Mendelian randomization study reveals opposing roles for IL6 and IL6R in long-term mortality

A new research paper was published in Volume 18 of Aging-US on February 6, 2026, titled "Causal effects of inflammation on long-term mortality: a Mendelian randomization study."

Led by Eliano P. Navarese from Department of Life and Health Sciences, Link Campus University and SIRIO MEDICINE Research Network, Nicolaus Copernicus University, who is also the corresponding author - the study used large-scale Mendelian randomization (MR) to test whether genetically proxied levels of inflammatory biomarkers causally influence long-term all-cause mortality. The analysis combined genome-wide association instruments from more than 750,000 individuals and used FinnGen mortality data (median follow-up 11.7 years) to assess effects on overall survival and major cardiovascular endpoints. 

Using robust MR methods and multiple sensitivity analyses, the authors report that genetically higher IL6R (soluble IL-6 receptor) levels were associated with reduced all-cause mortality (odds ratio per 1-SD increase: 0.95; 95% CI: 0.91–0.98), and with lower risk of atrial fibrillation, coronary artery disease, stroke, and lung cancer. By contrast, genetically higher IL6 levels were associated with increased mortality (OR 1.05; 95% CI: 1.02–1.08). No significant causal effects were observed for CRP or GDF15, suggesting those markers more likely reflect disease burden than drive it.

"These results support IL6R antagonism as a potential strategy for cardiovascular disease prevention."

The authors emphasize that the opposing directions for IL6 and IL6R point to distinct biological mechanisms: IL6 likely promotes chronic pro-inflammatory states that increase cardiovascular risk, while higher circulating IL6R (reflecting altered receptor shedding and signaling) appears to dampen harmful IL6 activity at the vessel wall and myocardium, yielding cardiovascular protection. Sensitivity and cis-MR analyses reinforced the IL6R protective signal and showed minimal evidence of directional pleiotropy. Together, the genetic evidence aligns with clinical trial data for IL6R antagonists in other settings and supports further evaluation of IL6R-targeted strategies for cardiovascular prevention.

The paper also notes important limitations and next steps. Analyses were restricted to individuals of European ancestry, so results require replication in other ancestries. Translating genetic evidence into preventive therapies will need careful clinical evaluation, long-term safety assessment, and trials designed for primary prevention in high-risk populations. The authors also call for additional mechanistic work to map how IL6/IL6R modulation alters vascular inflammation and downstream disease processes.