Maternal diabetes and obesity influence the fetal epigenome in a largely Hispanic population

Alarming rates of increase in childhood obesity and type-2 diabetes (T2D) are being seen in the U.S. In 2015, an estimated 30.3 million people in the U.S. had T2D. Approximately 12.7 million children and adolescents — ages 2 to 19 — are obese, and there are estimates that >25% of children will be classified as overweight or obese by the time they enter kindergarten (ages 5-6). This rapid increase strongly indicates these do not represent DNA mutations, but rather they must be caused by alterations in the epigenome.

Hispanic Americans are particularly at risk for obesity, T2D, and end-stage renal disease; risk of obesity is ~35% higher in the Hispanic population — obese Hispanic and non-Hispanic black adolescent females being among those at highest risk for developing T2D. Concomitant obesity and diabetes during pregnancy are also associated with increased risk of Metabolic Syndrome in offspring. In South Texas alone, 29% of mothers have a pre-pregnancy body-mass index (BMI) of 30 or above, and 4.8% of mothers go on to develop gestational diabetes mellitus (GDM).

Recall (from these GEITP pages previously) that multifactorial traits (e.g. T2D, obesity) reflect the combination of genetics (i.e. changes in DNA sequence), epigenetic effects (no changes in DNA sequence), environmental factors (e.g. diet, lifestyle), endogenous influences (e.g. heart, lung or kidney disease), and the individual’s microbiome (bacteria, viruses, fungi especially in gut). Also recall that epigenetic effects include DNA methylation, RNA interference (RNAi), histone modifications, and chromatin remodeling. Hypermethylation (increases in methylated DNA) is associated with promoter regions of genes to inhibit gene expression and can also arise secondarily to oncogene suppressor silencing (sometimes this might be a clinical target for epigenetic therapy). Hypomethylation generally arises earlier during development, and is often linked to increased gene expression, but also chromosomal instability and loss of imprinting.

Exposure to a diabetic intrauterine environment during pregnancy is associated with increased dyslipidemia, subclinical vascular inflammation, and endothelial dysfunction processes in offspring — all of which are known to be correlated with development of cardiovascular disease later in life. Maternal obesity and GDM have also been linked to increased risk of asthma, poorer cognitive performance, mental health disorders, neurodevelopmental disorders including cerebral palsy, and immune and infectious disease-related outcomes.

The concept of “gestational programming” is associated with alterations in the epigenome. Significant hypermethylation of DNA may also occur globally in placenta of mothers with GDM — as well as in the cord and neonatal blood of infants born to mothers with GDM, particularly genes associated with Metabolic Syndrome (hypermethylation may repress transcription — leading to dysregulation of metabolic pathways; epigenetic mechanisms also may contribute to altered beta cell mass and beta cell failure in pancreas, similar to that seen in T2D).

Authors [see attached article] measured DNA-methylation levels in cord blood of 69 newborns, looking at more than 850,000 sites — to determine whether maternal obesity and/or T2D directly affected DNA methylation; epigenome-wide and regional analyses were performed to search for significant CpG sites (regions of DNA — where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5′ → 3′ direction — are those typically methylated). After correction for multiple-testing, 15 CpG sites showed methylation that differed from that seen in normal-term newborns.

[These sites were associated with ten differentially-methylated genes between diabetic and non-diabetic subgroups — CCDC110, KALRN, PAG1, GNRH1, SLC2A9 which encodes a glucose transporter, CSRP2BP, HIVEP1, RALGDS, DHX37, and SCNN1D. Effects of diabetes were partially mediated by altered methylation of HOOK2, LCE3C, and TMEM63B. Effects of obesity were partially mediated by differential methylation of LTF and DUSP22.] Authors recommend that additional larger population studies should be carried out in those of Hispanic ancestry. These data suggest that potential future drug-targeting of transgenerational propagation, and a better understanding of developmental programming in utero, may reduce the risk of population obesity and T2D. 😊


Clin Epigenet 2002; 12: 34

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