PT - JOURNAL ARTICLE AU - Karhunen, Ville AU - Gill, Dipender AU - Huang, Jian AU - Bouras, Emmanouil AU - Malik, Rainer AU - Ponsford, Mark J AU - Ahola-Olli, Ari AU - Papadopoulou, Areti AU - Palaniswamy, Saranya AU - Sebert, Sylvain AU - Wielscher, Matthias AU - Auvinen, Juha AU - Veijola, Juha AU - Herzig, Karl-Heinz AU - Timonen, Markku AU - Keinänen-Kiukaanniemi, Sirkka AU - Dichgans, Martin AU - Salmi, Marko AU - Jalkanen, Sirpa AU - Lehtimäki, Terho AU - Salomaa, Veikko AU - Raitakari, Olli AU - Jones, Simon A AU - Hovingh, G Kees AU - Tsilidis, Konstantinos K AU - Järvelin, Marjo-Riitta AU - Dehghan, Abbas TI - The interplay between inflammatory cytokines and cardiometabolic disease: bi-directional mendelian randomisation study AID - 10.1136/bmjmed-2022-000157 DP - 2023 Feb 01 TA - BMJ Medicine PG - e000157 VI - 2 IP - 1 4099 - http://bmjmedicine.bmj.com/content/2/1/e000157.short 4100 - http://bmjmedicine.bmj.com/content/2/1/e000157.full SO - bmjmed2023 Feb 01; 2 AB - 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.Data may be obtained from a third party and are not publicly available. The NFBC1966 data are available by application via http://oulu.fi/nfbc/. The genome-wide association study summary statistics generated in this work are publicly available at: https://doi.org/10.5281/zenodo.7215468. The software scripts for the analyses are available from the authors on request.