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.

The DIMENSION consortium investigates dynamically the causal impacts of diet on epigenetic regulation of gene function across tissues, and their impact on subsequent cardio-metabolic health outcomes. 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.

Results from DIMENSION consortium so far have contributed to workflow component (ii) characterizing links between diet, epigenetics, and cardio-metabolic health, with contributions to 5 specific outputs to date. Examples include identification of epigenetic signatures of diet quality (Do et al. 2020 and Ma et al. 2020), and biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D (Liu et al. 2019). To aid large-scale epigenomic data processing and quality assessment DIMENSION consortium partners have also developed computational tools for methylome data analysis (DNAmArray). Ongoing work focuses on epigenomic and transcriptomic signatures of specific dietary intakes, and their links with cardio-metabolic health.

The consortium has also completed epigenetic profiling from three targeted postprandial and nutritional intervention studies as part of workflow component (i), and data analysis is underway. These data allow the exploration of causal relationships between diet, epigenetics and gene function. Lastly, DIMENSION partners have initiated experiments that tackle the final component of the workflow, assessing functional impacts of diet-induced epigenetic and transcriptomic signals.

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. These insights will complement traditional population-based guidelines and have potential impacts to inform the rapidly evolving area of individualised nutrition-based strategies.

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 here.

Analysis of dietary-induced dynamic epigenetic and transcriptional profiles, and further dietary and cardio-metabolic health population-based epigenomic analyses are currentlyunderway.