HDHL: A precision nutri-epigenetic approach to tackle the mother-to-child transmission of impaired glucose metabolism

There is a long-standing tracking of the risk of impaired glycaemic health being transmitted from one generation to another that is hypothesised to causally link exposure to adverse glycaemic health in pregnancy and the offspring glycaemic health via epigenetic mechanisms. The potential biological and nutritional pathways underlying the paradigm can be of paramount importance to understand, prevent or reverse the consequences of gestational diabetes for life-long obesity, glycaemic adversity and type 2 diabetes; the key outcomes here. PREcisE project joins a consortium with complementary domains of expertise and data to uncover DNA methylation markers sensitive to variation by maternal glycaemic health in pregnancy, considering pre- and postnatal dietary exposures as possible modulators, and characterise their importance in explaining the mother-to -offspring transmission of impaired glycaemic health. We integrate human data spanning from pre-conception to age 50 years with dense DNA methylation data in the mother, the newborn and the adult with repeated measure tochallenge the question of replicability, specificity and persistency. Precisely, PREcisE consortium will organise its working plan into three workpackages to i) perform epigenome wide association study on glucose level exposure in utero followed by downstream analysis in a biobank of liver, skeletal muscles and adipose tissues, ii) infer the primary role of pre- and postnatal dietary exposures in modulating the association of methylation with adiposity and glycaemic health outcomes and iii) integrate its findings further into a life-course model for adiposity and glycaemic health outcomes trained in large birth cohort data. PREcisE will aim to answer the expected impact of the call focusing on causality, nutrition and tissue specificity. Causality will be tested by three complementary design: randomised control trial, mendelian randomisation and causal modelling including triangulation to validate results. Tissue-specific molecular pathways will be addressed by a unique transcriptomic DNAmethylation approach. PREcisE project will aim to bring sufficient evidence to three key exploitable results: DNA methylation risk scores at maternal glucose response loci for precision epigenetics, dietary recommendations to help optimising the DNA methylation at these loci and a life-course model to inform policy on the long-lasting effects and opportunity to promote life-long glycaemic health.

PREcisE will operate the overarching hypothesis that the transgenerational association between maternal gestational diabetes and risk of T2D and glycaemic adversity in the next generation(s) can be
partially explained by a causal association mediated by durable epigenetic modification of 'maternal glucose responsive (MGR)' loci. The hypothesis is that:
- The risk is causal, dose dependent and interplay with maternal psycho-social factors;
- The risk is mediated and/or modulated by the glycaemic load and/or the inflammatory score of the diet;
- The risk is causally associated with the regulation of genes in the major metabolic tissues (i.e. liver, skeletal muscles, adipose tissues);
- There are causal pathways linking the alteration of MGR loci and glycaemic health in the offspring, part of which is mediated through early growth.

PREcisE project harnesses very large data prospectively collected from Spain, Germany, Finland, France and The Netherlands, including randomised control trial and combines with long lasting
collaboration with the pregnancy and childhood (PACE), the early growth (EGG) and recent Global MethQTL consortia, to establish the mother-to-offspring transmission of glycaemic health through robust epigenetic factors. The consortium will reach sufficient power to perform its research through the use of data and biological atlas collected prospectively by its PIs.

The PREcisE project is ambitious and realistic joining teams from five EU countries and collaborators in Australia bringing experts in nutrition physiology, genetics and epigenetics, molecular biology, biostatistics, lifecourse
epidemiology, clinical sciences and public health. PREcisE's overarching goal studies life-course data from the pre-conceptual period up until adulthood to explore the life-course and molecular pathways pertaining the mother to offspring transmissibility of impaired glycaemic health. PREcisE will aim at breakthrough in understanding i) the causal epigenetic pathways underpinning fetal exposure to impaired glycaemic health, ii) the role played by the glycaemic and the inflammatory load of the diet in inducing and modulating DNA methylation and iii) the life-course consequences. In addition, PREcisE shall provide four Key Exploitable results: DNA methylation MGR risk scores; dietary
recommendations; a EU-Nutri-Epigenetic-Data platform and a life-course model.

The project aims to establish new DNA methylation marks linked to impaired maternal glucose metabolism, which represents a growing problem worldwide co-occuring with rapid changes in population diet and physical activity behaviour. We aim at evidence based solutions to create new bio-tools, diagnosis markers and recommendations, incorporate into a life-course model and to contribute to the 2030 vision of the ERA-HDHL. In this light, our project will have the potential to generate sustained impact through reducing the risk of adverse glycaemic outcomes associated with exposure to gestational diabetes and associated glycaemic phenotypes. The technologies developed by PREcisE will be rapidly transferable due to the robustness of the approach and quality data management. Moreover, the results from PREcisE will contribute to substantially improving maternal and childhood nutrition and reducing the number of children who become obese. This will yield substantial direct and indirect, current and future savings in healthcare costs. Next to improving maternal and offspring glycaemic health outcomes, the project will have a substantial impact on the competitiveness, innovation capacity and integration of new knowledge for all participants. Importantly, the project will strengthen the competitiveness of EU public-private research in nutrition, healthcare and epigenomics.