The interplay between inflammatory cytokines and cardiometabolic disease: bi-directional mendelian randomisation study.

Autor:	Karhunen V; Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland.; Research Unit of Population Health, University of Oulu, Oulu, Finland.; Department of Epidemiology and Biostatistics, Imperial College London, London, UK., Gill D; Department of Epidemiology and Biostatistics, Imperial College London, London, UK., Huang J; Department of Epidemiology and Biostatistics, Imperial College London, London, UK.; Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (ASTAR), Singapore., Bouras E; Department of Hygiene and Epidemiology, Faculty of Medicine, University of Ioannina, Ioannina, Epirus, Greece., Malik R; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Faculty of Medicine, Munchen, Bayern, Germany., Ponsford MJ; Division of Immunology, Infection, and Inflammation, Tenovus Institute, Cardiff University, Cardiff, UK., Ahola-Olli A; The Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland., Papadopoulou A; Department of Hygiene and Epidemiology, Faculty of Medicine, University of Ioannina, Ioannina, Epirus, Greece., Palaniswamy S; Research Unit of Population Health, University of Oulu, Oulu, Finland., Sebert S; Research Unit of Population Health, University of Oulu, Oulu, Finland., Wielscher M; Department of Epidemiology and Biostatistics, Imperial College London, London, UK.; Department of Dermatology, Medical University of Vienna, Vienna, Austria., Auvinen J; Research Unit of Population Health, University of Oulu, Oulu, Finland., Veijola J; Department of Psychiatry, Research Unit of Clinical Neuroscience, University of Oulu, Oulu, Finland., Herzig KH; Research Unit of Biomedicine, Medical Research Center (MRC), University of Oulu, University Hospital, Oulu, Finland.; Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland., Timonen M; Research Unit of Population Health, University of Oulu, Oulu, Finland.; Unit of Primary Care, Oulu University Hospital, Oulu, Finland., Keinänen-Kiukaanniemi S; Research Unit of Population Health, University of Oulu, Oulu, Finland.; Unit of Primary Care, Oulu University Hospital, Oulu, Finland.; Healthcare and Social Services of Selänne, Pyhäjärvi, Finland., Dichgans M; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Faculty of Medicine, Munchen, Bayern, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany., Salmi M; MediCity and Institute of Biomedicine, University of Turku, Turku, Finland., Jalkanen S; MediCity and Institute of Biomedicine, University of Turku, Turku, Finland., Lehtimäki T; Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland., Salomaa V; Finnish Institute for Health and Welfare, Helsinki, Uusimaa, Finland., Raitakari O; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.; Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland., Jones SA; Division of Immunology, Infection, and Inflammation, Tenovus Institute, Cardiff University, Cardiff, UK., Hovingh GK; Department of Vascular Medicine, Academic Medical Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Noord-Holland, Netherlands., Tsilidis KK; Department of Epidemiology and Biostatistics, Imperial College London, London, UK.; Department of Hygiene and Epidemiology, Faculty of Medicine, University of Ioannina, Ioannina, Epirus, Greece., Järvelin MR; Research Unit of Population Health, University of Oulu, Oulu, Finland.; Department of Epidemiology and Biostatistics, Imperial College London, London, UK.; Unit of Primary Care, Oulu University Hospital, Oulu, Finland.; MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.; Biocenter Oulu, University of Oulu, Oulu, Finland.; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK., Dehghan A; Department of Epidemiology and Biostatistics, Imperial College London, London, UK.; MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.; UK Dementia Research Institute, Imperial College London, London, UK.
Jazyk:	angličtina
Zdroj:	BMJ medicine [BMJ Med] 2023 Feb 14; Vol. 2 (1), pp. e000157. Date of Electronic Publication: 2023 Feb 14 (Print Publication: 2023).
DOI:	10.1136/bmjmed-2022-000157
Abstrakt:	Objective: To leverage large scale genetic association data to investigate the interplay between circulating cytokines and cardiometabolic traits, and thus identifying potential therapeutic targets. Design: Bi-directional Mendelian randomisation study. Setting: Genome-wide association studies from three Finnish cohorts (Northern Finland Birth Cohort 1966, Young Finns Study, or FINRISK study), and genetic association summary statistics pooled from observational studies for expression quantitative trait loci and cardiometabolic traits. Participants: Data for 47 circulating cytokines in 13 365 individuals from genome-wide association studies, summary statistic data for up to 21 735 individuals on circulating cytokines, summary statistic gene expression data across 49 tissues in 838 individuals, and summary statistic data for up to 1 320 016 individuals on cardiometabolic traits. Interventions: Relations between circulating cytokines and cardiovascular, anthropometric, lipid, or glycaemic traits (coronary artery disease, stroke, type 2 diabetes mellitus, body mass index, waist circumference, waist to hip ratio, systolic blood pressure, glycated haemoglobin, high density lipoprotein cholesterol, low density lipoprotein cholesterol, total cholesterol, triglycerides, C reactive protein, glucose, fasting insulin, and lifetime smoking). Main Outcome Methods: Genetic instrumental variables that are biologically plausible for the circulating cytokines were generated. The effects of cardiometabolic risk factors on concentrations of circulating cytokines, circulating cytokines on other circulating cytokines, and circulating cytokines on cardiometabolic outcomes were investigated. Results: Genetic evidence (mendelian randomisation P<0.0011) suggests that higher body mass index, waist circumference, smoking, higher concentrations of lipids, and systolic blood pressure increase circulating concentrations of several inflammatory cytokines and C reactive protein. Evidence for causal relations (mendelian randomisation P<0.0011) were noted between circulating cytokines, including a key role of vascular endothelial growth factor on influencing the concentrations of 10 other cytokines. Both mendelian randomisation (P<0.05) and colocalisation (posterior probability >0.5) suggested that coronary artery disease risk is increased by higher concentrations of circulating tumour necrosis factor related apoptosis-inducing ligand (TRAIL), interleukin-1 receptor antagonist (IL1RA), and macrophage colony-stimulating factor (MCSF). Conclusion: This study offers insight into inflammatory mediators of cardiometabolic risk factors, cytokine signalling cascades, and effects of circulating cytokines on different cardiometabolic outcomes. Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: DG is employed part-time by Novo Nordisk and has received consultancy fees from Policy Wisdom. VS has received honoraria from Novo Nordisk and Sanofi for consultations and travel support from Novo Nordisk. He also has ongoing research collaboration with Bayer Ltd. GKH reports institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; speaker’s bureau and consulting fees from Amgen, Aegerion, Sanofi, and Regeneron (fees paid to the academic institution); and part-time employment at Novo Nordisk, outside of the submitted work. These declarations are all unrelated to this study. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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