measures of secondhand smoke exposure in childhood/adolescence consisted of parental self-reports of smoking and participants’ serum cotinine levels. Participants were classified into 3 exposure groups: 1) no exposure (nonsmoking parents, cotinine <1.0 ng/mL); 2) hygienic parental smoking (1–2 smoking parents, cotinine <1.0 ng/mL); and 3) nonhygienic parental smoking (1–2 smoking parents, cotinine ≥1.0 ng/mL). Analyses adjusted for sex, age, family socioeconomic status, polygenic risk score for cognitive function, adolescent/adult smoking, blood pressure, and serum total cholesterol level. Compared with the nonexposed, participants exposed to nonhygienic parental smoking were at higher risk of poor (lowest quartile) midlife episodic memory and associative learning (relative risk (RR) = 1.38, 95% confidence interval (CI): 1.08, 1.75), and a weak association was found for short-term and spatial working memory (RR = 1.25, 95% CI: 0.98, 1.58). Associations for those exposed to hygienic parental smoking were nonsignificant (episodic memory and associative learning: RR = 1.19, 95% CI: 0.92, 1.54; short-term and spatial working memory: RR = 1.10, 95% CI: 0.85, 1.34). We conclude that avoiding childhood/adolescence secondhand smoke exposure promotes adulthood cognitive function.
Abstract We investigated whether temperament modifies an association between polygenic intelligence potential and cognitive test performance in midlife. The participants (n = 1647, born between 1962 and 1977) were derived from the Young Finns Study. Temperament was assessed with Temperament and Character Inventory over a 15-year follow-up (1997, 2001, 2007, 2012). Polygenic intelligence potential was assessed with a polygenic score for intelligence. Cognitive performance (visual memory, reaction time, sustained attention, spatial working memory) was assessed with CANTAB in midlife. The PGSI was significantly associated with the overall cognitive performance and performance in visual memory, sustained attention and working memory tests but not reaction time test. Temperament did not correlate with polygenic score for intelligence and did not modify an association between the polygenic score and cognitive performance, either. High persistence was associated with higher visual memory (B = 0.092; FDR-adj. p = 0.007) and low harm avoidance with higher overall cognitive performance, specifically better reaction time (B = −0.102; FDR-adj; p = 0.007). The subscales of harm avoidance had different associations with cognitive performance: higher “anticipatory worry,” higher “fatigability,” and lower “shyness with strangers” were associated with lower cognitive performance, while the role of “fear of uncertainty” was subtest-related. In conclusion, temperament does not help or hinder one from realizing their genetic potential for intelligence. The overall modest relationships between temperament and cognitive performance advise caution if utilizing temperament-related information e.g. in working-life recruitments. Cognitive abilities may be influenced by temperament variables, such as the drive for achievement and anxiety about test performance, but they involve distinct systems of learning and memory.
Abstract Objective: Growth-based determination of pubertal onset timing would be cheap and practical. We aimed to determine this timing based on pubertal growth markers. Secondary aims were to estimate the differences in growth between cohorts and identify the role of overweight in onset timing. Design: This multicohort study includes data from three Finnish cohorts—the Type 1 Diabetes Prediction and Prevention (DIPP, N = 2,825) Study, the Special Turku Coronary Risk Factor Intervention Project (STRIP, N = 711), and the Boy cohort (N = 66). Children were monitored for growth and Tanner staging (except in DIPP). Methods: The growth data were analyzed using a Super-Imposition by Translation And Rotation growth curve model, and pubertal onset analyses were run using a time-to-pubertal onset model. Results: The time-to-pubertal onset model used age at peak height velocity (aPHV), peak height velocity (PHV), and overweight status as covariates, with interaction between aPHV and overweight status for girls, and succeeded in determining the onset timing. Cross-validation showed a good agreement (71.0% for girls, 77.0% for boys) between the observed and predicted onset timings. Children in STRIP were taller overall (girls: 1.7 [95% CI: 0.9, 2.5] cm, boys: 1.0 [0.3, 2.2] cm) and had higher PHV values (girls: 0.13 [0.02, 0.25] cm/year, boys: 0.35 [0.21, 0.49] cm/year) than those in DIPP. Boys in the Boy cohort were taller (2.3 [0.3, 4.2] cm) compared with DIPP. Overweight girls showed pubertal onset at 1.0 [0.7, 1.4] year earlier compared with other girls. In boys, there was no such difference. Conclusions: The novel modeling approach provides an opportunity to evaluate the Tanner breast/genital stage–based pubertal onset timing in cohort studies including longitudinal data on growth but lacking pubertal follow-up.
Abstract Nonalcoholic fatty liver is associated with obesity-related metabolic disturbances, but little is known about the metabolic perturbations preceding fatty liver disease. We performed comprehensive metabolic profiling to assess how circulating metabolites, such as lipoprotein lipids, fatty acids, amino acids, and glycolysis-related metabolites, reflect the presence of and future risk for fatty liver in young adults. Sixty-eight lipids and metabolites were quantified by nuclear magnetic resonance metabolomics in the population-based Young Finns Study from serum collected in 2001 (n = 1,575), 2007 (n = 1,509), and 2011 (n = 2,002). Fatty liver was diagnosed by ultrasound in 2011 when participants were aged 34–49 years (19% prevalence). Cross-sectional associations as well as 4-year and 10-year risks for fatty liver were assessed by logistic regression. Metabolites across multiple pathways were strongly associated with the presence of fatty liver (P < 0.0007 for 60 measures in age-adjusted and sex-adjusted cross-sectional analyses). The strongest direct associations were observed for extremely large very-low-density lipoprotein triglycerides (odds ratio [OR] 5 4.86 per 1 standard deviation, 95% confidence interval 3.48–6.78), other very-low-density lipoprotein measures, and branched-chain amino acids (e.g., leucine OR = 2.94, 2.51–3.44). Strong inverse associations were observed for high-density lipoprotein measures, e.g., high-density lipoprotein size (OR = 0.36, 0.30–0.42) and several fatty acids including omega-6 (OR = 0.37, 0.32–0.42). The metabolic associations were attenuated but remained significant after adjusting for waist, physical activity, alcohol consumption, and smoking (P < 0.0007). Similar aberrations in the metabolic profile were observed already 10 years before fatty liver diagnosis. Conclusion: Circulating lipids, fatty acids, and amino acids reflect fatty liver independently of routine metabolic risk factors; these metabolic aberrations appear to precede the development of fatty liver in young adults.
Abstract Objective: An adverse psychosocial environment in childhood may harm cognitive development, but the associations for adulthood cognitive function remain obscure. We tested the hypothesis that adverse childhood psychosocial factors associate with poor cognitive function in midlife by leveraging the prospective data from the Young Finns Study. Method: At the age of 3–18 years, the participants’ psychosocial factors (socioeconomic and emotional environment, parental health behaviors, stressful events, child’s self-regulatory behavior, and social adjustment) were collected. In addition to the separate psychosocial factors, a score indicating their clustering was created. Cognitive function was measured at the age of 34–49 years with a computerized test addressing learning and memory (N =1,011), working memory (N = 1,091), sustained attention and information processing (N = 1,071), and reaction and movement time (N =999). Results: We observed an inverse association between the accumulation of unfavorable childhood psychosocial factors and poorer learning and memory in midlife (age, sex, education, adulthood smoking, alcohol drinking, and physical activity adjusted β = −0.032, SE = 0.01, p = .009). This association corresponded approximately to the effect of 7 months aging. Specifically, poor self-regulatory behavior (β= −0.074, SE = 0.03, p = .032) and social adjustment in childhood (β = −0.111, SE = 0.03, p = .001) associated with poorer learning ability and memory 30 years later. No associations were found for other cognitive domains. Conclusions: The findings suggest an association of childhood psychosocial factors with midlife learning ability and memory. If these links are causal, the results highlight the importance of a child’s self-regulation and social adjustment as plausible determinants for adulthood cognitive health.
Abstract Introduction: The role of risk factor profile in childhood and adolescence on adulthood cognitive function and whether it differs by genetic risk is still obscure. To bring this evidence, we determined cognitive domain-specific youth risk factor profiles leveraging the childhood/adolescence data from the Cardiovascular Risk in Young Finns Study and examined whether genetic propensity for poor cognitive function modifies the association between the risk profiles and adulthood cognitive function. Methods: From 1980, a population-based cohort of 3,596 children (age 3–18 years) has been repeatedly followed up for 31 years. Computerized cognitive test measuring (1) memory and learning, (2) short-term working memory, (3) reaction time, and (4) information processing was performed for 2,026 participants (age 34–49 years). Cognitive domain-specific youth risk profile scores, including physical and environmental factors, were assessed from the data collected at baseline and categorized into favourable, intermediate, and unfavourable. A polygenic risk score for a poor cognitive function was categorized into low, intermediate, and high risk. Results: At all genetic risk levels, a favourable youth risk factor profile is associated with better learning and memory, short-term working memory, and information processing compared to unfavourable risk profile (e.g., β = 0.501 SD, 95% CI: 0.043–0.959 for memory and learning among participants with high genetic risk). However, no significant interactions were observed between the youth risk factor profile score and genetic propensity for any cognitive domain (p > 0.299 for all). Conclusions: A favourable youth risk factor profile may be beneficial for cognitive function in adulthood, irrespective of genetic propensity for poor cognitive function.
Abstract 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.
Abstract Purpose: To investigate whether exposure to systemic antibiotics influences the risk of developing type 2 diabetes and overweight/obesity. Methods: The study sample comprised 2209 (110 with incident diabetes) participants from the population-based Cardiovascular Risk in Young Finns Study (YFS) aged 24–39 years in 2001. The exposure was national linked register data on purchased antibiotic courses between 1993 and 2001. Clinical examinations including BMI were conducted in 2001, 2007 and 2011. Participants with prevalent diabetes in 2001 were excluded. Data on type 2 diabetes was also obtained from two national registers until 2017. Data from four population-based National FINRISK studies were used for replication (N = 24,674, 1866 with incident diabetes). Results: Prior antibiotic exposure (> 5 versus 0–1 antibiotic courses) was associated with subsequent type 2 diabetes in both YFS (OR 2.29; 95%CI 1.33–3.96) and FINRISK (HR 1.73; 95%CI 1.51–1.99). An increased risk for type 2 diabetes was observed in YFS (OR 1.043; 95%CI 1.013–1.074) and FINRISK (HR 1.022; 95%CI 1.016–1.029) per course. Exposure to antibiotics increased the risk of overweight/obesity (BMI > 25 kg/m2) after a 10-year follow-up in YFS (OR 1.043; 95%CI 1.019–1.068) and in FINRISK (OR 1.023; 95%CI 1.018–1.029) at baseline per antibiotic course. Adjustments for confounders from early life in YFS and at baseline in FINRISK, including BMI, socioeconomic status, smoking, insulin, blood pressure, and physical activity, did not appreciably alter the findings. Conclusion: Our results show that exposure to antibiotics was associated with increased risk for future type 2 diabetes and overweight/obesity and support judicious antibiotic prescribing.
Abstract Coffee’s long-term effect on cognitive function remains unclear with studies suggesting both benefits and adverse effects. We used Mendelian randomization to investigate the causal relationship between habitual coffee consumption and cognitive function in mid- to later life. This included up to 415,530 participants and 300,760 coffee drinkers from 10 meta-analysed European ancestry cohorts. In each cohort, composite cognitive scores that capture global cognition and memory were computed using available tests. A genetic score derived using CYP1A1/2 (rs2472297) and AHR (rs6968865) was chosen as a proxy for habitual coffee consumption. Null associations were observed when examining the associations of the genetic score with global and memory cognition (β = −0.0007, 95% C.I. −0.009 to 0.008, P = 0.87; β = −0.001, 95% C.I. −0.005 to 0.002, P = 0.51, respectively), with high consistency between studies (Pheterogeneity > 0.4 for both). Domain specific analyses using available cognitive measures in the UK Biobank also did not support effects by habitual coffee intake for reaction time, pairs matching, reasoning or prospective memory (P ≥ 0.05 for all). Despite the power to detect very small effects, our meta-analysis provided no evidence for causal long-term effects of habitual coffee consumption on global cognition or memory.
Abstract The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. DHCR7(rs12785878), CYP2R1 rs12794714) and their combined synthesis score were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, pcurvature ≤ 0.006), with much of the curvature attributed to a single study. DHCR7, CYP2R1, and the synthesis score were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for DHCR7 and CYP2R1, with no overall association observed for the synthesis score. Coefficients for the synthesis score and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.
Abstract Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74<rg<-0.55) and blood pressure (-0.35<rg<-0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.
Abstract Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.