The Role of Inflammatory Cytokines as Intermediates in the Pathway from Increased Adiposity to Disease
Marita Kalaoja, Laura J. Corbin, Vanessa Y. Tan, Ari 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 Viikari, Sirpa Jalkanen, Mikael Maksimow, Veikko Salomaa, Marko Salmi, Olli T. Raitakari, Johannes Kettunen, Nicholas J. Timpson
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.