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The molecular characterisation of the cardiometabolic syndrome could improve our understanding of its pathogenesis and pathophysiology and guide the identification of new treatment strategies. We identified the combinations of features that help to define the cardiometabolic syndrome using a multi-omic penalised logistic regression approach, from in-depth phenotyping, including transcriptome and epigenome profiling of innate immune cells, platelets, plasma metabolomics and extensive biochemistry, of 202 blood donors and two groups with extreme phenotypes (obese and lipodystrophy). This allowed us to determine the likelihood of the individuals in the donor group of having an increased cardio-metabolic risk and to determine the molecular mechanisms at play. To investigate if the observed effects were reversible, we repeated the in-depth phenotyping six months after bariatric surgery. These analyses revealed patterns of abnormal activation in innate immunity cells in the extreme phenotype groups, which were abrogated after surgery with the establishment of new gene expression landscapes. ### Competing Interest Statement The authors have declared no competing interest.

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