University of Oulu

Karhunen V, Gill D, Huang J, et al. (2023). The interplay between inflammatory cytokines and cardiometabolic disease: Bi-directional mendelian randomisation study. BMJ Medicine, 2(1), e000157.

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

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Author: Karhunen, Ville1,2,3; Gill, Dipender3; Huang, Jian3,4;
Organizations: 1Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland
2Research Unit of Population Health, University of Oulu, Oulu, Finland
3Department of Epidemiology and Biostatistics, Imperial College London, London, UK
4Singapore Institute for Clinical Sciences (SICS), Agency for Science Technology and Research (A*STAR), Singapore
5Department of Hygiene and Epidemiology, Faculty of Medicine, University of Ioannina, Ioannina, Epirus, Greece
6Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Faculty of Medicine, Munchen, Bayern, Germany
7Division of Immunology, Infection, and Inflammation, Tenovus Institute, Cardiff University, Cardiff, UK
8The Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, US
9Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
10Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
11Department of Dermatology, Medical University of Vienna, Vienna, Austria
12Department of Psychiatry, Research Unit of Clinical Neuroscience, University of Oulu, Oulu, Finland
13Research Unit of Biomedicine, Medical Research Center (MRC), University of Oulu, University Hospital, Oulu, Finland
14Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland
15Unit of Primary Care, Oulu University Hospital, Oulu, Finland
16Healthcare and Social Services of Selänne, Pyhäjärvi, Finland
17Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
18German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany
19MediCity and Institute of Biomedicine, University of Turku, Turku, Finland
20Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
21Finnish Institute for Health and Welfare, Helsinki, Uusimaa, Finland
22Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
23Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
24Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
25Department of Vascular Medicine, Academic Medical Center, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Noord-Holland, Netherlands
26MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
27Biocenter Oulu, University of Oulu, Oulu, Finland
28Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK
29UK Dementia Research Institute, Imperial College London, London, UK
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.2 MB)
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Language: English
Published: BMJ, 2023
Publish Date: 2023-09-12


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.

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Series: BMJ medicine
ISSN: 2754-0413
ISSN-E: 2754-0413
ISSN-L: 2754-0413
Volume: 2
Issue: 1
Article number: e000157
DOI: 10.1136/bmjmed-2022-000157
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Funding: VK is funded by the European Union’s Horizon 2020 grant agreement (no. 848158; EarlyCause), Academy of Finland Profi 5 (Project 326291), and EU's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant (no. 721567; CAPICE). DG was supported by the Wellcome Trust 4i Programme (203928/Z/16/Z) and British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London. MJP is funded by the Welsh Clinical Academic Training (WCAT) programme and is a participant in the National Institutes of Health Graduate Partnership Program. VS was supported by the Finnish Foundation for Cardiovascular Research. SP is funded by the EU's Horizon 2020 Framework EDCMET (825762), iHealth-T2D (643774), Yrjö Jahnsson Foundation, and Päivikki and Sakari Sohlberg Foundation. KKT was supported by Cancer Research UK (C18281/A29019). MRJ is funded by the EU’s Horizon 2020 programmes: EDCMET (825762), DynaHEALTH (633595), LifeCycle (733206), iHealth-T2D (643774), LongITools (874739), and Medical Research Council/Biotechnology and Biological Sciences Research Council (PREcisE, MR/M013138/1, MR/ S03658X/1, under Nutrition and Epigenome, The Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI HDHL/EU-H2020, project number 665)). AD is funded by the Wellcome Trust seed award (206046/Z/17/Z) and LongITools (874739). This project has also received funding from the EU’s Horizon 2020 research and innovation programme (666881), SVDs@target (to MD; 667375), CoSTREAM (to MD); the DFG as part of the Munich Cluster for Systems Neurology (SyNergy, EXC EXC 2145 SyNergy – ID 390857198), the CRC 1123 (B3; to MD), and project DI 722/13-1; the Corona Foundation (to MD); the LMUexcellent fond (to MD); the e:Med program (e:AtheroSysMed; to MD), and the FP7/2007-2103 EU project CVgenes@target (grant agreement number Health-F2-2013-601456; to MD). NFBC1966 received core funding for data generation and curation from the Academy of Finland (285547 (EGEA)), University Hospital Oulu, Finland (65354, 75617), Biocenter Oulu, Finland. The NFBCs are also funded by EU-Horizon 2020 EUCAN Connect (824989). The Young Finns Study has been financially supported by the Academy of Finland: grants 322098, 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (755320 for TAXINOMISIS and 848146 for To Aition); European Research Council (742927 for MULTIEPIGEN project); and Tampere University Hospital Supporting Foundation. The original cytokine measurements were funded by Academy of Finland (141136). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.
EU Grant Number: (848158) EarlyCause - Causative mechanisms & integrative models linking early-life-stress to psycho-cardio-metabolic multi-morbidity
(825762) EDCMET - Metabolic effects of Endocrine Disrupting Chemicals: novel testing METhods and adverse outcome pathways
(633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging
(733206) LIFECYCLE - Early-life stressors and LifeCycle health
(643774) iHealth-T2D - Family-based intervention to improve healthy lifestyle and prevent Type 2 Diabetes amongst South Asians with central obesity and prediabetes
(874739) LONGITOOLS - Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases
(824989) EUCAN-Connect - A federated FAIR platform enabling large-scale analysis of high-value cohort data connecting Europe and Canada in personalized health
Academy of Finland Grant Number: 285547
Detailed Information: 285547 (Academy of Finland Funding decision)
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