HDHL-Biomarkers: Early life programming of childhood health: a nutritional and epigenetic investigation (ALPHABET)

The rising prevalence of obesity, cardiometabolic disease, asthma, osteoporosis and neurodevelopmental disorders over recent decades cannot be fully explained by genetic or adult lifestyle factors. Increasing evidence suggests links to early life environmental factors. If such links exist, then there must be non-genetic mechanisms that retain memory of early life exposures such as suboptimal nutrition during pregnancy or early childhood and that influence health decades later. DNA methylation, the addition of methyl groups to DNA, has been proposed as a possible mechanism because it is responsive to the environment and influences gene expression.

Maternal diet during pregnancy is a modifiable behaviour that could impact on maternal, neonatal and child health. However the specific dietary requirements during pregnancy for optimal fetal growth and development are unknown in large part because effects on health only begin to appear decades after exposure. DNA methylation patterns however should be affected almost immediately and, if they are linked to later health outcomes, should remain throughout life. This project will utilise biological samples and data from existing European longitudinal birth cohorts to investigate the complex relationships between maternal diet summarised by indices of diet quality and inflammatory potential, health outcomes and DNA methylation patterns from birth throughout childhood and into adulthood. Hence, we will be able to observe how prenatal diet modifies infant DNA methylation patterns and if and how these modifications are maintained throughout life and relate to health outcomes in adulthood. These observations may aid development of more refined dietary recommendations for promoting optimal health throughout life.

DNA methylation is known to be associated with a wide variety of exposures, phenotypes and health outcomes. Animal models have provided evidence that in many cases DNA methylation mediates the effects of exposures such as diet on health outcomes. Direct evidence for similar mediating relationships in humans is sparse partly due to ethical limitations that restrict experimental approaches and analysis of the most relevant tissues. To address these limitations, alternatives to experimentation have been proposed. Structural equation modelling has been used to determine how well causal network models fit observational data, and instrumental variable analysis has been used to interrogate causal relationships. Mendelian randomisation (MR), an instrumental variable approach based on genetic variants, has been used to successfully discriminate between causal and non-causal relationships in health research that were later confirmed by randomised control trials (RCTs). We propose here to apply structural equation modelling to evaluate evidence that the effects of prenatal diet on later health and developmental outcomes are mediated by DNA methylation and to apply Mendelian randomisation to assess the causality of such relationships. In addition to adiposity, cardiometabolic, bone, respiratory and neurodevelopmental health.

We will 1) test associations between prenatal diet as summarised by DII and DASH scores and blood DNA methylation pattern, 2) determine the extent to which these associations change throughout childhood, 3) test associations in adulthood between diet as summarised by DII and DASH scores and blood DNA methylation patterns, 4) test associations between health outcomes (adiposity and cardiometabolic, bone, respiratory and neurodevelopmental health) and blood DNA methylation patterns, and 5) examine evidence that DNA methylation may be on the causal pathway between diet and health outcomes using structural equation modelling and Mendelian randomisation.

The results of this research programme may have the potential to inform health relevant policy, clinical practice, patient care and health behaviour. This may be achieved through generating evidence for policy and production of, or at least citation of, our findings in evidence based clinical or public health guidelines or policy documents. It is anticipated that our findings will highlight areas of action for policymakers with responsibility for addressing maternal and childhood obesity (key areas already identified both at European and International level). Thus our findings may aid development of new public health strategies for prevention, with an emphasis on early development. For example data relating to nutritional intake during pregnancy may inform revision of existing National guidelines or development of new guidelines or policies for optimal nutrition in pregnancy, which may reduce adverse health outcomes in future generations.

The potential health and socio-economic impacts may be significant considering the health service and societal costs associated with obesity alone, currently and for future generations. Our results will improve understanding of the relationships between maternal nutrition, pregnancy outcome and subsequent child health. For example improved dietary quality and/or reduced pro-inflammatory dietary status achieved through revision of existing guidelines or development of new guidelines for optimal nutrition in pregnancy or development of functional foods may lead to beneficial health effects in women of reproductive years and their offspring which may have long term effects on their health into adulthood.