Genetic regulation of the placental transcriptome underlies birth weight and risk of childhood obesity.
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ABSTRACT:
SUBMITTER: Peng S
PROVIDER: S-EPMC6329610 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Childhood obesity is a global public health problem. Understanding the molecular mechanisms that underlie early origins of childhood obesity can facilitate interventions. Consistent phenotypic and genetic correlations have been found between childhood obesity traits and birth weight (a proxy for in-utero growth), suggesting shared genetic influences (pleiotropy). We aimed to (1) investigate whether there is significant shared genetic influence between birth weight and childhood obesity traits, and (2) to identify genetic loci with shared effects. Using a statistical approach that integrates summary statistics and functional annotations for paired traits, we found strong evidence of pleiotropy (P < 3.53 × 10-127) and enrichment of functional annotations (P < 1.62 × 10-39) between birth weight and childhood body mass index (BMI)/obesity. The pleiotropic loci were enriched for regulatory features in skeletal muscle, adipose and brain tissues and in cell lines derived from blood lymphocytes. At 5% false discovery rate, 6 loci were associated with birth weight and childhood BMI and 13 loci were associated with birth weight and childhood obesity. Out of these 19 loci, one locus (EBF1) was novel to childhood obesity and one locus (LMBR1L) was novel to both birth weight and childhood BMI/obesity. These findings give evidence of substantial shared genetic effects in the regulation of both fetal growth and childhood obesity.
| S-EPMC7794220 | biostudies-literature
Project description:Few studies have investigated the association between the full range of birth weight and the risk of childhood obesity in high-, middle- and low-income countries. The aim of the present study is to assess the association between different levels of birth weight and the risk of obesity among children aged 9-11 years in 12 countries.A multinational, cross-sectional study of 5141 children aged 9-11 years was conducted in 12 countries. Height and weight were obtained using standardized methods. Time spent in moderate-to-vigorous physical activity (MVPA), sedentary and sleeping were objectively measured using 24-h, waist-worn accelerometer (Actigraph GT3X+) monitored for 7 days. Birth weight and other factors (regions, parental education, maternal history of gestational diabetes, children age, gender, breast feeding, gestational age, unhealthy diet scores and healthy diet scores) were collected by parental and children's questionnaires. Multilevel modeling was used to account for the nested nature of the data.The overall prevalence of obesity (BMI z-score>+2 s.d.) was 15.4% for boys and 10.0% for girls. There was a positive association between birth weight and BMI z-scores. The multivariable-adjusted odds ratios (ORs) of childhood obesity were significantly higher among children whose birth weights were 3500-3999 g (OR 1.45; 95% confidence interval (CI): 1.10-1.92), and >4000 g (OR 2.08; 95% CI: 1.47-2.93), compared with the reference group (2500-2999 g). The positive association between birth weight and the odds of childhood obesity was seen in girls, whereas a U-shaped association appeared in boys.High levels of birth weight, defined as birth weight ⩾3500 g, were associated with increased odds of obesity among 9-11-year-old children in 12 countries. However, sex differences in the association between birth weight and the risk of obesity need to be considered when planning interventions to reduce childhood obesity.
| S-EPMC4850624 | biostudies-other
Project description:BackgroundBirth weight (BW) is associated with risk of cardiometabolic disease (CMD) in adulthood, which may depend on the state of obesity, in particular if developed at a young age. We hypothesised that BW and a polygenic score (PGS) for BW were associated with cardiometabolic risk and related plasma protein levels in children and adolescents. We aimed to determine the modifying effect of childhood obesity on these associations.MethodsWe used data from The cross-sectional HOLBAEK Study with 4263 participants (median [IQR] age, 11.7 [9.2, 14.3] years; 57.1% girls and 42.9% boys; 48.6% from an obesity clinic and 51.4% from a population-based group). We gathered information on BW and gestational age, anthropometrics, cardiometabolic risk factors, calculated a PGS for BW, and measured plasma proteins using Olink Inflammation and Cardiovascular II panels. We employed multiple linear regression to examine the associations with BW as a continuous variable and performed interaction analyses to assess the effect of childhood obesity on cardiometabolic risk and plasma protein levels.FindingsBW and a PGS for BW associated with cardiometabolic risk and plasma protein levels in childhood and adolescence. Childhood obesity modified the associations between BW and measures of insulin resistance, including HOMA-IR (βadj [95% CI per SD] for obesity: -0.12 [-0.15, -0.08]; normal weight: -0.04 [-0.08, 0.00]; Pinteraction = 0.004), c-peptide (obesity: -0.11 [-0.14, -0.08]; normal weight: -0.02 [-0.06, 0.02]; Pinteraction = 5.05E-04), and SBP SDS (obesity: -0.12 [-0.16, -0.08]; normal weight: -0.06 [-0.11, -0.01]; Pinteraction = 0.0479). Childhood obesity also modified the associations between BW and plasma levels of 14 proteins (e.g., IL15RA, MCP1, and XCL1; Pinteraction < 0.05).InterpretationWe identified associations between lower BW and adverse metabolic phenotypes, particularly insulin resistance, blood pressure, and altered plasma protein levels, which were more pronounced in children with obesity. Developing effective prevention and treatment strategies for this group is needed to reduce the risk of future CMD.FundingNovo Nordisk Foundation (NNF15OC0016544, NNF0064142 to T.H., NNF15OC0016692 to T.H. and A.K., NNF18CC0033668 to S.E.S, NNF18SA0034956 to C.E.F., NNF20SA0067242 to DCA, NNF18CC0034900 to NNF CBMR), The Innovation Fund Denmark (0603-00484B to T.H.), The Danish Cardiovascular Academy (DCA) and the Danish Heart Foundation (HF) (PhD2021007-DCA to P.K.R, 18-R125-A8447-22088 (HF) and 21-R149-A10071-22193 (HF) to M.A.V.L., PhD2023009-HF to L.A.H), EU Horizon (668031, 847989, 825694, 964590 to A.K.), Innovative Health Initiative (101132901 for A.K.), A.P. Møller Foundation (19-L-0366 to T.H.), The Danish National Research Foundation, Steno Diabetes Center Sjælland, and The Region Zealand and Southern Denmark Health Scientific Research Foundation.
| S-EPMC11293585 | biostudies-literature
Project description:BackgroundThere are both genetic and environmental factors which contribute to a child's chances of being obese. When low birth weight (LBW) has been specifically evaluated relative to its association with childhood obesity, the results have produced conflicting findings. This study aims to describe the relationship between birth weight and childhood obesity and investigate the influence that residence and household wealth has on this relationship.MethodsI performed a secondary analysis on the 2013 Riskesdas (or Basic Health Research), a cross-sectional, nationally representative survey of the Indonesian population. Height, weight, information regarding child's birth weight, and basic characteristics of the study population were collected from parents with children aged 0 to 5 years (n = 63,237) in 2013. The exposure was child's birth weight and the outcomes were child's current weight, BMI z-score, and obesity. Data were analyzed by using multiple linear regression and multiple logistic regression.ResultsI found a significant increase in the weight, BMI z-score, and risk of childhood obesity to be associated with LBW. LBW children in rural area were associated with higher BMI z-score (mean ± standard error: 1.44 ± 0.02) and higher odds (odds ratio (95% confidence interval): 7.46 (6.77-8.23)) of obesity than those in urban area. LBW children from low class families were associated with higher BMI z-score (1.79 ± 0.04) and had higher odds (14.79 (12.47-17.54)) of obesity than those from middle class and wealthy families.ConclusionsEffective prevention and intervention to childhood obesity as early as possible are imperative. As far as this study was concerned, efforts, policies, and targets are required to reduce the prevalence of LBW. Children born of LBW, who live in a rural area and from low income families, should be emphatically intervened as early as possible.
| S-EPMC8111737 | biostudies-literature
Project description:Dynamic changes in body weight have long been recognized as important indicators of risk for human health. Many population-based observational studies have shown that rapid weight gain during infancy, including a catch-up growth phenomenon or adiposity rebound in early childhood, predisposes a person to the development of obesity, type 2 diabetes, and cardiovascular diseases later in life. However, a consensus has not been established regarding which period of weight gain contributes to future risks. This review evaluates recent evidence on the relationship between early rapid growth and future obesity and cardiometabolic risk, with a focus on the differential significance of rapid weight gain in infancy and early childhood. Although there is a need for attention to childhood growth during early infancy before 1 yr of age as it may be related to future obesity, emerging evidence strongly suggests that toddlers showing an increase in body mass index (BMI) before 3 yr of age, a period normally characterized by decreased BMI, are prone to developing later cardiometabolic risk.
| S-EPMC7534524 | biostudies-literature
Project description:ObjectiveColorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Obesity is a well-established risk factor for CRC, and fetal or developmental origins of obesity may underlie its effect on cancer in adulthood. We examined associations of maternal obesity, pregnancy weight gain, and birth weight and CRC in adult offspring.DesignThe Child Health and Development Studies is a prospective cohort of women receiving prenatal care between 1959 and 1966 in Oakland, California (N=18 751 live births among 14 507 mothers). Clinical information was abstracted from mothers' medical records 6 months prior to pregnancy through delivery. Diagnoses of CRC in adult (age ≥18 years) offspring were ascertained through 2019 by linkage with the California Cancer Registry. We used Cox proportional hazards models to estimate adjusted HR (aHR); we examined effect measure modification using single-referent models to estimate the relative excess risk due to interaction (RERI).Results68 offspring were diagnosed with CRC over 738 048 person-years of follow-up, and half (48.5%) were diagnosed younger than age 50 years. Maternal obesity (≥30 kg/m2) increased the risk of CRC in offspring (aHR 2.51, 95% CI 1.05 to 6.02). Total weight gain modified the association of rate of early weight gain (RERI -4.37, 95% CI -9.49 to 0.76), suggesting discordant growth from early to late pregnancy increases risk. There was an elevated association with birth weight (≥4000 g: aHR 1.95, 95% CI 0.8 to 4.38).ConclusionOur results suggest that in utero events are important risk factors for CRC and may contribute to increasing incidence rates in younger adults.
| S-EPMC8866526 | biostudies-literature
Project description:INTRODUCTION:Preterm birth (PTB) and in-utero inflammation are recognized risk factors of neurodevelopmental disabilities (NDDs); however, their combined role in NDDs is unknown. We examined the independent and joint association of PTB and placental histological findings with the childhood risk of NDDs (overall and by subgroups including autism spectrum disorder (ASD) and ADHD). METHODS:We analyzed data from the Boston Birth Cohort, where mother-infant pairs were enrolled at birth and followed from birth onwards. Birth outcomes, placental pathology and NDDs were obtained from electronic medical records. Placental pathology was categorized using a standardized classification system proposed by the Amsterdam Placental Workshop Group. RESULTS:PTB (all, including spontaneous, medically indicated) was an independent risk factor for NDDs. Placental histological chorioamnionitis (CA) and PTB additively increased the odds of NDDs (aOR: 2.16, 95% CI: 1.37, 3.39), as well as ADHD (aOR: 2.75, 95% CI: 1.55, 4.90), other developmental disabilities (aOR: 1.96, 95% CI: 1.18, 3.25) and possibly ASD (aOR: 2.31, 95% CI: 0.99, 5.39). The above associations were more pronounced in spontaneous than medically indicated PTB. PTB alone in the absence of CA only had a moderate association with ASD and ADHD. Placental maternal vascular malperfusion alone or in combination with PTB was not associated with the risk of NDDs. DISCUSSION:Our study provided new insights on PTB and NDDs by further considering preterm subtypes and placental histology. We revealed that children of spontaneous PTB along with histological CA were at the highest risk for a spectrum of NDDs.
| S-EPMC6727987 | biostudies-literature
Project description:ObjectivesTo investigate the impact of gestational weight gain (GWG) on the body mass index-for-age z score (BAZ) and obesity risk among twin offspring.MethodsThis study included 263 women who were pregnant with twins and their offspring. Maternal GWG was measured in each trimester, and infant weight and length were measured at 6, 12, and 24 months.ResultsTotal GWG was positively correlated with offspring birthweight and BAZ at 6, 12 and 24 months [adjusted β 0.013 (95% CI: 0.008-0.019), 0.028 (95% CI: 0.005-0.050), 0.033 (95% CI: 0.010-0.056) and 0.025 (95% CI: 0.004-0.047), respectively]. Excessive total GWG was related to an increased relative risk (RR) of large for gestational age (LGA) and overweight at 6 and 12 months. Only the second trimester gestational weight gain rate (GWGR) was positively correlated with birthweight (adjusted β 0.380, 95% CI: 0.256-0.504), and RRs of 6.818 (95% CI: 1.568-29.642) and 2.852 (95% CI: 1.466-5.548) were found for LGA and overweight at 12 months, respectively.ConclusionsTotal GWG and the second trimester GWGR were correlated with BAZ and overweight/obesity risk in twin offspring; the impact was obvious in the first year of life and gradually disappeared over time.Clinical trial registrationChiCTR-OOC-16008203, Registered on 1 April 2016 at the Chinese Clinical Trial Registry.
| S-EPMC9378839 | biostudies-literature
Project description:Heavy metal exposures, such as cadmium, can have negative effects on infant birth weight (BW)-among other developmental outcomes-with placental dysfunction potentially playing a role in these effects. In this study, we examined how differential placental expression of long non-coding RNAs (lncRNAs) may be associated with cadmium levels in placenta and whether differences in the expression of those lncRNAs were associated with fetal growth. In the Rhode Island Child Health Study, we used data from Illumina HiSeq whole transcriptome RNA sequencing (n = 199) to examine association between lncRNA expression and measures of infant BW as well as placental cadmium concentrations controlled for appropriate covariates. Of the 1191 lncRNAs sequenced, 46 demonstrated associations (q < 0.05) with BW in models controlling for infant sex, maternal age, BMI, maternal education, and smoking during pregnancy. Furthermore, four of these transcripts were associated with placental cadmium concentrations, with MIR22HG and ERVH48-1 demonstrating increases in expression associated with increasing cadmium exposure and elevated odds of small for gestational age birth, while AC114763.2 and LINC02595 demonstrated reduced expression associated with cadmium, but elevated odds of large for gestational age birth with increasing expression. We identified relationships between lncRNA expression with both placental cadmium concentrations and BW. This study provides evidence that disrupted placental expression of lncRNAs may be a part of cadmium's mechanisms of reproductive toxicity.
| S-EPMC7211362 | biostudies-literature
Project description:BackgroundObservational studies have revealed associations between birth weight, childhood obesity, age at menarche, and ovarian dysfunction. However, these studies are susceptible to unavoidable confounding factors, leading to ongoing debates regarding their conclusions and making causal relationships challenging to infer. In light of these challenges, Mendelian randomization was employed in this study to investigate the causal relationships between birth weight, childhood obesity, age at menarche, and ovarian dysfunction.MethodsThis study employed a two-sample Mendelian randomization approach using genetic variation as instrumental variables to investigate causal relationships. Genetic variation data were sourced from summary data of genome-wide association studies in European populations. Instrumental variables were selected based on the principles of Mendel's three assumptions. The study utilized the inverse variance weighted method to assess the relationships between birth weight, childhood obesity, age at menarche, and ovarian dysfunction. Supplementary analyses were conducted using MR-Egger regression, the weighted median method, and the weighted median mode to complement the IVW results. Furthermore, the study conducted heterogeneity, horizontal pleiotropy, and sensitivity analyses to evaluate the robustness of the results.ResultsBased on the inverse variance weighted method, it was found that there exists a causal relationship between childhood obesity (OR = 1.378, 95% CI: 1.113∼1.705, p = 0.003), age at menarche (OR = 0.639, 95% CI: 0.468∼0.871, p = 0.005), and ovarian dysfunction, while no causal relationship was observed between birth weight and ovarian dysfunction. Heterogeneity tests, multiplicity tests, and leave-one-out sensitivity analyses did not detect any heterogeneity or multiplicity effects in the estimated impact of these three exposure factors on the risk of ovarian dysfunction.ConclusionsThis study represents the first evidence suggesting a potential causal relationship between childhood obesity, age at menarche, and ovarian dysfunction. Childhood obesity was found to increase the risk of ovarian dysfunction, while a later age at menarche was associated with a reduced risk of ovarian dysfunction.
| S-EPMC11257363 | biostudies-literature