Causal effects of inflammation on long-term mortality: A mendelian randomization study

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.

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.

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.

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.