Epigenetic mechanisms linking maternal pre-conceptional micronutrient supplementation with offspring health in India and The Gambia

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Deficiencies of essential vitamins and minerals (micronutrients) due to poor quality diets are a major public health problem in low-and-middle-income countries (LMICs). In pregnant women they impair fetal development and cause childhood stunting. Recent research pioneered in the UK suggests that they cause long-term problems in the offspring including poor brain and muscle development, increased body fat, and adult heart disease and diabetes. These chronic diseases are rising rapidly in LMICs, where they disable working-age people and require costly treatment. Efforts to prevent them currently focus on promoting healthier adult lifestyles. Research into the developmental origins of health and disease (DOHaD) opens up the potential to both improve child development and prevent adult disease by optimising maternal nutrition. Until recently, evidence for long-term effects of maternal undernutrition was based on observational studies. The research groups in this application have made a step-change by conducting pre- and peri-conceptional randomised controlled nutrition trials among undernourished mothers in India and The Gambia. These trials provide ideal vehicles to study epigenetic mechanisms by which the 'memory' of an individual's nutritional environment in utero could be retained into later life and influence health. One such mechanism is DNA methylation in which the sequence of genes in DNA is overlaid with chemical (methyl) groups which control whether genes are switched on or off. Methylation patterns ('epigenetic signatures') are laid down in early fetal life and are influenced by the mother's nutritional state. In experimental animals, altering maternal diet peri-conceptionally permanently changes offspring DNA methylation, gene expression and adult metabolism. There is growing indirect evidence of similar effects in humans but there are as yet no comparable studies from specific peri-conceptional nutritional interventions.The UK, Indian and Gambian groups have already built strong evidence in observational work that maternal deficiencies of 'methyl donor' nutrients such as vitamins B2, B6, B12 and folate impair fetal growth and the child's brain function, increase heart disease and diabetes risk markers, and disrupt the methylation of specific genes. The proposed work will build on these observations using a gold-standard study design. We will analyse DNA methylation in children from two complementary randomised controlled trials in which mothers were supplemented with micronutrients before conception and into early pregnancy. These are: 1) the Mumbai Maternal Nutrition Project, in which women living in Mumbai slums received a daily snack made from micronutrient-rich foods and 2) the Peri-conceptional Multiple Micronutrient Supplementation Trial in rural Gambia, which supplemented women with multiple micronutrient capsules. Fetal growth and newborn size were recorded and the children are being tracked. The UK-India group is funded by MRC for 3 years to study body composition, risk factors for later heart disease and diabetes, and brain function in the Mumbai children at the age of 5-6 years. DNA is being collected from blood samples and cheek swabs. Children from the Gambian trial have been re-traced at the age of 7-8 years and we will collect the same outcome data. This proposal seeks funds to study DNA methylation in both cohorts of children (Mumbai N=1100, The Gambia N=350). Genome-wide methylation patterns will be compared between intervention groups and between cohorts, and related to the children's body fat, muscle and bone, disease risk factors, and brain function, as well as birth outcomes and stunting. An over-arching objective is to build capacity for epigenetic studies in India and The Gambia. The project will lead to a better understanding of the effects of maternal nutrition on the child, and ultimately to the design of improved nutritional interventions for mothers preparing for pregnancy.