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Objective: This study investigated whether changes in DNA methylation (DNAm) at TXNIP are associated with glycemic changes and whether such an association differs with early-life adiposity changes., Methods: A total of 594 Bogalusa Heart Study participants who had blood DNAm measurements at two time points in midlife were included. Of them, 353 participants had at least four BMI measurements during childhood and adolescence. The incremental area under the curve was calculated as a measure of long-term trends of BMI during childhood and adolescence., Results: Increase in DNAm at TXNIP was significantly associated with decrease in fasting plasma glucose (FPG) independent of covariates (p < 0.001). The study found that the strength of this relationship was significantly modified by a trend of increasing BMI during childhood and adolescence (p-interaction = 0.003). Each 1% increase in DNAm at TXNIP was associated with a 2.90- (0.77) mg/dL decrease in FPG among participants with the highest tertile of BMI incremental area under the curve and a 0.96- (0.38) mg/dL decrease among those with the middle tertile, whereas no association was observed among participants with the lowest tertile., Conclusions: These results indicate that changes in blood DNAm at TXNIP are significantly associated with changes in FPG in midlife, and this association was modified by BMI trends during childhood and adolescence., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Objective: This study aimed to examine the temporal relationship between body mass index (BMI) and uric acid (UA), and their joint effect on blood pressure (BP) in children and adults., Methods: The longitudinal cohorts for temporal relationship analyses consisted of 564 and 911 subjects examined twice 5-14 years apart from childhood to adulthood. The cross-sectional cohorts for mediation analyses consisted of 3102 children and 3402 nondiabetic adults. Cross-lagged panel analysis models were used to examine the temporal relationship between BMI and UA, and mediation analysis models the mediation effect of UA on the BMI-BP association., Results: After adjusting for age, race, sex and follow-up years in children, and additionally smoking and alcohol drinking in adults, the path coefficients (standardized regression coefficients) from baseline BMI to follow-up UA (0.145 in children and 0.068 in adults) were significant, but the path coefficients from baseline UA to follow-up BMI (0.011 in children and 0.016 in adults) were not. In mediation analyses, indirect effects through UA on the BMI-systolic BP association were estimated at 0.028 (mediation effect = 8.8%) in children and 0.033 (mediation effect = 13.5%) in adults (P < 0.001 for both). Direct effects of BMI on systolic BP (0.289 in children and 0.212 in adults) were significant. The mediation effect parameters did not differ significantly between Blacks and Whites., Conclusions: Changes in BMI precede alterations in UA, and the BMI-BP association is in part mediated through BMI-related increase in UA both in children and in adults. These findings have implications for addressing mechanisms of obesity hypertension beginning in early life.

Background: It has been controversial whether to adjust for current body weight while examining the relationship between birthweight and blood pressure (BP)., Objective: The present study aims to partition the total effect of birthweight on BP into its direct effect and indirect effect through current body mass index (BMI)., Methods: The study cohort consisted of 6251 participants who had birthweight information with 13 443 observations on BMI and BP in pre-adolescence (4-11 years), adolescence (12-19 years), young adulthood (20-30 years) and mid-adulthood (31-58 years). General third-variable models were used to distinguish the mediation and suppression effects of current BMI on the birthweight-BP association at different ages., Results: The total effect of birthweight on systolic BP measured as standardized regression coefficient (β) without current BMI included in the model was 0.003 (P = .810) in pre-adolescents, -0.032 (P = .029) in adolescents, -0.066 (P = .002) in young adults and -0.051 (P = .023) in midlife adults. With additional adjustment for BMI, the direct effect of birthweight on systolic BP was strengthened to β = -0.066 (P = .013), β = -0.058 (P = .014), β = -0.094 (P = .020), β = -0.066 (P = .023); the suppression effects of BMI were calculated at 0.070, 0.027, 0.028 and 0.015 in the respective age groups. The decreasing trend of suppression effects with increasing age mimicked the trends of birthweight-BMI and BMI-BP correlations., Conclusions: Current body weight has a suppression effect, not a mediation effect, on the birthweight-BP association, with pre-adolescents having the greatest suppression effect. The suppression effect is predominantly determined by birthweight-BMI and BMI-BP correlations., (© 2020 World Obesity Federation.)

Background Data are limited regarding the relationship between the life-course burden of risk factors and adult cardiac function. This study sought to examine the impact of long-term burden of body mass index (BMI) and blood pressure (BP) levels on changes in adult left ventricular (LV) structure and function in a community-based cohort. Methods and Results The longitudinal study cohort consisted of 1108 adult patients (726 White; 41.9% men; mean age, 48.2 years in the last survey) who had been examined 4 to 16 times for BMI and BP and echocardiographic LV structure and function in adulthood, with a mean follow-up period of 38.8 years. The area under the curve was used as a measure of long-term burden of BMI and BP. Adult LV mass index was significantly associated with childhood and adulthood BMI and systolic BP (SBP), and their area under the curve values (β=0.07-0.37; P <0.05 for all). Adult LV ejection fraction was negatively associated with childhood BMI (β=-0.08), adult BMI (β=-0.07) and BMI area under the curve (β=-0.07) ( P <0.05 for all); the effects of SBP measures were not significant. Adult E/A ratio was negatively associated with adulthood SBP (β=-0.13; P <0.01) and total area under the curve of SBP (β=-0.13; P <0.01). E/e' ratio was positively associated with BMI and SBP measures. The effects of diastolic BP measures were substantially similar to those of SBP measures. Participants with LV hypertrophy, eccentric hypertrophy, and concentric hypertrophy had significantly lower LV ejection fraction and higher E/e' ratio. Conclusions These observations provide strong evidence that early-life adiposity and BP levels and their life-course cumulative burdens are associated with subclinical changes in adult LV structure and function in the general population.

Background and Objectives: Adult class II/III obesity (BMI ≥ 35 kg/m 2 ) has significant adverse health outcomes. Early prevention and treatment are critical, but prospective childhood risk estimates are lacking. This study aimed to define the prospective risk of adult class II/III obesity, using childhood BMI., Methods: Children ages 3-19 years enrolled in cohorts of the International Childhood Cardiovascular Cohort (i3C) consortium with measured BMI assessments in childhood and adulthood were included. Prospective risk of adult class II/III obesity was modeled based on childhood age, sex, race, and BMI., Results: A total of 12,142 individuals (44% male, 85% white) were assessed at median age 14 [Interquartile range, IQR: 11, 16] and 33 [28, 39] years. Class II/III adult obesity developed in 6% of children with normal weight; 29% of children with overweight; 56% of children with obesity; and 80% of children with severe obesity. However, 38% of the 1440 adults with class II/III obesity (553/1440) were normal weight as children. Prospective risk of adult class II/III obesity varied by age, sex, and race within childhood weight status classifications, and is notably higher for girls, black participants, and those in the United States. The risk of class II/III obesity increased with older adult age., Conclusions: Children with obesity or severe obesity have a substantial risk of adult class II/III obesity, and observed prospective risk estimates are now presented by age, sex, race, and childhood BMI. Clinical monitoring of children's BMI for adult class II/III obesity risk may be especially important for females and black Americans.

Rationale: Data are limited regarding the influence of life-course cumulative burden of increased body mass index (BMI) and elevated blood pressure (BP) on the progression of left ventricular (LV) geometric remodeling in midlife., Objective: To investigate the dynamic changes in LV mass and LV geometry over 6.4 years during midlife and to examine whether the adverse progression of LV geometric remodeling is influenced by the cumulative burden of BMI and BP from childhood to adulthood., Methods and Results: The study consisted of 877 adults (604 whites and 273 blacks; 355 males; mean age=41.4 years at follow-up) who had 5 to 15 examinations of BMI and BP from childhood and 2 examinations of LV dimensions at baseline and follow-up 6.4 years apart during adulthood. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI and systolic BP (SBP). After adjusting for age, race, sex, smoking, alcohol drinking, and baseline LV mass index, the annual increase rate of LV mass index was associated with all BMI measures (β=0.16-0.36, P <0.05 for all), adult SBP (β=0.07, P =0.04), and total AUC of SBP (β=0.09, P =0.01) but not with childhood and incremental AUC values of SBP. All BMI and SBP measures (except childhood SBP) were significantly associated with increased risk of incident LV hypertrophy, with odds ratios of BMI (odds ratio=1.85-2.74, P <0.05 for all) being significantly greater than those of SBP (odds ratio=1.09-1.34, P <0.05 for all except childhood SBP). In addition, all BMI measures were significantly and positively associated with incident eccentric and concentric LV hypertrophy., Conclusions: Life-course cumulative burden of BMI and BP is associated with the development of LV hypertrophy in midlife, with BMI showing stronger associations than BP. Visual Overview: An online visual overview is available for this article.

Background: Historically, cutoff points for childhood and adolescent overweight and obesity have been based on population-specific percentiles derived from cross-sectional data. To obtain cutoff points that might better predict overweight and obesity in young adulthood, we examined the association between childhood body-mass index (BMI) and young adulthood BMI status in a longitudinal cohort., Methods: In this study, we used data from the International Childhood Cardiovascular Cohort (i3C) Consortium (which included seven childhood cohorts from the USA, Australia, and Finland) to establish childhood overweight and obesity cutoff points that best predict BMI status at the age of 18 years. We included 3779 children who were followed up from 1970 onwards, and had at least one childhood BMI measurement between ages 6 years and 17 years and a BMI measurement specifically at age 18 years. We used logistic regression to assess the association between BMI in childhood and young adulthood obesity. We used the area under the receiver operating characteristic curve (AUROC) to assess the ability of fitted models to discriminate between different BMI status groups in young adulthood. The cutoff points were then compared with those defined by the International Obesity Task Force (IOTF), which used cross-sectional data, and tested for sensitivity and specificity in a separate, independent, longitudinal sample (from the Special Turku Coronary Risk Factor Intervention Project [STRIP] study) with BMI measurements available from both childhood and adulthood., Findings: The cutoff points derived from the longitudinal i3C Consortium data were lower than the IOTF cutoff points. Consequently, a larger proportion of participants in the STRIP study was classified as overweight or obese when using the i3C cutoff points than when using the IOTF cutoff points. Especially for obesity, i3C cutoff points were significantly better at identifying those who would become obese later in life. In the independent sample, the AUROC values for overweight ranged from 0·75 (95% CI 0·70-0·80) to 0·88 (0·84-0·93) for the i3C cutoff points, and the corresponding values for the IOTF cutoff points ranged from 0·69 (0·62-0·75) to 0·87 (0·82-0·92). For obesity, the AUROC values ranged from 0·84 (0·75-0·93) to 0·90 (0·82-0·98) for the i3C cutoff points and 0·57 (0·49-0·66) to 0·76 (0·65-0·88) for IOTF cutoff points., Interpretation: The childhood BMI cutoff points obtained from the i3C Consortium longitudinal data can better predict risk of overweight and obesity in young adulthood than can standards that are currently used based on cross-sectional data. Such cutoff points should help to more accurately identify children at risk of adult overweight or obesity., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Rationale: Previous EWASs (Epigenome-Wide Association Studies) suggest that obesity may be the cause, not a consequence, of changes in DNA methylation (DNAm). However, longitudinal observations are lacking., Objective: To identify 5'-cytosine-phosphate-guanine-3' in DNA (CpG) sites associated with body mass index (BMI) and examine the temporal relationship between dynamic changes in DNAm and BMI in a longitudinal cohort., Methods and Results: Race-specific EWASs were performed in 995 whites and 490 blacks from the Bogalusa Heart Study. Suggestive CpG sites were further replicated in 252 whites and 228 blacks from the Georgia Stress and Heart Study. Cross-lagged panel analysis was used to examine the temporal relationship between DNAm and BMI in 439 whites and 201 blacks who were examined twice 6.2 years apart. In discovery and replication samples, 349 CpG sites (266 novel) in whites and 36 (21 novel) in blacks were identified to be robustly associated with BMI, with 8 (1 novel) CpG sites overlapping between the 2 races. Cross-lagged panel analyses showed significant unidirectional paths (P FDR <0.05) from baseline BMI to follow-up DNAm at 18 CpG sites in whites and 7 in blacks; no CpG sites showed significant paths from DNAm at baseline to BMI at follow-up. Baseline BMI was associated with a DNAm score (calculated from DNAm levels at the associated CpG sites) at follow-up ( P <0.001 both in blacks and in whites)., Conclusions: The findings provide strong evidence that obesity is the cause, not a consequence, of changes in DNAm over time.

Background: Childhood body mass index (BMI) predicts adult obesity. How growth trajectories during childhood relate to adult obesity risk is not well defined., Objective: We aimed to characterize BMI growth trajectories from childhood to midlife and to examine the associations between BMI growth rates at childhood age points and adult obesity risk., Methods: The longitudinal study included 2732 participants with repeated BMI measurements from childhood (4-19 y) to adulthood (20-51 y). A random-effects model was used to construct BMI growth curves by race and sex. Model-estimated levels and linear growth rates of BMI were linked to adult obesity in separate multivariable logistic regression models at individual childhood age points., Results: BMI followed cubic growth curves. Childhood BMI linear slope estimates were higher in adults with obesity than in adults without obesity (P < 0.001). The association between childhood BMI growth rate and adult obesity was significantly higher in puberty and postpuberty (12-19 y) than in early childhood (4-11 y) with a peak at age 14 (odds ratio = 3.1 and 95% confidence interval, 2.7-3.5)., Conclusions: Rates of change in BMI at different childhood ages are differentially associated with adult obesity. Puberty and postpuberty are crucial periods for the development of obesity in later life., (© 2019 World Obesity Federation.)

Childhood obesity predicts adult cardiovascular risk. We hypothesized that the association between childhood body mass index (BMI) and adult carotid intima-media thickness (CIMT) may be modified by levels of adiponectin, an adipocytokine that connects body fatness with cardiovascular risk. The study sample included 1,052 adults (71% white and 29% black, 57% female) aged 23.8 to 43.5 years who were previously examined as children in the Bogalusa Heart Study cohort, with an average follow-up period of 26.5 (range 14.1 to 29.6) years. Childhood BMI, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and systolic blood pressure were standardized to age-specific z-scores. General linear models were used for data analyses. Childhood BMI (p = 0.034), low-density lipoprotein cholesterol (p <0.001), and systolic blood pressure (p = 0.005), along with adult adiponectin levels (p = 0.002) were associated with adult CIMT, adjusted for race, sex, adult age, and cigarette smoking. Further, adult adiponectin levels significantly modified the association between childhood BMI and adult CIMT (P for interaction = 0.0003) such that a significant association between childhood BMI and adult CIMT (p <0.0001) was only observed in those with adiponectin levels below the median. In conclusion, these results suggest that serum adiponectin levels modify the association between childhood obesity and adult atherosclerosis, which has implications for risk stratification and targeted intervention for obese children with low levels of adiponectin., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Although obesity and insulin resistance are closely correlated, their temporal sequences in early life and influence on adult hypertension are largely unknown. This study aims to delineate the temporal relationship patterns between body mass index (BMI) and insulin in childhood and their impact on adult hypertension. The longitudinal cohort consisted of 990 adults (630 whites and 360 blacks) who had BMI and fasting insulin measured twice 5.4 years apart in childhood (mean age, 10.5 years at baseline and 15.9 years at follow-up) and blood pressure measured 14.7 years later in adulthood (mean age, 30.5 years). Cross-lagged panel and mediation analysis models were used to examine the temporal relationship between childhood BMI and insulin and its impact on adult hypertension. After adjusting for age, race, sex, and follow-up years, the cross-lagged path coefficient (β=0.33; P<0.001) from baseline BMI to follow-up insulin was significantly greater than the path coefficient (β=-0.02; P>0.05) from baseline insulin to follow-up BMI in childhood with P<0.001 for the difference in βs. Blacks and whites showed similar patterns of the temporal relationship. The path coefficient (β=0.59; P<0.001) from BMI to insulin in the hypertensive group was significantly greater than that (β=0.24; P<0.001) in normotensive group, with P<0.001 for the difference in βs between these 2 groups. The mediation effect of childhood insulin on the childhood BMI-adult hypertension association was estimated at 21.1% (P<0.001). These findings provide evidence that higher BMI levels precede hyperinsulinemia during childhood, and this 1-directional relation plays a role in the development of hypertension., (© 2016 American Heart Association, Inc.)

Background Adult obesity is associated with infertility; however, childhood obesity has received little consideration. Objectives The present study sought to evaluate the impact of childhood adiposity on fertility. Methods Associations between childhood adiposity and self-reported fertility difficulties were estimated among women participating in a long-term study of cardiovascular risks and reproductive health ( n = 1061). Results Participants with obesity between ages 9 and 12 were more likely to report fertility difficulties (adjusted relative risk [aRR], 1.82, 95% CI 1.17-2.82) and inability to become pregnant when trying (aRR = 1.94, 95% CI 1.22-3.08) as were those with obesity prior to age 9 (aRR = 1.76, 95% CI 1.04-2.97). Similar associations were seen among those ever overweight or obese in childhood. High subscapular skinfold thickness (age < 12) increased risk of receiving help becoming pregnant (aRR = 2.16, 95% CI 1.15-4.06), inability to become pregnant (aRR = 1.46, 95% CI 1.05-2.04) and any fertility difficulties (aRR = 1.56, 95% CI 1.13-2.14); associations for triceps skinfold were attenuated. Participants with increased adiposity also had fewer pregnancies and live births. Effects persisted, excluding women with polycystic ovarian syndrome. Conclusions This study supports an association between childhood adiposity and infertility, not solely driven by polycystic ovarian syndrome. [ABSTRACT FROM AUTHOR]