Increased Obesity Is Causal for Increased Inflammation—A Mendelian Randomisation Study

Inflammation is endemic to obesity and type 2 diabetes (T2D) but it is unclear if it is a cause or a consequence. If the latter, then inflammation may increase the risk of obesity and diabetes complications. Large genome-wide association studies (GWAS) of inflammation and cardiometabolic traits can be used to investigate causal mechanisms. Summary statistics were assembled from GWAS of 49 cytokine (N=840-80,000) and 20 cardiometabolic traits (N=2,447-465,333). Shared genetic background was measured using LD score regression. Polygenic scores (PGS) were generated from GWAS data for 49 cytokines (representing inflammation) and 20 cardiometabolic traits and used in two-way Mendelian Randomisation (MR) analyses. Causal relationships were identified using summary statistics for all traits, and individual data (UK Biobank, N=465,333) to test the association of cytokine PGS with body mass index (BMI) and T2D. LD score regression analysis demonstrated that BMI and T2D shared a genetic background with acute phase cytokines. However, MR analyses showed that genetically-driven variation in cytokine levels were not associated with increased BMI or T2D risk. This argues against a causal role for inflammation (as represented by these cytokines) in the development of obesity and T2D. In contrast, genetically driven obesity was associated with increased inflammation: a PGS for increased BMI was associated with increased C-reactive protein (Beta [95% CI], 0.40 [0.34,0.46], p=1.3×10-36) and activated plasminogen inhibitor (Beta [95% CI], 0.39 [0.19, 0.59], p=7.8×10-5) levels. Genetically-driven variation in cytokine levels were causally linked with chronic kidney disease in subjects with T2D: fibroblast growth factor 2 (OR[95% CI], 0.58[0.46,0.72], p=1.8×10-6) and interleukin 13 (OR[95% CI], 1.28[1.15,1.43], p=7.0×10-6) We conclude that chronic inflammation is a consequence, rather than a cause, of T2D and obesity, and may contribute to some of their complications. Disclosure N. van Zuydam: None. M. Wielscher: None. M. McCarthy: Research Support; Self; Eli Lilly and Company, Takeda Pharmaceuticals U.S.A., Inc., Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S, Pfizer Inc.. Research Support; Self; Pfizer Inc., Sanofi, Boehringer Ingelheim GmbH, AstraZeneca, Merck Sharp & Dohme Corp.. M. Jarvelin: None.