DNA methylation signature in blood mirrors successful weight-loss during lifestyle interventions: the CENTRAL trial.

Lydia Hopp, Iris Shai, Peter Kovacs, Matthias Blüher, Michael Stumvoll, Peter F Stadler, Yvonne Böttcher, Kerstin Rohde, Luise Müller, Maria Keller, Hila Zelicha, Gal Tsaban, Dan Schwarzfuchs, Ilan Shelef, Yftach Gepner, Stephan H Bernhart, Anat Yaskolka Meir

Journal: Genome medicine 2021;12(1):97

PMID: 33198820

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Abstract

BACKGROUND

One of the major challenges in obesity treatment is to explain the high variability in the individual's response to specific dietary and physical activity interventions. With this study, we tested the hypothesis that specific DNA methylation changes reflect individual responsiveness to lifestyle intervention and may serve as epigenetic predictors for a successful weight-loss.

METHODS

We conducted an explorative genome-wide DNA methylation analysis in blood samples from 120 subjects (90% men, mean ± SD age = 49 ± 9 years, body mass-index (BMI) = 30.2 ± 3.3 kg/m) from the 18-month CENTRAL randomized controlled trial who underwent either Mediterranean/low-carbohydrate or low-fat diet with or without physical activity.

RESULTS

Analyses comparing male subjects with the most prominent body weight-loss (responders, mean weight change - 16%) vs. non-responders (+ 2.4%) (N = 10 each) revealed significant variation in DNA methylation of several genes including LRRC27, CRISP2, and SLFN12 (all adj. P < 1 × 10). Gene ontology analysis indicated that biological processes such as cell adhesion and molecular functions such as calcium ion binding could have an important role in determining the success of interventional therapies in obesity. Epigenome-wide association for relative weight-loss (%) identified 15 CpGs being negatively correlated with weight change after intervention (all combined P < 1 × 10) including new and also known obesity candidates such as NUDT3 and NCOR2. A baseline DNA methylation score better predicted successful weight-loss [area under the curve (AUC) receiver operating characteristic (ROC) = 0.95-1.0] than predictors such as age and BMI (AUC ROC = 0.56).

CONCLUSIONS

Body weight-loss following 18-month lifestyle intervention is associated with specific methylation signatures. Moreover, methylation differences in the identified genes could serve as prognostic biomarkers to predict a successful weight-loss therapy and thus contribute to advances in patient-tailored obesity treatment.

Address: Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich at the University of Leipzig and University Hospital Leipzig, 04103, Leipzig, Germany.; Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103, Leipzig, Germany.; IFB Adiposity Diseases, University of Leipzig, Liebigstrasse 19-21, 04103, Leipzig, Germany.; Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.Box 653, 84105, Beer Sheva, Israel.; Interdisciplinary Center for Bioinformatics, University of Leipzig, 04107, Leipzig, Germany.; Bioinformatics Group, Department of Computer Science, University of Leipzig, 04107, Leipzig, Germany.; Transcriptome Bioinformatics, LIFE Research Center for Civilization Diseases, University of Leipzig, 04107, Leipzig, Germany.; Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine and Sylvan Adams Sports Institute, Tel Aviv University, 6997801, Ramat Aviv, Israel.; Soroka University Medical Center, 84101, Beer-Sheva, Israel.; Nuclear Research Center-Negev, 84190, Dimona, Israel.; Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, 0316, Oslo, Norway.; Medical Division, Akershus University Hospital, 1478, Lørenskog, Norway.; Competence Center for Scalable Data Services and Solutions Dresden/Leipzig, German Centre for Integrative Biodiversity Research (iDiv), and Leipzig Research Center for Civilization Diseases, University of Leipzig, 04109, Leipzig, Germany.; Max Planck Institute for Mathematics in the Sciences, 04103, Leipzig, Germany.; Fraunhofer Institute for Cell Therapy and Immunology, 04103, Leipzig, Germany.; Department of Theoretical Chemistry, University of Vienna, 1090, Vienna, Austria.; Center for RNA in Technology and Health, University of Copenhagen, 1871, Frederiksberg, Denmark.; Santa Fe Institute, Santa Fe, NM, 87501, USA.; Deutsches Zentrum für Diabetesforschung, Helmholtz Zentrum München, Neuherberg, 85764, USA.; Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103, Leipzig, Germany. [email protected].; Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.Box 653, 84105, Beer Sheva, Israel. [email protected].

DOI: 10.1186/s13073-020-00794-7

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MeSH Terms: Acid Anhydride Hydrolases, Adult, Body Mass Index, Cell Adhesion Molecules, DNA Methylation, Diet, Epigenomics, Female, Humans, Intracellular Signaling Peptides and Proteins, Israel, Life Style, Male, Middle Aged, Nuclear Receptor Co-Repressor 2, Obesity, Weight Loss