The role of inflammatory cytokines as intermediates in the pathway from increased adiposity to disease

Marita Kalaoja; Laura J Corbin; Y Tan; Ari V Ahola-Olli; Aki S Havulinna; Kristiina Santalahti; Niina Pitkänen; Terho Lehtimäki; Leo Pekka Lyytikäinen; Emma Raitoharju; Ilkka Seppala; Mika Kahonen; Samuli Ripatti; Aarno Palotie; Markus Perola; Jorma 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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

19 Downloads (Pure)

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.

Original language	English
Pages (from-to)	428-437
Number of pages	10
Journal	Obesity
Volume	29
Issue number	2
Early online date	24 Jan 2021
DOIs	https://doi.org/10.1002/oby.23060
Publication status	Published - 1 Feb 2021

Structured keywords

ICEP

Access to Document

10.1002/oby.23060

Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via Wiley at https://doi.org/10.1002/oby.23060. Please refer to any applicable terms of use of the publisher.
Final published version, 1.2 MBLicence: CC BY

Embargoed Document

Full-text PDF (author accepted manuscript)
Accepted author manuscript, 293 KB
Request copy

Embargoed Document

Supplementary information PDF
Accepted author manuscript, 1.8 MB
Request copy

Embargoed Document

Supplementary tables
Accepted author manuscript, 19.6 KB
Request copy

1 Active

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. & Davey Smith, G.
1/04/18 → 31/03/23
Project: Research

Cytokines GWAS results
Corbin, L. J. (Creator), Timpson, N. J. (Creator) & Tan, V. (Contributor), University of Bristol, 31 Oct 2020
DOI: 10.5523/bris.3g3i5smgghp0s2uvm1doflkx9x, http://data.bris.ac.uk/data/dataset/3g3i5smgghp0s2uvm1doflkx9x
Dataset

Cite this

Kalaoja, M., Corbin, L. J., Tan, Y., Ahola-Olli, A. V., Havulinna, A. S., Santalahti, K., Pitkänen, N., Lehtimäki, T., Lyytikäinen, L. P., Raitoharju, E., Seppala, I., Kahonen, M., Ripatti, S., Palotie, A., Perola, M., Viikari, J., Jalkanen, S., Maksimow, M., Salomaa, V., ... Timpson, N. J. (2021). The role of inflammatory cytokines as intermediates in the pathway from increased adiposity to disease. Obesity, 29(2), 428-437. https://doi.org/10.1002/oby.23060

Kalaoja, Marita ; Corbin, Laura J ; Tan, Y ; Ahola-Olli, Ari V ; Havulinna, Aki S ; Santalahti, Kristiina ; Pitkänen, Niina ; Lehtimäki, Terho ; Lyytikäinen, Leo Pekka ; Raitoharju, Emma ; Seppala, Ilkka ; Kahonen, Mika ; Ripatti, Samuli ; Palotie, Aarno ; Perola, Markus ; Viikari, Jorma ; Jalkanen, Sirpa ; Maksimow, Mikael ; Salomaa, Veikko ; Salmi, Marko ; Raitakari, Olli T. ; Kettunen, Johannes ; Timpson, Nicholas J. / The role of inflammatory cytokines as intermediates in the pathway from increased adiposity to disease. In: Obesity. 2021 ; Vol. 29, No. 2. pp. 428-437.

@article{af9d62069a904eafbb5fe4c902b14dd4,

title = "The role of inflammatory cytokines as intermediates in the pathway from increased adiposity to disease",

abstract = "ObjectiveThis study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease.MethodsBMI 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.ResultsObservationally, 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.ConclusionsObservational 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.",

author = "Marita Kalaoja and Corbin, {Laura J} and Y Tan and Ahola-Olli, {Ari V} and Havulinna, {Aki S} and Kristiina Santalahti and Niina Pitk{\"a}nen and Terho Lehtim{\"a}ki and Lyytik{\"a}inen, {Leo Pekka} and Emma Raitoharju and Ilkka Seppala and Mika Kahonen and Samuli Ripatti and Aarno Palotie and Markus Perola and Jorma Viikari and Sirpa Jalkanen and Mikael Maksimow and Veikko Salomaa and Marko Salmi and Raitakari, {Olli T.} and Johannes Kettunen and Timpson, {Nicholas J.}",

year = "2021",

month = feb,

day = "1",

doi = "10.1002/oby.23060",

language = "English",

volume = "29",

pages = "428--437",

journal = "Obesity",

issn = "1930-7381",

publisher = "John Wiley & Sons, Inc",

number = "2",

}

Kalaoja, M, Corbin, LJ , Tan, Y, Ahola-Olli, AV, Havulinna, AS, Santalahti, K, Pitkänen, N, Lehtimäki, T, Lyytikäinen, LP, Raitoharju, E, Seppala, I, Kahonen, M, Ripatti, S, Palotie, A, Perola, M, Viikari, J, Jalkanen, S, Maksimow, M, Salomaa, V, Salmi, M, Raitakari, OT, Kettunen, J & Timpson, NJ 2021, 'The role of inflammatory cytokines as intermediates in the pathway from increased adiposity to disease', Obesity, vol. 29, no. 2, pp. 428-437. https://doi.org/10.1002/oby.23060

The role of inflammatory cytokines as intermediates in the pathway from increased adiposity to disease. / Kalaoja, Marita; Corbin, Laura J ; Tan, Y; Ahola-Olli, Ari V; Havulinna, Aki S; Santalahti, Kristiina; Pitkänen, Niina; Lehtimäki, Terho; Lyytikäinen, Leo Pekka; Raitoharju, Emma; Seppala, Ilkka; Kahonen, Mika; Ripatti, Samuli; Palotie, Aarno; Perola, Markus; Viikari, Jorma; Jalkanen, Sirpa; Maksimow, Mikael; Salomaa, Veikko; Salmi, Marko; Raitakari, Olli T.; Kettunen, Johannes; Timpson, Nicholas J.

In: Obesity, Vol. 29, No. 2, 01.02.2021, p. 428-437.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - The role of inflammatory cytokines as intermediates in the pathway from increased adiposity to disease

AU - Kalaoja, Marita

AU - Corbin, Laura J

AU - Tan, Y

AU - Ahola-Olli, Ari V

AU - Havulinna, Aki S

AU - Santalahti, Kristiina

AU - Pitkänen, Niina

AU - Lehtimäki, Terho

AU - Lyytikäinen, Leo Pekka

AU - Raitoharju, Emma

AU - Seppala, Ilkka

AU - Kahonen, Mika

AU - Ripatti, Samuli

AU - Palotie, Aarno

AU - Perola, Markus

AU - Viikari, Jorma

AU - Jalkanen, Sirpa

AU - Maksimow, Mikael

AU - Salomaa, Veikko

AU - Salmi, Marko

AU - Raitakari, Olli T.

AU - Kettunen, Johannes

AU - Timpson, Nicholas J.

PY - 2021/2/1

Y1 - 2021/2/1

N2 - ObjectiveThis study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease.MethodsBMI 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.ResultsObservationally, 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.ConclusionsObservational 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.

AB - ObjectiveThis study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease.MethodsBMI 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.ResultsObservationally, 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.ConclusionsObservational 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.

U2 - 10.1002/oby.23060

DO - 10.1002/oby.23060

M3 - Article (Academic Journal)

C2 - 33491305

VL - 29

SP - 428

EP - 437

JO - Obesity

JF - Obesity

SN - 1930-7381

IS - 2

ER -

The role of inflammatory cytokines as intermediates in the pathway from increased adiposity to disease

Abstract

Structured keywords

Access to Document

Embargoed Document

Embargoed Document

Embargoed Document

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cytokines GWAS results

Cite this