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

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.

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.

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.