Predictors and consequences of global DNA methylation in cord blood and at three years

Abstract

DNA methylation changes have been implicated in many common chronic diseases leading to the hypothesis that environmental and age-related DNA methylation changes within individuals are involved in disease etiology. Few studies have examined DNA methylation changes within an individual over time and all of these studies have been conducted in adults. Here, we aim to characterize how global DNA methylation changes from birth to age three within a longitudinal birth cohort study and to determine whether there are consistent predictors of DNA methylation levels measured three years apart. We measured global DNA methylation in the same children at birth (cord blood) and again at three years of age among 165 children, using an immunoassay. We found that on average, DNA methylation was significantly higher in blood at age 3-years than in cord blood (p,0.01). However, for any individual child, the difference was less than would be expected by chance. We found that pre-pregnancy BMI was negatively predictive of both cord and three-year DNA methylation, even after statistical adjustment to account for the correlation between cord blood and three-year DNA methylation. The biologic implications of small changes in global DNA methylation are unknown. However, the observation that global DNA methylation levels persist within an individual from birth to age three supports the belief that factors that influence global DNA methylation, including pre-pregnancy BMI, may confer long-term effects.

Association of Maternal Prepregnancy Weight with Offspring Adiposity Throughout Adulthood over 37 Years of Follow‐up

“…The association between maternal prepregnancy overweight and obesity and offspring BMI, which persists after adjustment for genetic and lifestyle factors, supports previous research describing intergenerational inheritance of metabolic outcomes beyond the inheritance of genetic sequence variants and learned behavior. Although the mechanism underlying fetal programming of obesity is not fully understood, both animal and human models examining the fetal overnutrition hypothesis have supported a possible epigenetic link between maternal and offspring adiposity . Numerous genomic regulatory mechanisms have been implicated in the intergenerational epigenetic inheritance of metabolic disease, including nuclear and ribosomal DNA methylation, histone modifications, and noncoding microRNAs.…”

“…Extending the Barker hypothesis that fetal programming because of maternal undernutrition contributes to offspring obesity and CVD , maternal obesity leads to fetal overnutrition, which may also contribute to deleterious cardiometabolic outcomes in the offspring . Fetal programming and epigenetic inheritance are potential mechanisms . Although many studies have demonstrated a robust association between maternal and offspring obesity , little is known about how this association persists beyond young adulthood or changes over an offspring’s lifetime in excess of genetic variation and learned lifestyle behaviors .…”

A biocultural study of the effects of maternal stress on mother and newborn health in the Democratic Republic of Congo

“…Since first publishing our results on NR3C1, we have moved beyond gene‐specific analyses to an analysis of total genome‐wide methylation, specifically methylation at 431,048 CpG dinucleotides spanning >20,000 genes as represented on the Illumina 450 Methylation BeadChip. In this study, we analyze mean global methylation, which has been proposed as a biomarker for disease risk (Choi et al, ; Liao et al, ; Cash et al, ) and also may be reflective of shared factors that confer long‐term effects on health (Herbstman et al, ). (Choi et al, ; Liao et al, ; Cash et al, ; Gomes et al, ; Iwasaki et al, ; Zhao et al, ; Herbstman et al, ; Kuchiba et al, )…”

“…Many studies have used mean global methylation to investigate different aspects of health. Studies of human blood samples have documented consistent, age‐related changes in mean global methylation (Gomes et al, ; Herbstman et al, ), an association with insulin resistance as a hallmark of type 2 diabetes (Zhao et al, ), and an association with endogenous sex hormones in women (Iwasaki et al, ). There is an hypothesis for the development of cancer, supported by several studies, that global hypomethylation may cause genomic instability leading to cancer (Choi et al, ; Liao et al, ; Cash et al, ; Kuchiba et al, ).…”

“…In the current study, we look at methylation across the genome, specifically at >400,000 CpG sites spanning >20,000 genes. With these data, we analyze mean global methylation, a measure that has been proposed as a biomarker for disease risk (Choi et al, ; Liao et al, ; Cash et al, ) and also may be reflective of shared factors that confer long‐term effects on health (Herbstman et al, ). Many studies have used mean global methylation to investigate different aspects of health.…”