Investigation of metabolomic biomarkers for childhood executive function and the role of genetic and dietary factors : The GUSTO cohort

Background Few studies have investigated molecular biomarkers of specific executive function (EF) skills in children. We aimed to characterise the prospective associations between metabolome and multiple domains of EF using a bidirectional design. Methods This study was conducted within a longitudinal birth cohort, the Growing Up in Singapore Towards healthy Outcomes (GUSTO). Circulating levels of 165 metabolites were quantified using a nuclear magnetic resonance based metabolomics platform (n = 457 (~6yrs) and n = 524 (~8yrs)). Parent-reported EF was available for 495 children (~7yrs). Multivariate linear regression was used to assess the metabolite-EF relationships. We examined the role of body composition, dietary factors, and genetics in the metabolite-EF associations. Findings Higher leucine level (~6yrs) was associated with poorer EF (~7yrs, Initiate (P = 0.003) and Working Memory (P = 0.004)). EF (~7yrs) was not associated with leucine (~8yrs). Importantly, we found weak evidence for associations of dietary factors (~5yrs) with leucine (~6yrs) and EF (~7yrs). Each copy of C allele in rs1260326 (a leucine-related polymorphism) was associated with higher leucine level and poorer Initiate and Working Memory (P < 0.05). Amongst those with less strongly genetically influenced leucine, inverse association between leucine and cognitive regulation were weaker among those with higher BMI. Interpretation The observed association between higher leucine level and poorer EF may be determined by genetics and may not be easily amenable to dietary interventions. Further research is needed for validation and to understand mechanisms. Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Variability in newborn telomere length is explained by inheritance and intrauterine environment

Background: Telomere length (TL) and its attrition are important indicators of physiological stress and biological aging and hence may vary among individuals of the same age. This variation is apparent even in newborns, suggesting potential effects of parental factors and the intrauterine environment on TL of the growing fetus. Methods: Average relative TLs of newborns (cord tissue, N = 950) and mothers (buffy coat collected at 26-28 weeks of gestation, N = 892) were measured in a birth cohort. This study provides a comprehensive analysis of the effects of heritable factors, socioeconomic status, and in utero exposures linked with maternal nutrition, cardiometabolic health, and mental well-being on the newborn TL. The association between maternal TL and antenatal maternal health was also studied. Results: Longer maternal TL (beta = 0.14, P = 1.99E-05) and higher paternal age (beta = 0.10, P = 3.73E-03) were positively associated with newborn TL. Genome-wide association studies on newborn and maternal TLs identified 6 genetic variants in a strong linkage disequilibrium on chromosome 3q26.2 (Tag SNP-LRRC34-rs10936600: P-meta = 5.95E-08). Mothers with higher anxiety scores, elevated fasting blood glucose, lower plasma insulin-like growth factor-binding protein 3 and vitamin B12 levels, and active smoking status during pregnancy showed a higher risk of giving birth to offspring with shorter TL. There were sex-related differences in the factors explaining newborn TL variation. Variation in female newborn TL was best explained by maternal TL, mental health, and plasma vitamin B12 levels, while that in male newborn TL was best explained by paternal age, maternal education, and metabolic health. Mother's TL was associated with her own metabolic health and nutrient status, which may have transgenerational effects on offspring TL. Conclusions: Our findings provide a comprehensive understanding of the heritable and environmental factors and their relative contributions to the initial setting of TL and programing of longevity in early life. This study provides valuable insights for preventing in utero telomere attrition by improving the antenatal health of mothers via targeting the modifiable factors.Peer reviewe

Exploring how socioeconomic status affects neighbourhood environments? : effects on obesity risks : a longitudinal study in Singapore

Research on how socioeconomic status interacts with neighbourhood characteristics to influence disparities in obesity outcomes is currently limited by residential segregation-induced structural confounding, a lack of empirical studies outside the U.S. and other 'Western' contexts, and an over-reliance on cross-sectional analyses. This study addresses these challenges by examining how socioeconomic status modifies the effect of accumulated exposures to obesogenic neighbourhood environments on children and mothers' BMI, drawing from a longitudinal mother-child birth cohort study in Singapore, an Asian city-state with relatively little residential segregation. We find that increased access to park connectors was associated with a decrease in BMI outcomes for mothers with higher socioeconomic status, but an increase for those with lower socioeconomic status. We also find that increased access to bus stops was associated with an increase in BMIz of children with lower socioeconomic status, but with a decrease in BMIz of children with higher socioeconomic status, while increased access to rail stations was associated with a decrease in BMIz of children with lower socioeconomic status only. Our results suggest that urban interventions might have heterogeneous effects by socioeconomic status.Peer reviewe

Dietary Pattern Trajectories from 6 to 12 Months of Age in a Multi-Ethnic Asian Cohort

10.3390/nu8060365Nutrients86365GUSTO (Growing up towards Healthy Outcomes

Validation of the Children’s Eating Behavior Questionnaire in 5 and 6 Year-Old Children: The GUSTO Cohort Study

Revised subscales of the Children’s Eating Behavior Questionnaire (CEBQ) have been proposed to be more appropriate for assessing appetitive traits in Singaporean 3 year-olds, but the CEBQ has not yet been validated in older children in this population. The current study aimed to validate the CEBQ at ages 5 (n = 653) and 6 (n = 449) in the ethnically diverse GUSTO cohort. Confirmatory factor analysis (CFA) examined whether the established eight-factor model of the CEBQ was supported in this sample. Overall, the CFA showed a poor model fit at both ages 5 and 6. At both ages 5 and 6, an exploratory factor analysis revealed a six-factor structure: food fussiness, enjoyment of food, slowness in eating, emotional undereating, emotional overeating and desire to drink. Cronbach’s alpha estimates ranged from 0.70 to 0.85 for all subscales. Criterion validity was tested by correlating subscales with the weight status of 6 years of age. At age 5 and 6, lower scores of slowness of eating while higher scores of enjoyment of food was associated with child overweight. At age 6, higher scores of desire to drink was also associated child overweight. In conclusion, a revised six factor-structure of the CEBQ at ages 5 and 6 were more appropriate for examining appetitive traits in this sample

The Kynurenine Pathway Metabolites in Cord Blood Positively Correlate With Early Childhood Adiposity

Context The kynurenine pathway generates metabolites integral to energy metabolism, neurotransmission, and immune function. Circulating kynurenine metabolites positively correlate with adiposity in children and adults, yet it is not known whether this relationship is present already at birth. Objective In this prospective longitudinal study, we investigate the relationship between cord blood kynurenine metabolites and measures of adiposity from birth to 4.5 years. Methods Liquid chromatography-tandem mass spectrometry was used to quantify cord blood kynurenine metabolites in 812 neonates from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study. Fat percentage was measured by air displacement plethysmography and abdominal adipose tissue compartment volumes; superficial (sSAT) and deep subcutaneous (dSAT) and internal adipose tissue were quantified by magnetic resonance imaging at early infancy in a smaller subset of neonates, and again at 4 to 4.5 years of age. Results Cord blood kynurenine metabolites appeared to be higher in female newborns, higher in Indian newborns compared with Chinese newborns, and higher in infants born by cesarean section compared with vaginal delivery. Kynurenine, xanthurenic acid, and quinolinic acid were positively associated with birthweight, but not with subsequent weight during infancy and childhood. Quinolinic acid was positively associated with sSAT at birth. Kynurenic acid and quinolinic acid were positively associated with fat percentage at 4 years. Conclusion Several cord blood kynurenine metabolite concentrations were positively associated with birthweight, with higher kynurenic acid and quinolinic acid correlating to higher percentage body fat in childhood, suggesting these cord blood metabolites as biomarkers of early childhood adiposity.Peer reviewe

Longitudinal Analysis Between Maternal Feeding Practices and Body Mass Index (BMI): A Study in Asian Singaporean Preschoolers

Bidirectional studies between maternal feeding practices with subsequent child weight are limited, with no studies in Asian populations. In longitudinal analyses, we assessed the directionality of the associations between maternal feeding practices and body mass index (BMI) in preschoolers. Participants were 428 mother child dyads from the GUSTO (Growing Up in Singapore Toward healthy Outcomes) cohort. Feeding practices were assessed using the Comprehensive Feeding Practices Questionnaire (CFPQ) at age 5 y. Child BMI was measured at ages 4 and 6 y. BMI and maternal feeding practices subscales were transformed to SD scores and both directions of their associations examined with multivariable linear regression and pathway modeling. Higher BMI at age 4 was associated with lower encouragement of balance and variety (β = −0.33; 95%CI: −0.53, −0.13), lower pressure to eat (β = −0.49; −0.68, −0.29) and higher restriction (β = 1.10; 0.67, 1.52) at age 5, adjusting for confounders and baseline feeding practices at 3 years. In the reverse direction, only pressure and restriction at age 5 were associated with lower and higher child BMI at age 6 years, respectively. After the adjustment for baseline BMI at age 5, the association with pressure was attenuated to non-significance (β = 0.01 (−0.01, 0.03), while the association with restriction remained significant (β = 0.02; 0.002, 0.03). Overall, associations from child BMI to maternal restriction for weight control and pressure feeding practices was stronger than the association from these maternal feeding practices to child BMI (Wald's statistics = 24.3 and 19.5, respectively; p &lt; 0.001). The strength and directionality suggests that the mothers in the Asian population were likely to adopt these feeding practices in response to their child's BMI, rather than the converse.Clinical Trial Registry Number and Website This study was registered at clinicaltrials.gov as NCT01174875 (www.clinicaltrials.gov, NCT01174875)

The socioeconomic landscape of the exposome during pregnancy

Background: While socioeconomic position (SEP) is consistently related to pregnancy and birth outcome dis-parities, relevant biological mechanisms are manifold, thus necessitating more comprehensive characterization of SEP-exposome associations during pregnancy. Objectives: We implemented an exposomic approach to systematically characterize the socioeconomic landscape of prenatal exposures in a setting where social segregation was less distinct in a hypotheses-generating manner. Methods: We described the correlation structure of 134 prenatal exogenous and endogenous sources (e.g., micronutrients, hormones, immunomodulatory metabolites, environmental pollutants) collected in a diverse, population-representative, urban, high-income longitudinal mother-offspring cohort (N = 1341; 2009-2011). We examined the associations between maternal, paternal, household, and areal level SEP indicators and 134 ex-posures using multiple regressions adjusted for precision variables, as well as potential effect measure modifi-cation by ethnicity and nativity. Finally, we generated summary SEP indices using Multiple Correspondence Analysis to further explore possible curved relationships. Results: Individual and household SEP were associated with anthropometric/adiposity measures, folate, omega-3 fatty acids, insulin-like growth factor-II, fasting glucose, and neopterin, an inflammatory marker. We observed paternal education was more strongly and consistently related to maternal exposures than maternal education. This was most apparent amongst couples discordant on education. Analyses revealed additional non-linear as-sociations between areal composite SEP and particulate matter. Environmental contaminants (e.g., per-and polyfluoroalkyl substances) and micronutrients (e.g., folate and copper) showed opposing associations by ethnicity and nativity, respectively. Discussion: SEP-exposome relationships are complex, non-linear, and context specific. Our findings reinforce the potential role of paternal contributions and context-specific modifiers of associations, such as between ethnicity and maternal diet-related exposures. Despite weak presumed areal clustering of individual exposures in our context, our approach reinforces subtle non-linearities in areal-level exposures.Peer reviewe

Family-focused contextual factors associated with lifestyle patterns in young children from two mother-offspring cohorts : GUSTO and EDEN

Background Integrated patterns of energy balance-related behaviours of preschool children in Asia are sparse, with few comparative analyses. Purpose Using cohorts in Singapore (GUSTO) and France (EDEN), we characterized lifestyle patterns of children and investigated their associations with family-focused contextual factors. Methods Ten behavioural variables related to child's diet, walking, outdoor play and screen time were ascertained by parental questionnaires at age 5-6 years. Using principal component analysis, sex-specific lifestyle patterns were derived independently for 630 GUSTO and 989 EDEN children. Contextual variables were organised into distal (family socio-economics, demographics), intermediate (parental health, lifestyle habits) and proximal (parent-child interaction factors) levels of influence and analysed with hierarchical linear regression. Results Three broadly similar lifestyle patterns were identified in both cohorts: "discretionary consumption and high screen time", "fruit, vegetables, and low screen time" and "high outdoor playtime and walking". The latter two patterns showed small differences between cohorts and sexes. The "discretionary consumption and high screen time" pattern was consistently similar in both cohorts; distal associated factors were lower maternal education (EDEN boys), no younger siblings (GUSTO boys) and Malay/Indian ethnicity (GUSTO), while intermediate and proximal associated factors in both cohorts and sexes were poor maternal diets during pregnancy, parents allowing high child control over food intake, snacking between meals and having television on while eating. Conclusions Three similar lifestyle patterns were observed among preschool children in Singapore and France. There were more common associated proximal factors than distal ones. Cohort specific family-focused contextual factors likely reflect differences in social and cultural settings. Findings will aid development of strategies to improve child health.Peer reviewe

Hypomethylating agent decitabine sensitizes diffuse large B-cell lymphoma to venetoclax

Despite recent advances in the therapy of diffuse large B-cell lymphoma (DLBCL), many patients are still not cured. Therefore, new therapeutic strategies are needed. The anti-apoptotic B-cell lymphoma 2 (BCL2) gene is commonly dysregulated in DLBCL due to various mechanisms such as chromosomal translocation t(14;18)(q32;q21) and copy number alterations; however, targeting BCL-2 with the selective inhibitor, venetoclax, led to response in only a minority of patients. Thus, we sought to identify a rational combination partner of venetoclax to improve its activity against DLBCL cells. Utilizing a functional assay, dynamic BH3 profiling, we found that the DNA hypomethylating agent decitabine increased mitochondrial apoptotic priming and BCL-2 dependence in DLBCL cells. RNA-sequencing analysis revealed that decitabine suppressed the pro-survival PI3K-AKT pathway and altered the mitochondria membrane composition in DLBCL cell lines. Additionally, it induced a DNA damage response and increased BAX and BAK activities. The combination of decitabine and venetoclax synergistically suppressed proliferation of DLBCL cells both in vitro and in vivo in a DLBCL cell line-derived xenograft mouse model. Our study suggests that decitabine plus venetoclax is a promising combination to explore clinically in DLBCL