Association of inflammatory cytokines with lung function, chronic lung diseases, and COVID-19

Marina O Rontogianni; Dipender Gill; Emmanouil Bouras; Alexandros-Georgios Asimakopoulos; Ioanna Tzoulaki; Ville Karhunen; Terho Lehtimäki; Olli Raitakari; Matthias Wielscher; Veikko Salomaa; Sirpa Jalkanen; Marko Salmi; Markku Timonen; James Yarmolinsky; Jing Chen; Martin D Tobin; Abril G Izquierdo; Karl-Heinz Herzig; Anne E Ioannides; Marjo-Riitta Jarvelin; Abbas Dehghan; Konstantinos K Tsilidis

doi:10.1016/j.isci.2024.110704

Association of inflammatory cytokines with lung function, chronic lung diseases, and COVID-19

iScience. 2024 Aug 9;27(10):110704. doi: 10.1016/j.isci.2024.110704. eCollection 2024 Oct 18.

Authors

Marina O Rontogianni¹, Dipender Gill², Emmanouil Bouras¹, Alexandros-Georgios Asimakopoulos¹, Ioanna Tzoulaki^{1

2}, Ville Karhunen^{3

4}, Terho Lehtimäki^{5

6

7}, Olli Raitakari^{8

9

10}, Matthias Wielscher², Veikko Salomaa¹¹, Sirpa Jalkanen^{12

13

14}, Marko Salmi^{12

13

14}, Markku Timonen^{15

16}, James Yarmolinsky^{17

18}, Jing Chen¹⁹, Martin D Tobin^{19

20}, Abril G Izquierdo²¹, Karl-Heinz Herzig^{16

22

23}, Anne E Ioannides²⁴, Marjo-Riitta Jarvelin^{2

3

25

26}, Abbas Dehghan^{2

27

28}, Konstantinos K Tsilidis^{1

2}

Affiliations

¹ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
² Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
³ Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁴ Research Unit of Mathematical Sciences, University of Oulu, Oulu, Finland.
⁵ Department of Clinical Chemistry, Faculty of Medicine & Health Technology, Tampere University, Tampere, Finland.
⁶ Finnish Cardiovascular Research Center Tampere, Faculty of Medicine & Health Technology, Tampere University, Tampere, Finland.
⁷ Fimlab Laboratories, Tampere, Finland.
⁸ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
⁹ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
¹⁰ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
¹¹ Finnish Institute for Health and Welfare, Helsinki, Finland.
¹² MediCity Research Laboratory, University of Turku, Turku, Finland.
¹³ Institute of Biomedicine, University of Turku, Turku, Finland.
¹⁴ InFLAMES Fiagship, University of Turku, Turku, Finland.
¹⁵ Research Unit of Population Health, University of Oulu, Oulu, Finland.
¹⁶ Medical Research Center (MRC) and University Hospital, Oulu, Finland.
¹⁷ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹⁸ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
¹⁹ Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
²⁰ National Institute for Health Research, Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²¹ Department of Health Sciences, University of Leicester, Leicester, UK.
²² Research Unit of Biomedicine and Internal Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland.
²³ Pediatric Gastroenterology and Metabolic Diseases, Pediatric Institute, Poznan University of Medical Sciences, Poznan, Poland.
²⁴ Department of Primary Care and Public Health, School of Public Health, Imperial College London, White City Campus, London, UK.
²⁵ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
²⁶ Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK.
²⁷ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
²⁸ UK Dementia Research Institute at Imperial College London, London, UK.

Abstract

We investigated the effects of 35 inflammatory cytokines on respiratory outcomes, including COVID-19, asthma (atopic and non-atopic), chronic obstructive pulmonary disease (COPD), and pulmonary function indices, using Mendelian randomization and colocalization analyses. The emerging associations were further explored using observational analyses in the UK Biobank. We found an inverse association between genetically predicted macrophage colony stimulating factor (MCSF), soluble intercellular adhesion molecule-1 (sICAM), and soluble vascular cell adhesion molecule-1 with risk of COVID-19 outcomes. sICAM was positively associated with atopic asthma risk, whereas tumor necrosis factor-alfa showed an inverse association. A positive association was shown between interleukin-18 and COPD risk (replicated in observational analysis), whereas an inverse association was shown for interleukin-1 receptor antagonist (IL-1ra). IL-1ra and monocyte chemotactic protein-3 were positively associated with lung function indices, whereas inverse associations were shown for MCSF and interleukin-18 (replicated in observational analysis). Our results point to these cytokines as potential pharmacological targets for respiratory traits.

Keywords: Association analysis; Disease; Health sciences; Respiratory medicine.