Research Paper Volume 18 pp 45—59
Causal effects of inflammation on long-term mortality: A mendelian randomization study
- 1 Department of Life and Health Sciences, Link Campus University, Rome, Italy
- 2 SIRIO MEDICINE Research Network, Nicolaus Copernicus University, Bydgoszcz, Poland
- 3 The Christ Hospital and Lindner Research Center, Cincinnati, OH 45219, USA
- 4 Radboud University Medical Center, Nijmegen, The Netherlands
- 5 Clinical Experimental Cardiology, University of Sassari, Sassari, Italy
- 6 Department of Cardiology, Republican Clinical Hospital, Azerbaijan Medical University, Baku, Azerbaijan
- 7 Department of Family Medicine, Republican Clinical Hospital, Azerbaijan Medical University, Baku, Azerbaijan
- 8 Departments of Academic Affairs and Cardiology, Cedars-Sinai Health System, Los Angeles, CA 90048, USA
- 9 Department of Cardiology and Internal Medicine, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
Received: August 20, 2025 Accepted: December 4, 2025 Published: February 6, 2026
https://doi.org/10.18632/aging.206352How to Cite
Copyright: © 2025 Navarese et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Interleukin-6 (IL6) signaling plays a key role in inflammation and cardiovascular disease, but its causal effect on long-term mortality remains unclear. We aimed to assess whether genetically proxied levels of IL6, soluble IL6 receptor (IL6R), C-reactive protein (CRP), and growth differentiation factor-15 (GDF15) exert causal effects on long-term all-cause mortality, and to examine potential opposing effects of IL6 and IL6R.
Methods: We conducted Mendelian randomization (MR) using genome-wide association study instruments from >750,000 individuals. The primary outcome was all-cause mortality over a median follow-up of 11.7 years. Secondary outcomes included cardiovascular events and selected non-cardiovascular conditions. Multiple sensitivity analyses were applied to evaluate robustness and directionality.
Results: Genetically higher IL6R levels were associated with reduced mortality (odds ratio (OR) per 1-SD increase: 0.95; 95% CI: 0.91–0.98, p = 0.007) and lower risk of atrial fibrillation, coronary artery disease, stroke, and lung cancer. Conversely, higher IL6 levels were linked to increased mortality (OR: 1.05; 95% CI: 1.02–1.08, p = 0.002). No significant causal effects were observed for CRP or GDF-15. All findings were consistent across sensitivity analyses.
Conclusions: IL6 and IL6R appear to be biologically opposing causal regulators of human survival: IL6 increases, while IL6R reduces mortality through cardiovascular mechanisms. CRP and GDF15 likely reflect disease risk rather than drive it. These results support IL6R antagonism as a potential strategy for cardiovascular disease prevention.
Abbreviations
AF: Atrial Fibrillation; CAD: Coronary Artery Disease; CI: Confidence Interval; CRP: C-Reactive Protein; GDF-15: Growth Differentiation Factor-15; GWAS: Genome-Wide Association Study; IL6: Interleukin-6; IL6R: Interleukin-6 Receptor; MR: Mendelian Randomization; OR: Odds Ratio; SD: Standard Deviation; SNP: Single nucleotide polymorphism.