Marita Kalaoja1,2, Laura J Corbin3,4, Vanessa Y Tan3,4, Johannes Kettunen1,2,5, Nicholas J Timpson3,4, Ari V Ahola-Olli6,7,8, Aki S Havulinna5, Kristiina Santalahti9, Niina Pitkänen10, Terho Lehtimäki11,12, Leo-Pekka Lyytikäinen11,12, Emma Raitoharju11,12, Ilkka Seppälä11,12, Mika Kähönen13,14, Samuli Ripatti8,15,16, Aarno Palotie6,7,8,16,17,18, Markus Perola8,5, Jorma S Viikari19,20, Sirpa Jalkanen9, Mikael Maksimow9, Veikko Salomaa5, Marko Salmi9, Olli T Raitakari10,21,22. 1. Computational Medicine, Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland. 2. Biocenter Oulu, University of Oulu, Oulu, Finland. 3. MRC Integrative Epidemiology Unit at University of Bristol, Bristol, UK. 4. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. 5. Finnish Institute for Health and Welfare, Helsinki, Finland. 6. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. 7. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. 8. Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland. 9. Medicity Research Laboratory and Institute of Biomedicine, University of Turku, Turku, Finland. 10. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. 11. Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland. 12. Department of Clinical Chemistry, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 13. Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland. 14. Department of Clinical Physiology, Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. 15. Department of Public Health, University of Helsinki, Helsinki, Finland. 16. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. 17. Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA. 18. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA. 19. Department of Medicine, University of Turku, Turku, Finland. 20. Division of Medicine, Turku University Hospital, Turku, Finland. 21. Centre for Population Health Research, University of Turku, Turku University Hospital, Turku, Finland. 22. Department of Clinical Physiology and Nuclear Medicine, University of Turku, Turku, Finland.
Abstract
OBJECTIVE: This study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease. METHODS: BMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI-driven cytokines on risk of obesity-related diseases. RESULTS: Observationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08-1.19), 1.08 (95% CI: 1.04-1.14), and 1.13 (95% CI: 1.04-1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00-1.06). There was inconsistent evidence for a protective role of MCP-1 against inflammatory bowel diseases. CONCLUSIONS: Observational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI-driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.
OBJECTIVE: This study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease. METHODS: BMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI-driven cytokines on risk of obesity-related diseases. RESULTS: Observationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08-1.19), 1.08 (95% CI: 1.04-1.14), and 1.13 (95% CI: 1.04-1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00-1.06). There was inconsistent evidence for a protective role of MCP-1 against inflammatory bowel diseases. CONCLUSIONS: Observational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI-driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.
Authors: G Kees Hovingh; Dipender Gill; Arjen J Cupido; Jordan M Kraaijenhof; Stephen Burgess; Folkert W Asselbergs Journal: Circ Genom Precis Med Date: 2022-02-01