Transcriptional, epigenetic and metabolic signatures in cardiometabolic syndrome defined by extreme phenotypes.
Creators: name: Seyres, Denis
name: Cabassi, Alessandra
name: Lambourne, John J
name: Burden, Frances
name: Farrow, Samantha
name: McKinney, Harriet
name: Batista, Joana
name: Kempster, Carly
name: Pietzner, Maik
name: Slingsby, Oliver
name: Cao, Thong Huy
name: Quinn, Paulene A
name: Stefanucci, Luca
name: Sims, Matthew C
name: Rehnstrom, Karola
name: Adams, Claire L
name: Frary, Amy
name: Ergüener, Bekir
name: Kreuzhuber, Roman
name: Mocciaro, Gabriele
name: D'Amore, Simona
name: Koulman, Albert
name: Grassi, Luigi
name: Griffin, Julian L
name: Ng, Leong Loke
name: Park, Adrian
name: Savage, David B
name: Langenberg, Claudia
name: Bock, Christoph
name: Downes, Kate
name: Wareham, Nicholas
name: Allison, Michael
name: Vacca, Michele
name: Kirk, Paul
name: Frontini, Mattia
Publisher: name: Apollo - University of Cambridge Repository
Year: 2022
Subjects: Research
Cardiovascular epigenetics
Epigenetics
Metabolites
Lipids
Multi-omics
Obesity
Lipodystrophy
Bariatric surgery
Classification
Innate immune cells
Cardiometabolic syndrome

description: Funder: British Heart Foundation Cambridge Centre of Excellence
description: Funder: The National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and NIHR Rare Disease Translational Research Collaboration
description: Funder: NHS Health Education England
description: Funder: NIHR Cambridge Biomedical Research Centre
description: Funder: Isaac Newton fellowship
description: Funder: NIHR Leicester Biomedical Research Centre and the John and Lucille Van Geest Foundation
description: BACKGROUND: This work is aimed at improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis by generating a multi-omic disease signature. METHODS/RESULTS: We combined classic plasma biochemistry and plasma biomarkers with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (morbidly obese and lipodystrophy) and lean individuals to identify the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells. Our analyses showed that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, 6 months after bariatric surgery, revealed the loss of the abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurred via the establishment of novel gene expression landscapes. NETosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. CONCLUSIONS: We showed that the morbidly obese and lipodystrophy groups, despite some differences, shared a common cardiometabolic syndrome signature. We also showed that this could be used to discriminate, amongst the normal population, those individuals with a higher likelihood of presenting with the disease, even when not displaying the classic features.