Genes-in-Action: Hepcidin, iron and anaemia (5QX00)ING Core Science

Anaemia continues to be one of the most common health problems facing children and pregnant women in low income countries. Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) within hepcidin regulatory genes that are associated with anaemia in African populations. Our study aims to investigate the impact of these genetic alterations on host iron status and on the pharmacokinetics of oral iron absorption. We will conduct a recall-by-genotype using an existing database of individuals in rural Gambia (West Kiang) who have been pre-genotyped and are known to have the SNPs of interest.

BRIGHT (BRain Imaging in Global HealTh) - Developing brain function-for-age curves using novel biomarkers of neurocognitive development from birth in Gambian and UK infants'. 5QX0K0 

There is a large body of research highlighting the detrimental effects of malnutrition on cognitive development. However, very little is known about the neural basis of this association. The BRIGHT study will use novel objective neuroimaging techniques; Functional Near Infrared Spectroscopy (fNIRS) and Electroencephalography (EEG), alongside behavioural assessment, anthropometric measurements, biological samples and questionnaires (http://www.globalfnirs.org/the-bright-project). Neuroimaging data is collected at 6 time points between birth and 24 months of age in babies in rural Gambia and Cambridge, UK. The data will be used to construct brain function-for-age curves and investigate roles of malnutrition, social and environmental factors in infant development.

MILQ (The Mothers, Infants, and Lactation Quality Project) 5QX0Q0

Exclusive breastfeeding is recommended by WHO for the first 6 months of life, and it is important to support this recommendation by all possible means. This includes paying more attention to the nutrient content (“quality”) of breast milk and the nutritional status of the mother and infant during the first 6 months postpartum, especially in resource-poor settings. The MILQ study is a four-centre (Gambia, Brazil, Bangladesh, Denmark) study to develop Reference Values for nutrients and other constituents of human milk, to improve estimates of nutrient requirements and intake gaps for infants and lactating women. Field work will start in late 2017. 

ENID (Early Nutrition and Immune Development) 5QX00 – ING Core Science

Observational research indicates that human immune development can be programmed by nutritional exposures early in life. The ENID Trial (ISRCTN49285450) was designed to test whether nutritional repletion can enhance infant immune development in a marginally malnourished population. During pregnancy, women were randomised to a combination of protein-energy and micronutrient supplements and, from six-months of age, their infants randomised to a micronutrient fortified weaning food or placebo. The primary outcome was thymic development, with antibody response to vaccination also measured. Full results from ENID will be published in 2017.

Impact of maternal diet on the epigenome and potentially modifiable effects on offspring health – MDEG 2 5QX0F0

Evidence indicates that the nutritional environment experienced by a developing embryo around conception may leave a lasting mark on the offspring’s epigenome. This suggests epigenetic mechanisms may in part underpin observed long-term adverse health effects arising from suboptimal nutrition in early life. In this study we assess the impact of deficiencies in methyl donor nutrients on areas of the methylome programmed in the developing embryo, including imprinted genes and metastable epialleles. Insights gained will inform the design of supplements to be tested first in non-pregnant women to assess their ability to influence the methyl donor metabolome. Full results expected in 2018. Later large-scale trials in women hoping to have a baby are anticipated. 

EMPHASIS (Epigenetic mechanisms linking maternal pre-conceptional micronutrient supplementation with offspring health in India and The Gambia) – 5QX0J0

EMPHASIS is a joint initiative between researchers in The Gambia, India and the UK, established to investigate epigenetic mechanisms by which maternal nutrition before and during pregnancy could influence offspring health. This study brings together two previous randomised controlled trials investigating the effectiveness of maternal dietary intervention on fetal development: the Mumbai Maternal Nutrition Project in India and the Peri-conceptional Multiple Micronutrient Supplementation Trial in The Gambia. In this study we are measuring DNA methylation in the children of these mothers, and assessing links to health outcomes in later life. Full results are expected in 2018.

Collaborative network for adolescent nutrition and health in sub-Saharan Africa and India -5QX0R0

The project seeks, in the pump-priming phase, to understand the diet and activity behaviour of human adolescents across diverse geographic and cultural settings. The work is designed to prepare for a larger-scale study, which will additionally include assessments of habitual diet (food frequency questionnaires and 24 hour recalls), physical activity (objective methods using accelerometers), body composition (bio-impedance and/or DXA), nutritional status (blood micronutrient and inflammatory biomarkers) and fitness (using simple 'beep' tests - timed running across a fixed distance). These studies are intended to address major knowledge gaps about the nutritional status of adolescents and will necessitate free-living human participants. The findings will be used to develop culture- and setting-specific interventions, and to influence regional and national policies for adolescent health and nutrition.

Creating a West African BioResource for Nutritional Genetics and Epigenetics

The project aims to create an open access West African BioResource to interrogate the mechanisms by which genetic and epigenetic variations influence susceptibility to diet-related diseases. It will also promote innovative research designs, building for instance on the recall-by-genotype paradigm, to more efficiently and robustly explore mechanisms of diet/ (epi) genetic interactions and hence to propose next-generation health interventions.

Neonatal iron metabolism and risk of infection

The Study aims to assess markers of iron metabolism among term, pre-term and small-forgestational-age infants during the early post-partum period, and to evaluate possible relationships between iron metabolism and the risk of newborn infections. In an effort to study the neonatal nutritional immunity and its role in neonatal susceptibility to infection, we will conduct an observational study in full-term, preterm and low birth weight vaginally-delivered neonates born at Serrekunda General Hospital, The Gambia.

Evaluation of MTHFR C677T genotype-dependent blood pressure response to riboflavin supplementation

The project aims to test whether differences in BP by MTHFR genotype seen in Caucasians are exacerbated in Gambians living in a riboflavin-deplete environment; and ii) to determine whether riboflavin supplementation has genotype-differential effects on BP reduction in this population.

A novel nano-iron supplement (IHAT) to safely combat iron deficiency and anemia (IDA) - 5QX0L0

We propose to conduct a Phase II clinical trial in The Gambia to demonstrate for the first time that a novel and unique nano iron compound, which is an engineered analogue of natural food iron, SAFELY corrects iron deficiency anemia (IDA) in children in resource-poor areas. Our pre-clinical data support progressing directly to the trial proposed here, and indicate that our award-winning compound (Iron Hydroxide Adipate Tartrate: IHAT) is highly bioavailable to humans through physiologically appropriate pathways and is not available to enteric pathogens. Importantly, IHAT’s manufacture is easily scalable and has a low cost due to the facile synthesis and inexpensive GRAS raw materials.

It is our absolute conviction that IHAT has the potential to transform IDA treatment in the near future because it constitutes a paradigm-shift to what has been tested before. However, until we obtain the first clinical data supporting IHAT effectiveness it will be very challenging to secure interest from other investors.

Pregnancy Interventions In Mothers Relating to Diabetes In Asian India and Low-income countries (The PRIMORDIAL Study)

The proposed study will be the first investigation to evaluate the effect of fermented yoghurt and Physical Activity (PA) initiated in early pregnancy and continued to late pregnancy on incidence of gestational diabetes (GDM) in Low- and Middle-Income Countries (LMICs). We hope to confirm that such realistic and feasible interventions are effective in preventing GDM. We will also examine the effect of such interventions on other pregnancy-related and new born outcomes. This project will build capacity for improved antenatal services in LMICs (The Gambia and India) specifically. The intervention may offer an efficient platform for future research into understanding diet and PA impact on alteration of the gut microbiota of the mother and its effects on child health. If we show that improving a mother's lifestyle during pregnancy using fermented yoghurt and PA reduces the incidence of GDM and improves metabolic health in both mother and the child, with a potential lifelong benefit, our findings will offer a scalable pathway for wide implementation.

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

The proposed project will characterise changes in DNA methylation in blood samples from children of women who took part in two trials of pre- and peri-conceptional micronutrient supplementation in Mumbai, India and Keneba, The Gambia, and correlate methylation changes with a range of phenotypes in these children.This project offers the opportunity to test DOHaD concepts and understand underlying mechanisms within the timeframe of a single project. 

Pump Priming: Establishment of the Sub-Saharan African MuSculOskeletal Network

The purpose of this grant is to facilitate inter-disciplinary partnerships between researchers in the UK and researchers in developing countries. These partnerships aim to develop high quality inter-disciplinary and innovative applications to address global challenges faced by developing countries I, for submission to other GCRF and other funding programmes.

Infection, inflammation and hepcidin-mediated iron deficiency anaemia in African children

This project seeks to identify the sources of persistent low-grade inflammation in well and sick Gambian children. It will additionally try to understand the complex interacting mechanisms linking iron absorption, distribution and erythropoiesis to the effects of inflammation mediated through hepcidin, erythropoietin (EPO) and the newly discovered hormone erythroferrone (ERFE) which signals to the liver that the bone marrow requires iron. Finally we will conduct a randomised controlled trial to test whether it is possible to circumvent the hepcidin-induced blockade of iron absorption by administering iron in the form of haem. Another arm of this trial will be a proof-of-principle trial to assess the impact of reducing inflammation by co-administering azithromycin and galacto-oligosaccharides with iron. These studies, if successful, would suggest the need for a radical revision of current policies to combat IDA.

Inter-generational risk factors for obesity: a path to prevention in low and middle-income countries based on a modifiable epigenetic signature in the POMC gene

Pro-opiomelanocortin (POMC) gives rise to melanocortin stimulating hormone (MSH) peptides that mediate the anorectic (appetite suppressing) action of leptin via melanocortin receptors (especially MC4R) in the hypothalamus. Mutations in the gene are associated with obesity.  Increased DNA methylation at a VMR at the POMC intron2/exon3 boundary correlates with BMI in children and adults.  In a Gambian cohort, we have shown that offspring methylation at the POMC VMR is correlated with mother's nutritional status (and therefore potentially modifiable) around conception.  POMC VMR methylation will be measured on banked DNA, taken from children during the first 2 years of life, from a previous cohort (ENID n=800). Growth data from these cohorts (ages 0-2 years) will be examined together with DNA methylation to establish any associations between weight changes and POMC methylation.  1-year prospective study:  500 mothers and children (5-9 year old) will have monthly anthropometry and bioimpedance together with measurement of POMC VMR methylation to assess effect on nutritionally (and seasonally) driven changes in weight and body composition over a year.  In addition, a subset will have DXA scans and measurement of an ab libitum breakfast.  Dietary influence over POMC methylation will be examined by correlating circulating maternal one carbon metabolites and offspring methylation. Potential intergenerational influences on offspring methylation will be assessed by measuring POMC VMR methylation in 100 mother-father-offspring trios.