Altered Methylation of IGF2 Locus 20 Years after Preterm Birth at Very Low Birth Weight

Abstract

IntroductionPeople born preterm at very low birth weight (VLBW, ≤1500g) have higher rates of risk factors for adult-onset diseases, including cardiovascular diseases and type 2 diabetes. These risks may be mediated through epigenetic modification of genes that are critical to normal growth and development.MethodsWe measured the methylation level of an imprinted insulin-like-growth-factor 2 (IGF2) locus (IGF2/H19) in young adults born preterm at VLBW and in their peers born at term. We studied 158 VLBW and 161 control subjects aged 18 to 27 years from the Helsinki Study of Very Low Birth Weight Adults. Methylation fraction at two IGF2 differentially methylated regions (DMRs) – IGF2 antisense transcript (IGF2AS, also known as IGF2 DMR0) and last exon of IGF2 (IGF2_05, also known as IGF2 DMR2) – were measured with Sequenom Epityper. We used linear regression and adjustment for covariates to compare methylation fractions at these DMRs between VLBW and control subjects.ResultsAt one IGF2AS CpG site, methylation was significantly lower in VLBW than in control subjects, mean difference −0.017 (95% CI; −0.028, −0.005), P = 0.004. Methylation at IGF2_05 was not different between the groups.ConclusionsMethylation of IGF2AS is altered 20 years after preterm birth at VLBW. Altered methylation may be a mechanism of later increased disease risk but more data are needed to indicate causality.

Dynamic Changes in DNA Methylation Occur during the First Year of Life in Preterm Infants

“…We found no persisting differences at 1 year of age. Whether further differences will emerge over longer follow-up is unknown; alterations in DNA methylation at key DMRs controlling the expression of IGF2 have been reported in adults exposed to altered nutrition or prematurity (16, 17, 42); however, these were not longitudinal studies, so that any differences may have arisen postnatally. Additionally, these studies may have been complicated by the phenomenon of reverse causation, where the development of disease leads to changes in DNA methylation rather than vice versa (41).…”

Epigenetic regulation of Newborns’ imprinted genes related to gestational growth: patterning by parental race/ethnicity and maternal socioeconomic status

“…Low birth weight has been linked with DNA methylation 20 years later 28. Social and physical exposures such as nutrition, psychosocial stressors and toxicants,29 all of which can be socially patterned, change DNA methylation.…”

Implications of Epigenetics and Stress Regulation on Research and Developmental Care of Preterm Infants

“…Premature birth due to obstetric infections, such as chorioamnionitis and funisitis, was found to be linked with significant DNA methylation at PLAGL1 imprinted-related gene (Liu et al, 2012). In a retrospective study, Wehkalampi et al (2013) reported that young adults born preterm exhibited genomewide DNA methylation alterations that might be suggestive of long-lasting epigenetic modifications related to preterm birth. Although these studies document an association between premature birth and altered epigenetic markers, it should be noted that methylation was not assessed at the level of specific candidate genes with functional implications for the HPA axis (i.e., NR3C1 gene methylation).…”