Insulin-Like Growth Factor 2/H19 Methylation at Birth and Risk of Overweight and Obesity in Children

Department of Community and Family Medicine, Duke University, Durham, NC 27710, USA.
The Journal of pediatrics (Impact Factor: 3.79). 02/2012; 161(1):31-9. DOI: 10.1016/j.jpeds.2012.01.015
Source: PubMed


To determine whether aberrant DNA methylation at differentially methylated regions (DMRs) regulating insulin-like growth factor 2 (IGF2) expression in umbilical cord blood is associated with overweight or obesity in a multiethnic cohort.
Umbilical cord blood leukocytes of 204 infants born between 2005 and 2009 in Durham, North Carolina, were analyzed for DNA methylation at two IGF2 DMRs by using pyrosequencing. Anthropometric and feeding data were collected at age 1 year. Methylation differences were compared between children >85th percentile of the Centers for Disease Control and Prevention growth charts weight-for-age (WFA) and children ≤ 85th percentile of WFA at 1 year by using generalized linear models, adjusting for post-natal caloric intake, maternal cigarette smoking, and race/ethnicity.
The methylation percentages at the H19 imprint center DMR was higher in infants with WFA >85th percentile (62.7%; 95% CI, 59.9%-65.5%) than in infants with WFA ≤ 85th percentile (59.3%; 95% CI, 58.2%-60.3%; P = .02). At the intragenic IGF2 DMR, methylation levels were comparable between infants with WFA ≤ 85th percentile and infants with WFA >85th percentile.
Our findings suggest that IGF2 plasticity may be mechanistically important in early childhood overweight or obese status. If confirmed in larger studies, these findings suggest aberrant DNA methylation at sequences regulating imprinted genes may be useful identifiers of children at risk for the development of early obesity.

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    • "Information on anthropometric measurements during pregnancy, birth outcomes , including birth weight and length, was abstracted from medical records. Umbilical cord blood specimens were also collected at birth, as previously described [36] [37]. "
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    ABSTRACT: At birth, elevated IGF-I levels have been linked to birth weight extremes; high birth weight and low birth weight are risk factors for adult-onset chronic diseases including obesity, cardiovascular disease, and type 2 diabetes. We examined associations between plasma IGF-I levels and birth weight among infants born to African American and White obese and nonobese women. Prepregnancy weight and height were assessed among 251 pregnant women and anthropometric measurements of full term infants (≥37 weeks of gestation) were taken at birth. Circulating IGF-I was measured by ELISA in umbilical cord blood plasma. Linear regression models were utilized to examine associations between birth weight and high IGF-I, using the bottom two tertiles as referents. Compared with infants with lower IGF-I levels (≤3rd tertile), those with higher IGF-I levels (>3rd tertile) were 130 g heavier at birth, (β-coefficient = 230, se = 58.0, P = 0.0001), after adjusting for gender, race/ethnicity, gestational age, delivery route, maternal BMI and smoking. Stratified analyses suggested that these associations are more pronounced in infants born to African American women and women with BMI ≥30 kg/m(2); the cross product term for IGF-I and maternal BMI was statistically significant (P ≤ 0.0004). Our findings suggest that the association between IGF-I levels and birth weight depends more on maternal obesity than African American race/ethnicity.
    Full-text · Article · May 2013 · International Journal of Pediatrics
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    • "It has been proposed that prenatal exposure to different compounds, among them xenoestrogens, might exert their effects by altering these tightly regulated epigenetic programs (Heindel and vom Saal, 2009). Interestingly, functional estrogen response elements (ERE), at least in rat testis, have been described in the IGF2-H19 locus, a key imprinted genomic region involved in the control of fetal growth and which is usually disregulated in cancer (Charalambous et al., 2007; Hamelers and Steenbergh, 2003; Koukoura et al., 2011; Nativio et al., 2011; Pathak et al., 2010; Perkins et al., 2012). In addition, the IGF2 gene is overexpressed in the hypothalamus of rats after estrogen treatment (Takeo et al., 2009). "
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    ABSTRACT: BACKGROUND: Fetal exposure to endocrine disrupting chemicals may increase the risk for adverse health effects at birth or later in life. OBJECTIVES: The objective of this study is to analyze the combined effect of xenoestrogens on reproductive and perinatal growth outcomes (child birthweight, early rapid growth and body mass index (BMI) at 14months) using the biomarker total effective xenoestrogen burden (TEXB). METHODS: 490 placentas were randomly collected in the Spanish prospective birth cohort Environment and Childhood (INMA) project. TEXB was used to assess the estrogenicity of placental samples in two fractions: that largely attributable to environmental organohalogenated xenoestrogens (TEXB-alpha), and that mostly due to endogenous estrogens (TEXB-beta), both expressed in estrogen equivalent units (Eeq) per gram of tissue. Linear or logistic regression models were performed adjusting for cohort and confounders. Sex interactions were investigated. RESULTS: The median TEXB-alpha level was 0.76pMEeq/g (interquartile range (iqr): 1.14). In multivariate models, higher TEXB-alpha levels (third tertile, >1.22pMEeq/g; iqr: 1.73) were associated with increased birthweight in boys but not in girls (β=148.2g, 95% CI: 14.01, 282.53, p(int)=0.057). Additionally, higher TEXB-alpha values in boys were related with a lower risk of early rapid growth (OR=0.37; 95% CI: 0.15, 0.88) and with a non significant association with larger BMI z-scores at 14months of age (β=0.29; 95% CI: -0.11, 0.69). CONCLUSIONS: These findings suggest that prenatal exposure to xenoestrogens may increase birthweight in boys, which might have an impact on child obesity and other later health outcomes.
    Full-text · Article · Dec 2012 · Environment international
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    • "In addition, periconceptional folic acid supplementation has also been associated with increased DNA methylation levels at the IGF2 DMR (upstream of exon 3) [28]. Such supplementation has also been associated with decreased methylation at the ICR region CTCF6 [29] that has been linked to overweight status at age one year [30]. We hypothesize that this overweight status may persist to age 17 years. "
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    ABSTRACT: Background The insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity. DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression. Results The principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units) positively correlated with skin fold thickness (at four CpG units) (P-values between 0.04 to 0.001) and subcutaneous adiposity (P = 0.023) at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. β-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC. Conclusions As greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we hypothesize that the HC may be a more sensitive marker of early life programming of the IGF axis and of fetal physiology than birth size. To verify this, investigations of the dynamics of IGF2/H19 methylation and expression from birth to adolescence are required.
    Full-text · Article · Nov 2012 · Clinical Epigenetics
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