Possible mechanisms by which insults in early life retain long-lasting effects are still poorly understood. One possibility is that permanent changes occur in an organ system due to sub-optimal conditions during a critical period of development, such as reduction in cell number (e.g. permanent reduction in beta cell mass in the pancreas or nephrons in the kidneys), or altered structure (e.g. thickness of blood vessels), or functioning (e.g. re-setting of the hypothalamic-pituitary-adrenal axis). The relatively new science of epigenetics offers a plausible explanation. Programming effects may act through ‘epigenetic’ mechanisms that alter expression of genes without altering the base sequence (i.e. change in phenotype independent of change in genotype). The expression of genes is thought to be regulated by three main processes: 1) methylation or de-methylation in gene promoter regions, 2) acetylation of histones, and 3) modification of micro RNAs. We are carrying out epigenetic studies in partnership with Giriraj Chandak and his team at the CSIR-Centre for Cellular and Molecular Biology in Hyderabad, India.

We will investigate epigenetic mechanisms for associations between maternal factors (nutrition and metabolism) and health outcomes in their children. Intervention studies are a particularly suitable platform for these studies, because they allow causal inference. We intend to adopt ‘multi-omics’ approaches in our intervention studies. We are also undertaking epigenetic studies in selected observational cohorts, focussing on specific exposures and outcomes of interest. We will continue to study genetic variants associated with cardiometabolic and cognitive outcomes in our intervention and observational cohorts. We will also use Mendelian Randomization analyses in our observational cohorts for understanding potential causal relationships.

Recently, in collaboration with Giriraj Chandak, and Matt Silver and Andrew Prentice at MRC The Gambia at London School of Hygiene and Tropical Medicine, we have completed the EMPHASIS study examining epigenetic changes in children born in the Mumbai trial (Project SARAS) and in children born in another pre-conceptional trial in The Gambia (Peri-conceptional Multiple Micronutrient Supplementation Trial; PMMST). The results are still being analysed. In contrast to the food supplement based India trial, the intervention in The Gambia was a daily multiple micronutrient tablet (UNIMMAP) providing one RNI of a range of micronutrients; control women received matching placebo tablets. The supplements were stopped when pregnancy was confirmed. We assessed epigenome-wide DNA methylation using the 850K Illumina Epic array, and at selected candidate loci not on EPIC. Three stages of analysis have been planned: 1) associations between the interventions and children’s DNA methylation; 2) associations between methylation and phenotypes; and 3) mediation analyses to assess the causality of associations.

In the Pune PRIYA study in collaboration with Chittaranjan Yajnik, we are collecting cord blood and placental samples for extensive molecular biology investigations. We will undertake high-throughput analysis of the methylome, transcriptome and the metabolome on cord blood samples. This will enable us to identify molecular signatures that predict fetal programming, and identify rationally refined strategies for nutritional intervention of young girls to reduce cardiometabolic disease in the next generation. In the HeLTI study, we will collect a range of bio-specimens from parents and children to undertake extensive mechanistic studies.

Selected recent publications (with links to Pubmed if possible, highlighted below):

  • Chandak GR, Silver MJ, Saffari A, Lillycrop KA, Shrestha S, Sahariah SA, Di Gravio C, Goldberg G, Tomar AS, Betts M, Sajjadi S, Acolatse L, James P, Issarapu P, Kumaran K, Potdar RD, Prentice AM, Chopra J, Cooper C, Darboe MK, Gandhi M, Janha R, Jarjou L, Kaur L, Kehoe SH, Ngum M, Nongmaithem SS, Owens S, Prentice A, Priyanka TDS, Sane H, Ward KA, Yadav DK, Yajnik CS, Fall CHD and the EMPHASIS Study Group. Protocol for the EMPHASIS study; epigenetic mechanisms linking maternal pre-conceptional nutrition and children’s health in India and Sub-Saharan Africa. BMC Nutrition 2017; 3: 81. Doi: 10.1186/s40795-017-0200-0. Not Pubmed listed
  • James P, Sajjadi S, Tomar AS, Saffari A, Fall CHD, Prentice AM, Shrestha S, Issarapu P, Yadav DK, Kaur L, Lillycrop K, Silver M, Chandak GR; EMPHASIS study group. Candidate genes linking maternal nutrient exposure to offspring health via DNA methylation: a review of existing evidence in humans with specific focus on one-carbon metabolism. Int J Epidemiol 2018; 47: 1910-37. PMID 30137462