Does abnormal one-carbon metabolism or hyperglycaemia in utero cause epigenetic change and fetal programming of cardiome

Lead Research Organisation: Queen Mary, University of London
Department Name: Blizard Institute of Cell and Molecular

Abstract

Diabetes and cardiovascular disease (the ‘cardiometabolic‘ diseases) are becoming increasingly common throughout the world. The risk of developing these diseases relates to both genetic inheritance and a person‘s environment. The effects of environment are particularly important during pregnancy, and studies of malnourished and diabetic mothers show an increased risk of cardiometabolic disease in their children. This idea of disease being ‘programmed‘ during fetal development has been studied across populations and in animal experiments, but the mechanisms through which it occurs are not understood.
In this respect, the field of epigenetics is providing an exciting insight into how this programming might occur. It describes how environmental triggers can affect how genes are switched on or off via a sequence of chemical reactions around the structure of DNA. This study will look at how high blood glucose levels and poor nutrition in mothers could cause epigenetic changes that put offspring at risk of cardiometabolic disease. The study will be done in mice as well as humans to identify whether these changes can be inherited through generations. New techniques involving both laboratory experiments and computerised mathematical analysis will be used to answer these questions.

Technical Summary

Aims and objectives: to understand the epigenetic basis of fetal programming of type 2 diabetes and cardiovascular disease. The study will look at two environmental insults in utero for which there is epidemiological and early experimental evidence to support a role in epigenetic-mediated disease pathogenesis. The study also seeks to study the transgenerational effects of this epigenetic change through both somatic tissues and the germline.

Design and methodology: A human model will identify individuals with gestational diabetes and hyperhomocysteinaemia from a local population at high risk of cardiometabolic disease. DNA from offspring cord blood will be studied and compared to parental DNA to examine de novo environmental effects on DNA methylation. A rodent model of gestational diabetes and methionine-induced hyperhomocysteinaemia will mirror this model, allowing investigation epigenetic variants and their inheritance between successive generations using sperm and oocytes and controlled breeding. In both models, epigenetic will be identified in offspring by the use of ‘next generation‘ sequencing (Solexa) and custom bioinformatic analysis. This will be followed by targeted bisulphite sequencing of familial epialleles of interest. Further study will examine tissue-specific epigenetic variants, RNA expression and chromatin remodelling.

Scientific and medical opportunities: The design of this study and techniques used will provide understanding of environmentally-mediated epigenetic reprogramming and inheritance from a truly genome-wide perspective. Identification of common dietary and metabolic insults in pregnancy that may predispose to disease risk in offspring will allow effective treatment interventions against a cluster of conditions that is increasing in prevalence globally.

Publications

10 25 50

publication icon
Barry E (2015) Time to question the NHS diabetes prevention programme. in BMJ (Clinical research ed.)

publication icon
Finer S (2015) Fetal programming via maternal diabetes: the controversy continues. in Diabetic medicine : a journal of the British Diabetic Association

publication icon
Finer S (2011) The hunt for the epiallele. in Environmental and molecular mutagenesis

publication icon
Finer S (2014) The role of the one-carbon cycle in the developmental origins of Type 2 diabetes and obesity. in Diabetic medicine : a journal of the British Diabetic Association

publication icon
Finer S (2012) Inadequate vitamin D status in pregnancy: evidence for supplementation. in Acta obstetricia et gynecologica Scandinavica

 
Description Barts and the London NHS Trust clinical guideline group for management of vitamin D deficiency
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description CLRN contingency funds
Amount £35,000 (GBP)
Organisation National Institute for Health Research 
Department Comprehensive Clinical Research Network (Coordinating Centre) – NIHR
Sector Public
Country United Kingdom
Start 01/2011 
End 01/2012
 
Description Conference grant/Society for Endocrinology
Amount £500 (GBP)
Organisation Society for Endocrinology 
Sector Learned Society
Country United Kingdom
Start 01/2010 
End 01/2010
 
Description Diabetes UK small project grant
Amount £15,000 (GBP)
Funding ID 09/0003866 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Epigenetic mechanisms linking mother's nutrition at time of conception to offspring health and development - co-investigator
Amount £50,000 (GBP)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2015 
End 01/2017
 
Description Genomic and lifestyle predictors of foetal outcome relevant to diabetes and obesity and their relevance to prevention strategies in South Asian peoples
Amount £3,000,000 (GBP)
Funding ID 278917 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2012 
End 01/2016
 
Description Gestational diabetes and the placenta. Small project grant
Amount £7,500 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2018 
End 12/2019
 
Description Isaac Shapera Funds/Barts and the London School of Medicine and Dentistry
Amount £950 (GBP)
Organisation Queen Mary University of London 
Sector Academic/University
Country United Kingdom
Start 01/2010 
End 12/2011
 
Description NIHR Academic Clinical Lecturer (salary)
Amount £1 (GBP)
Organisation University of Cambridge 
Sector Academic/University
Country United Kingdom
Start 04/2013 
End 04/2015
 
Description Samuel Leonard Simpson Fellowship in Endocrinology
Amount £6,000 (GBP)
Organisation Royal College of Physicians of London 
Sector Academic/University
Country United Kingdom
Start 01/2012 
End 04/2012
 
Description Samuel Leonard Simpson travelling fellowship
Amount £5,000 (GBP)
Organisation Royal College of Physicians of London 
Sector Academic/University
Country United Kingdom
Start 09/2012 
End 01/2013
 
Description Small grant programme
Amount £15,000 (GBP)
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 01/2011
 
Description East London Genes and Health (ELGH) 
Organisation Centre of the Cell
PI Contribution I am deputy lead for this large community genomics study. I contribute towards the overall running of this important study (including recruitment, study design and management, recall-by-genotype, community engagement) which is a large community genomics project of British Bangladeshis and Pakistanis (n=28,000). I am also the local PI for a UK consortium studying type 2 diabetes in this cohort, including running recall-by-genotype studies, analysis of big data (using electronic health records) and the design of future metabolic phenotyping studies.
Collaborator Contribution ELGH works with a large international consortium (including academic and industry partners) involved in many of its activities. I am working particularly with a UK-wide consortium of diabetes researchers in recall-by-genotype studies based on rare diabetes and obesity-associated variants.
Impact Currently this is work in progress and we are in the recruitment phase to recall-by-genotype studies. We have a broad range of multidisciplinary partnerships involved in our community engagement and outreach activities, including close work with community-based organisations (e.g. https://www.safh.org.uk) and engagement workshops involving anthropologists and experts in public engagement (https://www.centreofthecell.org).
Start Year 2017
 
Description East London Genes and Health (ELGH) 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution I am deputy lead for this large community genomics study. I contribute towards the overall running of this important study (including recruitment, study design and management, recall-by-genotype, community engagement) which is a large community genomics project of British Bangladeshis and Pakistanis (n=28,000). I am also the local PI for a UK consortium studying type 2 diabetes in this cohort, including running recall-by-genotype studies, analysis of big data (using electronic health records) and the design of future metabolic phenotyping studies.
Collaborator Contribution ELGH works with a large international consortium (including academic and industry partners) involved in many of its activities. I am working particularly with a UK-wide consortium of diabetes researchers in recall-by-genotype studies based on rare diabetes and obesity-associated variants.
Impact Currently this is work in progress and we are in the recruitment phase to recall-by-genotype studies. We have a broad range of multidisciplinary partnerships involved in our community engagement and outreach activities, including close work with community-based organisations (e.g. https://www.safh.org.uk) and engagement workshops involving anthropologists and experts in public engagement (https://www.centreofthecell.org).
Start Year 2017
 
Description East London Genes and Health (ELGH) 
Organisation Social Action for Health
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I am deputy lead for this large community genomics study. I contribute towards the overall running of this important study (including recruitment, study design and management, recall-by-genotype, community engagement) which is a large community genomics project of British Bangladeshis and Pakistanis (n=28,000). I am also the local PI for a UK consortium studying type 2 diabetes in this cohort, including running recall-by-genotype studies, analysis of big data (using electronic health records) and the design of future metabolic phenotyping studies.
Collaborator Contribution ELGH works with a large international consortium (including academic and industry partners) involved in many of its activities. I am working particularly with a UK-wide consortium of diabetes researchers in recall-by-genotype studies based on rare diabetes and obesity-associated variants.
Impact Currently this is work in progress and we are in the recruitment phase to recall-by-genotype studies. We have a broad range of multidisciplinary partnerships involved in our community engagement and outreach activities, including close work with community-based organisations (e.g. https://www.safh.org.uk) and engagement workshops involving anthropologists and experts in public engagement (https://www.centreofthecell.org).
Start Year 2017
 
Description East London Genes and Health (ELGH) 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I am deputy lead for this large community genomics study. I contribute towards the overall running of this important study (including recruitment, study design and management, recall-by-genotype, community engagement) which is a large community genomics project of British Bangladeshis and Pakistanis (n=28,000). I am also the local PI for a UK consortium studying type 2 diabetes in this cohort, including running recall-by-genotype studies, analysis of big data (using electronic health records) and the design of future metabolic phenotyping studies.
Collaborator Contribution ELGH works with a large international consortium (including academic and industry partners) involved in many of its activities. I am working particularly with a UK-wide consortium of diabetes researchers in recall-by-genotype studies based on rare diabetes and obesity-associated variants.
Impact Currently this is work in progress and we are in the recruitment phase to recall-by-genotype studies. We have a broad range of multidisciplinary partnerships involved in our community engagement and outreach activities, including close work with community-based organisations (e.g. https://www.safh.org.uk) and engagement workshops involving anthropologists and experts in public engagement (https://www.centreofthecell.org).
Start Year 2017
 
Description East London Genes and Health (ELGH) 
Organisation University of Exeter
Department Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution I am deputy lead for this large community genomics study. I contribute towards the overall running of this important study (including recruitment, study design and management, recall-by-genotype, community engagement) which is a large community genomics project of British Bangladeshis and Pakistanis (n=28,000). I am also the local PI for a UK consortium studying type 2 diabetes in this cohort, including running recall-by-genotype studies, analysis of big data (using electronic health records) and the design of future metabolic phenotyping studies.
Collaborator Contribution ELGH works with a large international consortium (including academic and industry partners) involved in many of its activities. I am working particularly with a UK-wide consortium of diabetes researchers in recall-by-genotype studies based on rare diabetes and obesity-associated variants.
Impact Currently this is work in progress and we are in the recruitment phase to recall-by-genotype studies. We have a broad range of multidisciplinary partnerships involved in our community engagement and outreach activities, including close work with community-based organisations (e.g. https://www.safh.org.uk) and engagement workshops involving anthropologists and experts in public engagement (https://www.centreofthecell.org).
Start Year 2017
 
Description East London Genes and Health (ELGH) 
Organisation University of Oxford
Department Oxford Centre for Diabetes Endocrinology and Metabolism (OCDEM)
Country United Kingdom 
Sector Academic/University 
PI Contribution I am deputy lead for this large community genomics study. I contribute towards the overall running of this important study (including recruitment, study design and management, recall-by-genotype, community engagement) which is a large community genomics project of British Bangladeshis and Pakistanis (n=28,000). I am also the local PI for a UK consortium studying type 2 diabetes in this cohort, including running recall-by-genotype studies, analysis of big data (using electronic health records) and the design of future metabolic phenotyping studies.
Collaborator Contribution ELGH works with a large international consortium (including academic and industry partners) involved in many of its activities. I am working particularly with a UK-wide consortium of diabetes researchers in recall-by-genotype studies based on rare diabetes and obesity-associated variants.
Impact Currently this is work in progress and we are in the recruitment phase to recall-by-genotype studies. We have a broad range of multidisciplinary partnerships involved in our community engagement and outreach activities, including close work with community-based organisations (e.g. https://www.safh.org.uk) and engagement workshops involving anthropologists and experts in public engagement (https://www.centreofthecell.org).
Start Year 2017
 
Description GIFTS 
Organisation Bangladesh Institute of Research and Rehabilitation for Diabetes Endocrine and Metabolic Disorders
PI Contribution EU FP7 Theme: Health; Collaborative Project (278917): 3 million Euros. GIFTS Study: Genomic and lifestyle predictors of foetal outcome relevant to diabetes and obesity and their relevance to prevention strategies in South Asian peoples. Member of Steering Committee, Co-applicant, and member of two work packages
Collaborator Contribution Multiple areas of research collaboration
Impact Ongoing research. Academic publications. Dissemination events including and e-learning programme contributed by a range of multidisciplinary collaborators.
Start Year 2012
 
Description GIFTS 
Organisation King Edward Memorial Hospital Research Centre
PI Contribution EU FP7 Theme: Health; Collaborative Project (278917): 3 million Euros. GIFTS Study: Genomic and lifestyle predictors of foetal outcome relevant to diabetes and obesity and their relevance to prevention strategies in South Asian peoples. Member of Steering Committee, Co-applicant, and member of two work packages
Collaborator Contribution Multiple areas of research collaboration
Impact Ongoing research. Academic publications. Dissemination events including and e-learning programme contributed by a range of multidisciplinary collaborators.
Start Year 2012
 
Description GIFTS 
Organisation Queen Mary University of London
Department Barts and The London School of Medicine and Dentistry
Country United Kingdom 
Sector Academic/University 
PI Contribution EU FP7 Theme: Health; Collaborative Project (278917): 3 million Euros. GIFTS Study: Genomic and lifestyle predictors of foetal outcome relevant to diabetes and obesity and their relevance to prevention strategies in South Asian peoples. Member of Steering Committee, Co-applicant, and member of two work packages
Collaborator Contribution Multiple areas of research collaboration
Impact Ongoing research. Academic publications. Dissemination events including and e-learning programme contributed by a range of multidisciplinary collaborators.
Start Year 2012
 
Description GIFTS 
Organisation Queen Mary University of London
Department Barts and The London School of Medicine and Dentistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Pilot data generated from this MRC project has been fed into a grant application from the EU FP7 programme and a 3million euro grant has been awarded (PI Graham Hitman) which will, in part, continue to develop these research themes. I am a co-investigator on this EU grant.
Collaborator Contribution Infrastructure support and broader expertise. Financial contribution will help to fund validation and replication experiments.
Impact EU FP7 funding (3million euros)
Start Year 2011
 
Description GIFTS 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution EU FP7 Theme: Health; Collaborative Project (278917): 3 million Euros. GIFTS Study: Genomic and lifestyle predictors of foetal outcome relevant to diabetes and obesity and their relevance to prevention strategies in South Asian peoples. Member of Steering Committee, Co-applicant, and member of two work packages
Collaborator Contribution Multiple areas of research collaboration
Impact Ongoing research. Academic publications. Dissemination events including and e-learning programme contributed by a range of multidisciplinary collaborators.
Start Year 2012
 
Description MRC The Gambia - fetal programming and miRNA study 
Organisation Medical Research Council (MRC)
Department MRC International Nutrition Group
Country United Kingdom 
Sector Public 
PI Contribution I have led a study looking serum samples from offspring born in a longitudinal cohort study in the Gambia to investigate whether maternal nutrition impacts circulating miRNA levels. This work has involved laboratory work in the Gambia and the UK, and supervision of a postgraduate student.
Collaborator Contribution MRC The Gambia have provided samples from an important longitudinal cohort study as well as clinical data to facilitate this study. The design and analysis of this study has been performed in collaboration with these colleagues, as well as with colleagues at the University of Cambridge who have contributed expertise in genomic technology.
Impact Development and optimisation of new lab protocols
Start Year 2016
 
Description MRC The Gambia - fetal programming and miRNA study 
Organisation University of Cambridge
Department Cambridge Genomic Services
Country United Kingdom 
Sector Academic/University 
PI Contribution I have led a study looking serum samples from offspring born in a longitudinal cohort study in the Gambia to investigate whether maternal nutrition impacts circulating miRNA levels. This work has involved laboratory work in the Gambia and the UK, and supervision of a postgraduate student.
Collaborator Contribution MRC The Gambia have provided samples from an important longitudinal cohort study as well as clinical data to facilitate this study. The design and analysis of this study has been performed in collaboration with these colleagues, as well as with colleagues at the University of Cambridge who have contributed expertise in genomic technology.
Impact Development and optimisation of new lab protocols
Start Year 2016
 
Description Matlab famine study 
Organisation International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)
Country Bangladesh 
Sector Charity/Non Profit 
PI Contribution Scientific contribution to a collaborative project on fetal programming of type 2 diabetes in a longitudonal cohort of maternal famine exposure. I have provided a novel molecular contribution to this clinical and epidemiological project and trained local Bangladeshi researchers in these scientific methods.
Collaborator Contribution Additional cohorts to develop hypothesis in a broader context.
Impact Peer-reviewed publication
Start Year 2010
 
Description Pune maternal nutrition study 
Organisation Council of Scientific and Industrial Research (CSIR)
Department Centre for Cellular and Molecular Biology (CCMB)
Country India 
Sector Academic/University 
PI Contribution We have collaborated with KEM (Pune, India) and CCMB (Hyderabad, India) to work on samples of offspring born to mothers with vitamin B12 deficiency in pregnancy so that we may investigate the role of epigenetics in the programming of childhood diabetes and obesity that has been identified.
Collaborator Contribution Knowledge transfer.Knowledge transfer
Impact Funding from Diabetes UK (small grant). The collaboration incorporates clinicals and molecular biologists from India.
Start Year 2008
 
Description Pune maternal nutrition study 
Organisation KEM Hospital Research Centre
Department Department of Diabetes
Country India 
Sector Hospitals 
PI Contribution We have collaborated with KEM (Pune, India) and CCMB (Hyderabad, India) to work on samples of offspring born to mothers with vitamin B12 deficiency in pregnancy so that we may investigate the role of epigenetics in the programming of childhood diabetes and obesity that has been identified.
Collaborator Contribution Knowledge transfer.Knowledge transfer
Impact Funding from Diabetes UK (small grant). The collaboration incorporates clinicals and molecular biologists from India.
Start Year 2008
 
Description Warwick collaboration 
Organisation University of Warwick
Department School of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative work on the effects of B12 deficiency on the epigenome in an in vitro system of adipose development. I am performing the epigenomic work and have led the study design and have had a joint role in obtaining funds.
Collaborator Contribution Provision of in vitro model system (adipose cell line) on which to study the effects of B12 deficiency in adipose.
Impact • Joint QMUL/Warwick Award for Collaborative Research Projects (2012): £18,000, Co-applicant
Start Year 2012
 
Description Warwick-QMUL 
Organisation University of Warwick
Department Diabetes
Country United Kingdom 
Sector Academic/University 
PI Contribution Jointly formed this collaboration, generated new data and obtained further research funding for a future project.
Collaborator Contribution As above
Impact QMUL-Warwick partnership pump priming grant. Joint manuscript submission
Start Year 2012
 
Description Lay panel meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentation of research proposal and study recruitment to lay panel

Advice on recruitment and access to patient groups
Year(s) Of Engagement Activity 2009
 
Description Outside project 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Ongoing
Year(s) Of Engagement Activity 2012
 
Description Xplore Health 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Schools
Results and Impact Implemented in QMUL Centre of the Cell and on EU-funded Xplore Health website

As above
Year(s) Of Engagement Activity 2012