The Role of Inflammatory Cytokines as Intermediates in the Pathway from Increased Adiposity to Disease

Marita Kalaoja; Laura J Corbin; Vanessa Y Tan; Ari V Ahola-Olli; Aki S Havulinna; Kristiina Santalahti; Niina Pitkänen; Terho Lehtimäki; Leo-Pekka Lyytikäinen; Emma Raitoharju; Ilkka Seppälä; Mika Kähönen; Samuli Ripatti; Aarno Palotie; Markus Perola; Jorma S Viikari; Sirpa Jalkanen; Mikael Maksimow; Veikko Salomaa; Marko Salmi; Olli T Raitakari; Johannes Kettunen; Nicholas J Timpson

doi:10.1002/oby.23060

The Role of Inflammatory Cytokines as Intermediates in the Pathway from Increased Adiposity to Disease

Obesity (Silver Spring). 2021 Feb;29(2):428-437. doi: 10.1002/oby.23060.

Authors

Marita Kalaoja^#^{1

2}, Laura J Corbin^#^{3

4}, Vanessa Y Tan^#^{3

4}, Ari V Ahola-Olli^{5

6

7}, Aki S Havulinna⁸, Kristiina Santalahti⁹, Niina Pitkänen¹⁰, Terho Lehtimäki^{11

12}, Leo-Pekka Lyytikäinen^{11

12}, Emma Raitoharju^{11

12}, Ilkka Seppälä^{11

12}, Mika Kähönen^{13

14}, Samuli Ripatti^{7

15

16}, Aarno Palotie^{5

6

7

16

17

18}, Markus Perola^{7

8}, Jorma S Viikari^{19

20}, Sirpa Jalkanen⁹, Mikael Maksimow⁹, Veikko Salomaa⁸, Marko Salmi⁹, Olli T Raitakari^{10

21

22}, Johannes Kettunen^#^{1

2

8}, Nicholas J Timpson^#^{3

4}

Affiliations

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 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁶ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁷ Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland.
⁸ Finnish Institute for Health and Welfare, 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.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adiposity / physiology*
Body Mass Index
Cohort Studies
Cytokines / blood*
Humans
Obesity / complications*

Substances

Cytokines

Abstract

Publication types

MeSH terms

Substances

Grants and funding