DIMENSION

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

Project description

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 investigated 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 was 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. To this end, the consortium completed epigenetic and transcriptomic profiling from up to three targeted postprandial and nutritional intervention studies and carried out a series of experimental studies in in-vitro systems. To aid large-scale epigenomic data processing and quality assessment DIMENSION consortium partners developed computational tools for methylome data analysis (DNAmArray).

The primary results from DIMENSION consortium identified epigenetic and transcriptomic postprandial molecular trajectories, and identified links between these molecular trajectories and the postprandial glucose response. The DIMENSION project also identified epigenetic changes that occur as a result of a diet and lifestyle intervention in older adults. Subsequent cohort-based analyses further characterised links between diet, epigenetics, and cardio-metabolic health. These included studies identifying epigenetic signatures of diet quality and habitual diet intakes, both at nutrient level and at the level of food groups. Large-scale analyses of cardio-metabolic health identified epigenetic biomarkers of multiple phenotypes, for example, accumulation of visceral fat, circulating lipid levels, and cytokines and adipokines. Follow-up dissection of these effects identified both signals that are putatively causal to cardiometabolic health, those that mediate effects of diet risk factors on metabolic health, as well as signals that appear to be secondary to the phenotypes. Longitudinal epigenetic data profiling in a sample subset identified that a subset of diet-induced epigenetic signals exhibits longitudinal stability. Integrating transcriptomic and metabolomic data allowed for a functional assessment of regulatory genomic diet-induced signals, which was further investigated in a series of in-vitro experiments of diet-induced regulatory genomic effects in cells and tissues.

In summary the DIMENSION consortium aimed to deliver novel mechanistic insights into how exactly nutritional modifications can modulate the regulatory and functional genome to promote cardio-metabolic health. The insights obtained can complement traditional population-based guidelines and have potential impacts to inform the rapidly evolving area of individualised nutrition-based strategies.

Consortium

Partner Organization Partner Country
Helmholtz Zentrum München Germany
Leiden University Medical Center The Netherlands
IMDEA Alimentacion Spain
INSERM U974 Center of Research in Myology France
Ludwig-Maximilians-Universität (LMU) München Germany

 

Highlights

  • Analyses within DIMENSION consortium datasets have contributed towards identifying epigenetic signatures of habitual diet composition and quality (Hellbach et al. 2022, Hellbach et al. 2022, Do et al. 2020 and Ma et al. 2020), many of which were also associated with multiple health outcomes or were only present in individuals who exhibit specific metabolic health characteristics.
  • The DIMENSION consortium identified an epigenetic signature of visceral fat, a key risk factor for metabolic disease, where some of the signals mediate the effects of diet on metabolic health (Christiansen et al. 2022). 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 Alonso et al. 2020).
  • Omixer, a Bioconductor package for multivariate and reproducible sample randomization in omics studies has been developed and can be accessed here.

Products

Title: An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis
Author: Liu J, Carnero-Montoro E, ... 52 authors..., Bell JT*, Demirkan A, and van Duijn CM.
Link: https://doi.org/10.1038/s41467-019-10487-4
Title: Dissecting the role of the gut microbiota and diet on visceral fat mass accumulation
Author: Le Roy CI, Bowyer RCE, Castillo-Fernandez JE, Pallister T, Menni C, Steves CJ, Berry SE*, Spector TD, and Bell JT*
Link: https://doi.org/10.1038/s41598-019-46193-w
Title: Bayesian reassessment of the epigenetic architecture of complex trait
Author: Trejo Banos D, McCartney D, Patxot Bertran M, Anchieri L, Battram T, Christiansen C*, Costeira R*, Walker R, Morris S, Campbell A, Zhang Q, Porteous D, McRae A, Wray N, Visscher P, Haley C, Evans K, Deary I, Mcintosh A, Hemani G, Bell JT*, Marioni R, Robinson M
Link: https://doi.org/10.1038/s41467-020-16520-1
Title: Epigenome-wide association study of diet quality in the Women's Health Initiative and TwinsUK cohort.
Author: Do WL, Whitsel EA, Costeira R*, Masachs OM, Le Roy CI, Bell JT*, Staimez LR, Stein AD, Smith AK, Horvath S, Assimes TL, Liu S, Manson JE, Shadyab AH, Li Y, Hou L, Bhatti P, Jordahl K, Narayan KMV, Conneely KN
Link: https://doi.org/10.1093/ije/dyaa215
Title: Whole Blood DNA Methylation Signatures of Diet Are Associated With Cardiovascular Disease Risk Factors and All-Cause Mortality
Author: Ma J, Rebholz CM, Braun KVE, Reynolds LM, Aslibekyan S, Xia R, Biligowda NG, Huan T, Liu C, Mendelson MM, Joehanes R, Hu EA, Vitolins MZ, Wood AC, Lohman K, Ochoa-Rosales C, van Meurs J, Uitterlinden A, Liu Y, Elhadad MA, Heier M, Waldenberger M*, Peters A, Colicino E, Whitsel EA, Baldassari A, Gharib SA, Sotoodehnia N, Brody JA, Sitlani CM, Tanaka T, Hill WD, Corley J, Deary IJ, Zhang Y, Schöttker B, Brenner H, Walker ME, Ye S, Nguyen S, Pankow J, Demerath EW, Zheng Y, Hou L, Liang L, Lichtenst
Link: https://doi.org/10.1161/circgen.119.002766
Title: Deciphering the Plasma Proteome of Type 2 Diabetes.
Author: Elhadad MA, Jonasson C, Huth C, Wilson R, Gieger C*, Matias P, Grallert H, Graumann J, Gailus-Durner V, Rathmann W, von Toerne C, Hauck SM, Koenig W, Sinner MF, Oprea TI, Suhre K, Thorand B, Hveem K, Peters A, Waldenberger M*.
Link: https://doi.org/10.2337/db20-0296
Title: DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures.
Author: Gomez-Alonso MDC, Kretschmer A, Wilson R, Pfeiffer L, Karhunen V, Seppälä I, Zhang W, Mittelstraß K, Wahl S, Matias-Garcia PR, Prokisch H, Horn S, Meitinger T, Serrano-Garcia LR, Sebert S, Raitakari O, Loh M, Rathmann W, Müller-Nurasyid M, Herder C, Roden M, Hurme M, Jarvelin MR, Ala-Korpela M, Kooner JS, Peters A, Lehtimäki T, Chambers JC, Gieger C*, Kettunen J, Waldenberger M*.
Link: https://doi.org/10.1186/s13148-020-00957-8
Title: Pooled analysis of epigenome-wide association studies of food consumption in KORA, TwinsUK and LLS
Author: Fabian Hellbach*, Lucy Sinke*, Ricardo Costeira*, Sebastian-Edgar Baumeister, Marian Beekman, Panayiotis Louca, Emily R. Leeming, Olatz Mompeo, Sarah Berry*, Rory Wilson*, Nina Wawro, Dennis Freuer, Hans Hauner, Annette Peters, Juliane Winkelmann, Wolfgang Koenig, Christa Meisinger, Melanie Waldenberger*, Bastiaan T. Heijmans*, P.Eline Slagboom*, Jordana T. Bell*, Jakob Linseisen*
Link: https://doi.org/10.1007/s00394-022-03074-9
Title: Omixer: multivariate and reproducible sample randomization to proactively counter batch effects in omics studies
Author: Lucy Sinke*, Davy Cats, Bastiaan T Heijmans*
Link: https://doi.org/10.1093/bioinformatics/btab159
Title: Genomic and phenomic insights from an atlas of genetic effects on DNA methylation.
Author: Min JL, Hemani G, Hannon E, Dekkers KF, Castillo-Fernandez J, Luijk R, Carnero-Montoro E, Lawson DJ, Burrows K, Suderman M, Bretherick AD, Richardson TG, Klughammer J, Iotchkova V, Sharp G, Al Khleifat A, Shatunov A, Iacoangeli A, McArdle WL, Ho KM, Kumar A, Söderhäll C, Soriano-Tárraga C, Giralt-Steinhauer E, Kazmi N, Mason D, McRae AF, Corcoran DL, Sugden K, Kasela S, Cardona A, Day FR, Cugliari G, Viberti C, Guarrera S, Lerro M, Gupta R, Bollepalli S, Mandaviya P, Zeng Y, Clarke T-K, Walker R
Link: https://doi.org/10.1038/s41588-021-00923-x
Title: DNA methylation signatures of incident coronary heart disease: findings from epigenome-wide association studies.
Author: Xia Y, Brewer A, Bell JT*
Link: https://doi.org/10.1186/s13148-021-01175-6
Title: Adipose methylome integrative-omic analyses reveal genetic and dietary metabolic health drivers and insulin resistance classifiers
Author: Christiansen C, Tomlinson M, Eliot M, Nilsson E, Costeira R*, Xia Y, Villicana S, Mompeo O, Wells P, Castillo-Fernandez J, Potier L, Vohl M-C, Tchernof A, El-Sayed Moustafa J, Menni C, Steves CJ, Kelsey K, Ling C, Grundberg E, Small KS, Bell JT*
Link: https://doi.org/10.1186/s13073-022-01077-z
Title: Muscle fibro-adipogenic progenitors from a single-cell perspective: Focus on their "virtual" secretome.
Author: Negroni E, Kondili M, Muraine L, Bensalah L, Butler-Browne GS*, Mouly V, Bigot A, Trollet C*
Link: https://doi.org/10.3389/fcell.2022.952041
Title: Assessment of PABPN1 nuclear inclusions on a large cohort of patients and in a human xenograft model of oculopharyngeal muscular dystrophy.
Author: Roth F, Dhiab J, Boulinguiez A*, Mouigni H-R, Lassche S, Negroni E, Muraine L, Marhic A, Oliver A, Lainé J, Rouche A, O’Ferrall EK, van Engelen B, Ottenheijm C, Greif H, Blumen S, St Guily JL, Perie S, Butler-Browne GS, Mouly V, Trollet C*
Link: https://doi.org/10.1007/s00401-022-02503-7

 

Target group Authors Means of communication Hyperlink Pdf
Researchers Fabian Hellbach, Sebastian-Edgar Baumeister, Rory Wilson, Nina Wawro, Chetana Dahal, Dennis Freuer, Hans Hauner, Anette Peters, Juliane Winkelmann, Lars Schwettmann, Wolfgang Rathmann, Florian Kronenberg, Wolfgang Koenig, Christa Meisinger, Melanie Waldenberger, Jakob Linseisen; Epigenomics of common diseases Online poster presentation    
Researchers Jakob Linseisen, Sebastian-Edgar Baumeister, Rory Wilson, Dennis Freuer, Hans Hauner, Christa Meisinger, Melanie Waldenberger, Fabian Hellbach; 22nd IUNS International Congress of Nutrition Online poster presentation    
Researchers Nathalie A. Reilly, Koen F. Dekkers, BIOS Consortium, GENIUS Consortium, J. Wouter Jukema, Bas T. Heijmans*. Poster at NWO Life Conference, 2019: “When immune cells meet lipids: deciphering causal molecular responses in large-scale population data” Poster presentation    
Expert and general audience Ordovás JM, Daimiel L., Martinez-Perez C. Gaining weight, is it a matter of genes? Eroski Consumer. May 2022 Dissemination article    
Scientific audience Martinez-Perez, C.; San-Cristobal, R.; Climent-Mainar, C.; Daimiel, L.; M Ordovás, J. Ultra-processed foods: evaluation of classification systems, consumption and associated epigenetic fingerprints. Rev. Española Nutr. Humana Y Dietética 2021, 25, 75–76. Congress conference    
Scientific audience Martinez-Perez, C.; San-Cristobal, R.; Climent-Mainar, C.; Guallar, P.; Rodríguez Artalejo, F.; Daimiel, L.; M Ordovás, J.M. Identification of methylation marks associated to ultra-processed food consumption. Congress conference    
Researchers Nathalie A. Reilly, Koen F. Dekkers, BIOS Consortium, GENIUS Consortium, J. Wouter Jukema, Bas T. Heijmans. Poster at Rembrandt Symposium, 2019: “When immune cells meet lipids: deciphering causal molecular responses in large-scale population data” Poster presentation    
Researchers Nathalie A. Reilly, Koen F. Dekkers, Lucy Sinke, Stan Hilt, GENIUS Consortium, Andreea Ioan-Facsinay, J. Wouter Jukema, Bas T. Heijmans. Poster at Rembrandt Symposium, 2020: “Fatty acid-induced transcriptomic and methylomic changes in T cells are involved in immunometabolism” Poster presentation    
Researchers Lucy Sinke, Marian Beekman, Thies Gehrmann, Yotam Raz, Fatih Bogaards, Stylianos Paraschiakos, Nico Lakenberg, H Eka D Suchiman, Mitra Hosseinzadeh, Thomas Jonkman, Ondine van de Rest, Erik van Zwet, Melanie Waldenberger, Rory Wilson, Bas T Heijmans, P Eline Slagboom. Poster at Epigenomics of Common Diseases, Online, 2021: “Growing Old Together: 13-week lifestyle intervention causes tissue-specific methylation changes in healthy, older adults” Poster presentation    
Researchers Nathalie A. Reilly, Koen F. Dekkers, Lucy Sinke, Stan Hilt, GENIUS Consortium, Andreea Ioan-Facsinay, J. Wouter Jukema, Bas T. Heijmans. Poster at European Atherosclerosis Society, 2021: “Fatty acid-induced transcriptomic and methylomic changes in T cells are involved in immunometabolism” Poster presentation    
Researchers Lucy Sinke, Jenny van Dongen, Thomas Delerue, Rory Wilson, Yujing Xia, Ricardo Costeira, Chao-Qiang Lai, Marian Beekman, Jose M. Ordovas, Jordana T Bell, Melanie Waldenberger, Dorret I Boomsma, P Eline Slagboom, Bastiaan T Heijmans. Poster at Epigenetics and Epigenomics in Health and Disease, Brussels, 2022: “Circulating interleukin-6 levels are associated with DNA methylation in regulatory regions of inflammatory genes” Poster presentation    
Researchers Lucy Sinke, Jenny van Dongen, Thomas Delerue, Rory Wilson, Yujing Xia, Ricardo Costeira, Chao-Qiang Lai, Marian Beekman, Jose M. Ordovas, Jordana T Bell, Melanie Waldenberger, Dorret I Boomsma, P Eline Slagboom, Bastiaan T Heijmans. Short talk at Epigenomics of Common Diseases, Cambridge, 2022: “Interleukin-6 levels are associated with DNA methylation in blood at regulatory regions of key inflammatory genes” Oral presentation    
Researchers Nathalie A. Reilly, Koen F. Dekkers, Friederike Sonnet, Lucy Sinke, Joanneke C. Kwekkeboom, Ellen van der Voort, GENIUSII consortium, Andreea Ioan-Facsinay, J. Wouter Jukema, Bastiaan T. Heijmans. Short talk at talk at Nationale Lipidendag, 2022: “Oleic acid-induced transcriptomic and methylomic changes in CD4+ T-cells are involved in immunometabolism” Oral presentation    
Researchers Bell JT "Diet and the human methylome: towards improvement of cardio-metabolic health"; Invited talk at the Paediatric Allergy and Nutrition Research Meeting, King's College London, March 2023. Oral presentation    
Academic researchers and industry partners Costeira*, Daimiel*, Sinke*, Christiansen, Heijmans*, Slagboom*, Waldenberger*, Berry*, Ordovás*, and Bell*. Human DNA methylation trajectories of the postprandial metabolic response to food". Oral presentation at the 22nd International Congress of Nutrition (22nd IUNS-ICN), Tokyo, Japan, December 2023. Oral presentation    

Features

Project number:
DIMENSION
Duration: 100%
Duration: 100 %
2019
2022
Project lead and secretary:
Jordana Bell
Responsible organisation:
King's College London, UK