The interplay between inflammatory cytokines and cardiometabolic disease: bi-directional mendelian randomisation study
Jian Huang,
Simon A Jones,
Abbas Dehghan,
Dipender Gill,
Rainer Malik,
Ari Ahola-Olli,
Olli Raitakari,
Veikko Salomaa,
Terho Lehtimäki,
Marko Salmi,
Sirpa Jalkanen,
Sirkka Keinänen-Kiukaanniemi,
Karl-Heinz Herzig,
Marjo-Riitta Järvelin,
Sylvain Sebert,
Mark J Ponsford,
Konstantinos K Tsilidis,
Martin Dichgans,
Ville Karhunen,
Saranya Palaniswamy,
G Kees Hovingh,
Juha Veijola,
Juha Auvinen,
Markku Timonen,
Emmanouil Bouras,
Areti Papadopoulou,
Matthias Wielscher
Affiliations
Jian Huang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
Simon A Jones
7 Division of Immunology, Infection, and Inflammation, Tenovus Institute, Cardiff University, Cardiff, UK
Abbas Dehghan
Imperial College London, London, UK
Dipender Gill
Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK
Rainer Malik
6 Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Faculty of Medicine, Munchen, Bayern, Germany
Ari Ahola-Olli
8 The Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Olli Raitakari
22 Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
Veikko Salomaa
21 Finnish Institute for Health and Welfare, Helsinki, Uusimaa, Finland
Terho Lehtimäki
5 Department of Clinical Chemistry, Tampere University, Tampere, Finland
Marko Salmi
19 MediCity and Institute of Biomedicine, University of Turku, Turku, Finland
Sirpa Jalkanen
19 MediCity and Institute of Biomedicine, University of Turku, Turku, Finland
Sirkka Keinänen-Kiukaanniemi
2 Research Unit of Population Health, University of Oulu, Oulu, Finland
Karl-Heinz Herzig
13 Research Unit of Biomedicine, Medical Research Center (MRC), University of Oulu, University Hospital, Oulu, Finland
Marjo-Riitta Järvelin
2 Research Unit of Population Health, University of Oulu, Oulu, Finland
Sylvain Sebert
2 Research Unit of Population Health, University of Oulu, Oulu, Finland
Mark J Ponsford
7 Division of Immunology, Infection, and Inflammation, Tenovus Institute, Cardiff University, Cardiff, UK
Konstantinos K Tsilidis
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
Martin Dichgans
18 German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany
Ville Karhunen
1 Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
Saranya Palaniswamy
2 Research Unit of Population Health, University of Oulu, Oulu, Finland
G Kees Hovingh
Department of Vascular Medicine, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands
Juha Veijola
12 Department of Psychiatry, Research Unit of Clinical Neuroscience, University of Oulu, Oulu, Finland
Juha Auvinen
2 Research Unit of Population Health, University of Oulu, Oulu, Finland
Markku Timonen
2 Research Unit of Population Health, University of Oulu, Oulu, Finland
Emmanouil Bouras
5 Department of Hygiene and Epidemiology, Faculty of Medicine, University of Ioannina, Ioannina, Epirus, Greece
Areti Papadopoulou
5 Department of Hygiene and Epidemiology, Faculty of Medicine, University of Ioannina, Ioannina, Epirus, Greece
Matthias Wielscher
3 Department of Epidemiology and Biostatistics, Imperial College London, London, UK
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.
