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

Introduction: People 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. Methods: We 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. Results: At one IGF2AS CpG site, methylation was significantly lower in VLBW than in control subjects, mean difference 20.017 (95% CI; -0.028, -0.005), P = 0.004. Methylation at IGF2_05 was not different between the groups. Conclusions: Methylation 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.