TwinLIFE: The Twin Longitudinal Investigation of FEtal Discordance.

Sophie G Groene,Erik W Van Zwet,Arno A W Roest,Melissa Van Pel,Romy J M Berkhout,Monique C Haak,Jeanine M M Van Klink,Enrico Lopriore,Pia Todtenhaupt,Bastiaan T Heijmans

doi:10.1017/thg.2019.38

Abstract

Lifelong health is thought to be partially set during intrauterine life by persistent epigenetic changes induced by the prenatal environment. To evaluate this hypothesis, we initiated a prospective longitudinal study in monochorionic (MC) twins: the TwinLIFE study. MC twins are monozygotic, thus in origin genetically identical, and share a single placenta. Although MC twins have many environmental factors in common, in one-third of the MC twin pairs, one fetus has significantly less access to nutrients and resources during pregnancy than its co-twin often resulting in a significant discordance in prenatal growth. Hence, MC twins constitute a unique natural experiment to study the influence of the prenatal environment on health. In TwinLIFE, we will chart intrapair differences in DNA methylation focusing on mesenchymal stromal cells isolated from cord as an advanced proxy of epigenetic dysregulation relevant for long-term health consequences. Next, we will follow up the MC twins for growth, cardiovascular and neurodevelopmental outcomes during childhood and evaluate the impact of an epigenetic signature at birth on future health. The current target is to include 100 MC twin pairs, but we aim to continue enrollment after procuring additional funding. TwinLIFE will not only address an unmet clinical need in the high-risk group of MC twins, but may also advance early-life strategies to prevent adverse growth, cardiovascular and neurodevelopmental outcomes in the general population.

Highlights

Lifelong cardiovascular and neurodevelopmental risk may be partially set before birth
Specific DNA methylation differences were observed to mediate the association of prenatal famine and adult BMI and blood lipids (Tobi et al, 2018). Despite such promising findings, it can be argued that the field still has to deliver robust mechanistic insight and early-life epigenetic biomarkers of long-term health outcomes
The objectives of TwinLIFE are: 1. To establish a longitudinal MC twin cohort with prospectively recorded data on growth, cardiovascular and neurodevelopmental parameters measured pre- and perinatally and at 2, 5 and 8 years of follow-up to quantify the discordance in the prenatal environment and health outcomes

Summary

Background

Lifelong cardiovascular and neurodevelopmental risk may be partially set before birth. Experimental perturbation of the intrauterine environment in animal models can induce persistent epigenetic changes at the level Despite such promising findings, it can be argued that the field still has to deliver robust mechanistic insight and early-life epigenetic biomarkers of long-term health outcomes. This may be achieved by focusing on defined present-day populations experiencing severe intrauterine adversity. To establish a longitudinal MC twin cohort with prospectively recorded data on growth, cardiovascular and neurodevelopmental parameters measured pre- and perinatally and at 2, 5 and 8 years of follow-up to quantify the discordance in the prenatal environment and health outcomes. To evaluate the link between the observed epigenetic alterations and growth, cardiovascular, and neurodevelopmental health outcomes assessed at birth and 2, 5 and 8 years of follow-up

Study Procedures

Findings

Uncovering epigenetic influences on CVD and NDI risk