HDHL DIMENSION: Dietary induced methylome and transcriptome dynamics assessing nutrition impacts on cardiovascular and metabolic health

Lead Research Organisation: King's College London
Department Name: Genetics and Molecular Medicine

Abstract

Cardiovascular and metabolic diseases are a primary cause of morbidity and mortality worldwide. Diet is a major risk factor for cardio-metabolic health, but is challenging to study in part because metabolic response to diet is highly individualised. Characterising the molecular pathways that mediate personalised responses to diet is critical to effectively tackle the current epidemic. Epigenetic mechanisms are key regulators of gene function that can change in response to external stimuli, including diet. However, longitudinal studies of epigenetic dynamics in response to diet are rare. Our hypothesis is that the identification of dietary induced epigenetic marks together with epigenetic signatures of cardio-metabolic traits explain inter-individual variability in metabolic response to diet and its downstream effects on health. The DIMENSION consortium will test this hypothesis by investigating dynamically the causal impacts of dietary intake on epigenetic regulation of gene function across tissues, and their impact on subsequent cardio-metabolic health outcomes. The proposal will explore the gene regulatory and functional pathways that occur immediately following food intake in the postprandial state, as well as with habitual dietary intakes. We will test postprandial metabolic responses that have been largely overlooked, despite revealing multiple aspects of diet induced metabolic health that would not be detectable from studying fasting status alone. Further, humans spend the majority of their lives in the postprandial glycemic and lipemic state, which are themselves independent risk factors of cardiovascular disease. The work programme is based on: (i) targeted postprandial and nutritional intervention studies to tackle the causal relationships between diet, epigenetic modifications and gene function, in combination with (ii) state-of-the-art analyses to characterize the links between diet, epigenetics, and cardio-metabolic health using novel diet measures including metabolomics in extensively studied cohorts, and (iii) functional follow-up experiments assessing the impact of diet-induced epigenetic and transcriptomic signals at the level of cells, within and across tissues. Using complementary approaches, the DIMENSION consortium will deliver novel mechanistic insights into how exactly nutritional modifications can modulate the regulatory and functional genome to promote cardio-metabolic health. These insights will complement traditional population-based guidelines and inform the rapidly evolving area of individualised nutrition-based strategies.

Technical Summary

Cardiovascular and metabolic diseases are a primary cause of morbidity and mortality worldwide. Diet is a major risk factor for cardio-metabolic health, but is challenging to study in part because metabolic response to diet is highly individualised. Characterising the molecular pathways that mediate personalised responses to diet is critical to effectively tackle the current epidemic. Epigenetic mechanisms are key regulators of gene function that can change in response to external stimuli, including diet. However, longitudinal studies of epigenetic dynamics in response to diet are rare. Our hypothesis is that the identification of dietary induced epigenetic marks together with epigenetic signatures of cardio-metabolic traits explain inter-individual variability in metabolic response to diet and its downstream effects on health. We will test this hypothesis by investigating dynamically the causal impacts of dietary intake on epigenetic regulation of gene function across tissues, and their impact on subsequent cardio-metabolic health outcomes. We will explore the gene regulatory and functional pathways that occur immediately following food intake in the postprandial state, as well as with habitual dietary intakes. The work programme is based on: (i) targeted postprandial and nutritional intervention studies to tackle the causal relationships between diet, epigenetic modifications and gene function, in combination with (ii) state-of-the-art analyses to characterize the links between diet, epigenetics, and cardio-metabolic health using novel diet measures including metabolomics in extensively studied cohorts, and (iii) functional follow-up experiments assessing the impact of diet-induced epigenetic and transcriptomic signals at the level of cells, within and across tissues. The DIMENSION consortium aims to deliver novel mechanistic insights into how exactly nutritional modifications can modulate the regulatory and functional genome to promote cardio-metabolic health.

Planned Impact

By systematically assessing the dynamic and chronic causal impacts of diet on epigenetic regulation of gene function across tissues and their impact on subsequent cardio-metabolic health outcomes, this project will generate valuable scientific data for a broad range of stakeholders. The dissemination programme will be designed to address key stakeholders, primarily by initiating new conduits for knowledge transfer and discussion between academic, scientists and with the food industry as well as informing public health policy makers about developments in the field and by empowering the public with more information about how and why they respond to food differently.

The DIMENSION project will combine observational studies with mechanistic insights towards building the evidence base for dietary guidelines and informing future personalised nutrition strategies for the maintaining and improving health. The expected results will deliver new biomarkers related to specific diet patterns and nutrient intakes and provide insights into causal pathways identifying diet induced molecular mechanisms that may impact cardiovascular or metabolic health. The results will have translatable impacts on several fronts, including:

(i) The Public Sector;
- Guide the design of dietary interventions to improve cardio-metabolic health
- Advancement of personalised strategies for prevention of cardio-metabolic disease

(ii) Industry
- Development of health-related applications including personalised nutrition programmes
- Informing the molecular potential of specific nutrients
These may be implemented through existing collaborative links with industry (Unilever, Philips, (Leiden) and collaborations with new private partners, such as Janssen, Nutricia, Frysland-C, which are being explored by LUMC in efforts to build a large public-private consortium on vitality and ageing.

(iii) Across sectors
- The methodology developed by the DIMENSION project could be used to help guide and refine other dietary guidelines.

Dissemination and Knowledge exchange
The design of the dissemination and exploitation strategy to achieve the above will be developed from the onset of the project as outlined in brief below:

1. Dissemination of information to academic beneficiaries.
2. Engagement with food industry and public health bodies. Research findings and technical advances arising from this project will have immediate impact for nutritional scientists, dieticians, the food industry, and potentially also for public health policy. We aim to provide a forum for dissemination of project-specific information, and more generally for exchange of information and ideas amongst relevant stakeholders.
Website: We will develop a project-specific website. This will provide a domain for academic, industrial and health professionals to provide access to general nutrition and epigenetic background information, study specific information, publications, mini-review, and other items.
Webinar: During the final year of the project a 60 minute Webinar will be hosted in collaboration with The British Nutrition Foundation (BNF) which will be accessible on-line live and post event
3. Engagement with the public. Public awareness of the issues surrounding individual responses to foods and nutrients is poor. Therefore, an important component of the impact pathway of our proposal will be to increase public understanding of why people respond differenty to different foods and why published evidence is not conclusive.

4. Research Network: A multi-disciplinary research network will be formed by the project Partners combining expertise in human epigenetics and genomics, nutrition, statistics, epidemiology, longitudinal studies, cardio-metabolic disease, and stratified medicine. Other academics will be invited to join this network, which will facilitate existing and newly formed collaborations.

Publications

10 25 50
 
Description Analyses within DIMENSION consortium datasets so far have contributed towards identifying epigenetic signatures of habitual diet quality (Do et al. 2020 and Ma et al. 2020), many of which were also associated with multiple health outcomes (Ma et al. 2020). We also contributed to identification of biological interactions between genetic variants underlying differential methylation and expression in the early pathogenesis of T2D (Liu et al. 2019). Our epigenome-wide analyses of lipid metabolites provide evidence of a link between DNA methylation with lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. A larger consortium analysis in currently underway (Gomez Alsonso et al. 2020).
Omixer, a Bioconductor package for multivariate and reproducible sample randomization in omics studies has been developed and can be accessed online (https://bioconductor.org/packages/release/bioc/html/Omixer.html).
Analysis of dietary-induced dynamic epigenetic and transcriptional profiles, and further dietary and cardio-metabolic health population-based epigenomic analyses are currentlyunderway.
Exploitation Route The DIMENSION project will combine observational studies with mechanistic insights towards building the evidence base for dietary guidelines and informing future personalised nutrition strategies for the maintaining and improving health. The expected results will deliver new biomarkers related to specific diet patterns and nutrient intakes and provide insights into causal pathways identifying diet induced molecular mechanisms that may impact cardiovascular or metabolic health. The results will have translatable impacts on several fronts, including academic beneficiaries.

A multi-disciplinary research network will be formed by the project Partners combining expertise in human epigenetics and genomics, nutrition, statistics, epidemiology, longitudinal studies, cardio-metabolic disease, and stratified medicine. Other academics will be invited to join this network, which will facilitate existing and newly formed collaborations. Our proof of concept approach will allow the analyses to be extended to larger samples within cohorts by forming the basis for further funding applications and establishing a diet-epigenetic research network across European population-based cohorts.

Data from this project will be published in high impact journals and communicated at Partner national and international scientific conferences. Relevant scientific audiences at national and international levels include the Epigenomics of Common Diseases, European Society for Human Genetics, International Congress of Nutrition, FENS. The DIMENSION consortium aims to operate an open access publication strategy, publishing results high-profile open access journals.
Sectors Agriculture, Food and Drink,Healthcare

 
Description Taiwan Partnering Award: Artificial intelligence applications to identify regulatory genomic signatures of diet and lifestyle disease risk factors
Amount £25,290 (GBP)
Funding ID BB/T019980/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2020 
End 03/2022
 
Description Collaboration on application of artificial intelligence (AI) method in JPI DIMENSION 
Organisation Chang Gung University
Country Taiwan, Province of China 
Sector Academic/University 
PI Contribution We applied for a BBSRC Taiwan Partnering Award: Artificial intelligence applications to identify regulatory genomic signatures of diet and lifestyle disease risk factors. The aim was to form a new collaborative research team to explore the application of AI to identify molecular markers of diet and lifestyle health risk factors, to enhance the work in the JPI DIMENSION project.
Collaborator Contribution We formed a collaboration between researchers in AI, epigenomics, and nutrition, to enhance data analysis is the DIMENSION project. The team consists of 8 members: 4 group leaders and 4 early career researchers (ECRs). Group leaders include Dr Bell (UK PI, and PI/coordinator of DIMENSION project (BB/S020845/1)) and Dr Berry (UK co-I, and PI of BB/N020987/1) at King's College London (KCL), and two partners at Chang Gung University (CGU) - Dr Tsai (TW PI, and PI of TWB epigenetic project CMRPD1J0081) and Prof Lin (TW co-I, and vice-dean of AI center at CGU). The aim of the new collaborative team is to explore the application of AI to identify molecular signatures of diet and lifestyle cardio-metabolic health risk factors, and to carry out targeted studies of specific risk factors for publications and as preliminary results for future larger-scale funding applications.
Impact A BBSRC Taiwan partnership grant was submitted, and we have just received notification that this has been awarded and is due to commence in 2020.
Start Year 2019
 
Description Collaboration on cardiovascular health epigenetic analysis across cohorts - 1946BC 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on cardiovascular health epigenetic analysis across the UK 1946 Birth Cohort study and TwinsUK cohort
Collaborator Contribution Lead the collaboration, oversee analysis, and guide project
Impact None so far
Start Year 2020
 
Description Collaboration on diet-epigenetic analyses across cohorts - LBC cohorts 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on diet-epigenetic analysis across the Lothian Birth Cohorts (LBC) cohorts and TwinsUK
Collaborator Contribution Planning to lead the project, guide analysis, and carry out meta-analysis
Impact None so far.
Start Year 2020
 
Description Collaboration on diet-epigenetic analyses across cohorts - RS cohort 
Organisation Erasmus MC
Country Netherlands 
Sector Hospitals 
PI Contribution Collaboration on diet-epigenetic analysis across RS and TwinsUK cohorts
Collaborator Contribution Planning to lead analysis of selected nutrients and food groups
Impact None so far.
Start Year 2021
 
Description Collaboration on diet-epigenetic analyses across cohorts - WHI cohort 
Organisation Emory University
Country United States 
Sector Academic/University 
PI Contribution Joint diet-epigenetic analyses across Women's Health Initiative (WHI) and TwinsUK cohorts.
Collaborator Contribution Contributed diet-epigenetic results.
Impact Publication (Do et al. 2021).
Start Year 2019
 
Description Collaboration with BIOS consortium on epigenetic analyses of cytoadipokines 
Organisation Biobanking and Biomolecular Resources Research Infrastructure
Department BIOS Consortium
Country Netherlands 
Sector Private 
PI Contribution Exploring the association between relevant phenotypes (e.g. cytokine levels) and epigenetic profiles in population-based cohorts
Collaborator Contribution Leading the analysis of the association between relevant phenotypes (e.g. cytokine levels) and epigenetic profiles in population-based cohorts
Impact No outputs yet
Start Year 2019
 
Description Collaboration with CHARGE consortium epigenetics working group on vit C and E intakes 
Organisation Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE)
Country Global 
Sector Academic/University 
PI Contribution Joint analysis assessing the association between intakes of vitamin C and E and epigenetic profiles in population-based cohorts
Collaborator Contribution Contributed results assessing the association between intakes of vitamin C and E and epigenetic profiles.
Impact No outputs yet
Start Year 2019
 
Description "Epigenetics, fertility, and health: insights from twin studies", 3rd Annual CeFH Symposium, Oslo, Sept 2020 (delivered online). 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact This was the 3rd Research Symposium of the Centre for Fertility and Health at the Norwegian Institute of Public Health, Oslo, Norway. The Symposium aims to advance the understanding of how changes in patterns of fertility and family structure influence child and adult health through social and biological pathways, using cross-discipline collaboration. The Symposium gave an overview and discussion of methodological approaches applied in economics, sociology, epidemiology and genetics to study family and health.

There were over 10 presentations from international researchers presenting recent findings in the field of family, fertility and health to an audience of international researchers, graduate students, industry members.
Year(s) Of Engagement Activity 2020
 
Description "Genetic impacts on human methylome variation", CANSSI Ontario STAGE program International Speaker Seminar Series, Toronto, Canada, November 2021 (delivered online). 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk at an international seminar series host by University of Toronto
Year(s) Of Engagement Activity 2021
 
Description "Genetic impacts on human methylome variation", Epigenetic Inheritance Symposium, ETH Zurich, Switzerland, August 2021 (delivered online). 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk at a symposium on epigenetics
Year(s) Of Engagement Activity 2021
 
Description "Genetic impacts on human methylome variation", FASEB conference "The Epigenome in Human Health and Diseases", University of Lorraine, October 2021 (delivered online). 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk at an international conference
Year(s) Of Engagement Activity 2021
 
Description "Twin studies for epigenomic markers in obesity", European Association for the Study of Obesity (EASO)'s 28th annual European Congress on Obesity (ECO2021), May 2021 (delivered online). 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited talk at a scientific conference on obesity
Year(s) Of Engagement Activity 2021
 
Description A poster presentation at the Epigenomics of Common Diseases conference 2019 (RC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A poster presentation at the Epigenomics of Common Diseases, Wellcome Genome Campus, UK:
Costeira R*, Lee J, Masachs OM, Mangino M, Le Roy CI, Bell JT*. 2019. Epigenome-wide association study of dietary patterns and target nutrients in the TwinsUK cohort.
Year(s) Of Engagement Activity 2019
 
Description A poster presentation at the Epigenomics of Common Diseases conference 2020 (CC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact A poster presentation at the Epigenomics of Common Diseases conference 2020: Colette Christiansen*, Louis Potier, Julia El-Sayed Moustafa, Kerrin Small, Jordana Bell*; Epigenetic signatures associated with visceral fat and their links with metabolic disease; Epigenomics of Common Diseases, Wellcome Genome Campus, UK (online); 2020.
Year(s) Of Engagement Activity 2020
 
Description A poster presentation at the Epigenomics of Common Diseases conference 2020 (RC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A poster presentation at the Epigenomics of Common Diseases conference 2020. Ricardo Costeira*, Fabian Hellbach*, Lucy Sinke*, Olatz M. Masachs, Caroline I. Le Roy, Massimo Mangino, Kerrin Small, Sarah Berry*, P. Eline Slagboom*, Bastiaan T. Heijmans*, Jakob Linseisen*, Jordana T. Bell*; Multi-tissue epigenome-wide associations of DNA methylation variation with dietary nutrient intakes; Epigenomics of Common Diseases, Wellcome Genome Campus, UK (online); 2020.
Year(s) Of Engagement Activity 2020
 
Description A poster presentation at the Epigenomics of Common Diseases conference 2020 (YX) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A poster presentation at the Epigenomics of Common Diseases conference 2020: Yujing Xia*, Colette Christiansen*, Massimo Mangino, Cristina Menni, Jordana Bell*; Epigenome-wide association study of ASCVD risk score; Epigenomics of Common Diseases, Wellcome Genome Campus, UK (online); 2020.
Year(s) Of Engagement Activity 2020
 
Description A poster presentation at the Epigenomics of Common Diseases conference 2021 (CC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A poster presentation at the Epigenomics of Common Diseases conference 2021: Colette Christiansen, Louis Potier, Tiphaine Martin, Juan Castillo-Fernandez, Juan Ordonana, Perminder Sachdev, Karen Mather, Kirsi Pietilainen, Christine Dalgaard, Kaare Christensen, Dorret Boomsma, Patrik Magnusson, Nancy Pedersen, Tim Spector, Elin Grundberg, Jordana Bell; Enhanced resolution epigenetic profiling in regulatory elements reveals novel differential methylation in Type 2 Diabetes; Epigenomics of Common Diseases, Wellcome Genome Campus, UK (online); 2021.
Year(s) Of Engagement Activity 2021
 
Description A poster presentation at the Epigenomics of Common Diseases conference 2021 (YX) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A poster presentation at the Epigenomics of Common Diseases conference 2021: Yujing Xia, Juan Castillo-Fernandez, Colette Christiansen, Massimo Mangino, George Ploubidis, Alissa Goodman, Andrew Wong, Nish Chaturvedi, Ken Ong, Jordana Bell*; Epigenome-wide blood DNA methylation signature of incident atherosclerotic cardiovascular disease in UK population-based samples; Epigenomics of Common Diseases, Wellcome Genome Campus, UK (online); 2021.
Year(s) Of Engagement Activity 2021
 
Description A poster presentation at the Metabolism Meets Epigenetics conference, EMBO / EMBL Symposium 2021 (RC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A poster presentation at the Metabolism Meets Epigenetics (Virtual Conference), EMBO | EMBL Symposium. Ricardo Costeira, Laila Evangelista, Rory Wilson, Xinyu Yan, Sergio Villicana, Fabian Hellbach, Lucy Sinke, Colette Christiansen, Olatz M. Masachs, Massimo Mangino, Cristina Menni, Sarah Berry, Eline Slagboom, Bastiaan Heijmans, Kerrin Small, Jakob Linseisen, Melanie Waldenberger, Jordana Bell; METABOLOMIC BIOMARKERS OF B VITAMIN INTAKES UNVEIL NOVEL DIFFERENTIALLY METHYLATED POSITIONS IN THE HUMAN GENOME; Epigenomics of Common Diseases, Wellcome Genome Campus, UK (online); 2021.
Year(s) Of Engagement Activity 2021
 
Description DIMENSION consortium annual research meeting, Oct 2020, held online. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Annual research meeting of the JPI DIMENSION consortium presenting research findings of diet-epigenetics.
Year(s) Of Engagement Activity 2020
 
Description DIMENSION consortium kick-off meeting, Sept 2019, London, UK. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The kick-off meeting for the DIMENSION consortium took place in London, UK with around 20-25 participants.
Year(s) Of Engagement Activity 2019
 
Description Talk at the Wellcome Trust Mathematical Genomics and Medicine PhD programme at the University of Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Invited research seminar to the mathematical genomics PhD students at the University of Cambridge - audience consisted of ~50 predominantly PhD students, postdocs, and academics.
Year(s) Of Engagement Activity 2021