ESPE Abstracts

Background: Epigenetic alterations due to maternal obesity may contribute to an increased metabolic risk in the offspring. IRS1 has a critical role in insulin signalling and its methylation has been previously associated with body fat distribution and glucose metabolism in human adipose tissue. The relationship between IRS1 methylation in birth tissues and obesity parameters in the offspring is unknown.

Objective: To identify placental DNA methylation marks associated prospectively with obesity parameters in children at 6 years of age and to analyse whether maternal obesity could modulate these associations.

Methodology: Population-based cohort study of pregnant women and their newborns followed up to 6 years of age. A global methylation array (Infinium® Methylation EPIC BeadChip) was performed in 24 placental samples to identify DNA methylation marks associated with BMI-SDS in offspring at 6 years. Differentially methylated genes were validated by pyrosequencing in 145 additional placental samples from the same cohort. Associations between placental methylation and several offspring obesity parameters [anthropometric data, body composition (by bioelectric impedance), and fat distribution (by ultrasound)] were sought.

Results: The placental methylation array identified 546 CpGs significantly associated with offspring BMI-SDS at 6 years. Among them, a CpGs in the IRS1 gene (FDR = 3.1x10-34, β = 0.793 and OR = 2.2) was selected because of its high odds ratio (OR) and its role in metabolic regulation. The validation analyses showed that IRS1 methylation associated positively with several obesity parameters in the offspring at 6 years: BMI-SDS, weight gain from birth-SDS, waist circumference, fat mass-SDS, subcutaneous and pre-peritoneal fat (r from 0.16 to 0.24; all P< 0.05) even after adjusting for confounding variables (β between 0.17 and 0.24; all P<0.05). When the results were analysed by subgroups of maternal pre-gestational weight [88 women with normal weight (BMI <25) and 57 women with overweight or obesity (BMI ≥ 25)], associations between IRS1 methylation and obesity parameters in the offspring were more robust in the group of pre-gestational overweight/obese mothers [BMI-SDS, weight gain from birth-SDS, fat mass-SDS, subcutaneous, and pre-peritoneal fat (r between 0.26 and 0.35 all P<0.05)].

Conclusions: Placental methylation levels of IRS1 associate with obesity parameters in 6 year-old children, especially in those born to mothers with pre-gestational obesity. We suggest that IRS1 differential methylation is an epigenomic alteration caused by maternal obesity, which could explain, at least in part, the increased risk for obesity in the offspring.