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

• Published in: BMJ Medicine
• Main Authors: Karhunen, Ville, Gill, Dipender, Huang, Jian, Bouras, Emmanouil, Malik, Rainer, Ponsford, Mark J, Ahola-Olli, Ari, Papadopoulou, Areti, Palaniswamy, Saranya, Sebert, Sylvain, Wielscher, Matthias, Auvinen, Juha, Veijola, Juha, Herzig, Karl-Heinz, Timonen, Markku, Keinänen-Kiukaanniemi, Sirkka, Dichgans, Martin, Salmi, Marko, Jalkanen, Sirpa, Lehtimäki, Terho, Salomaa, Veikko, Raitakari, Olli, Jones, Simon A, Hovingh, G Kees, Tsilidis, Konstantinos K, Järvelin, Marjo-Riitta, Dehghan, Abbas
• Other Authors: Cancer Research UK, EDCMET, Academy of Finland, Päivikki and Sakari Sohlberg Foundation, British Heart Foundation, Centre of Research Excellence, Yrjö Jahnsson Foundation, Wellcome Trust, Imperial College London, Medical Research Council/Biotechnology and Biological Sciences Research Council, Finnish Foundation for Cardiovascular Research, European Union, UK Biobank, NIH Graduate Partnership
• Format: Article in Journal/Newspaper
• Language: English
• Published: BMJ 2023
• Subjects: Northern Finland
• Online Access: http://dx.doi.org/10.1136/bmjmed-2022-000157; https://syndication.highwire.org/content/doi/10.1136/bmjmed-2022-000157

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) ...