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

Area of Science:

• Genetics and Medicine
• Cardiovascular Research
• Inflammation Biology

Background:

• Interleukin-6 (IL6) signaling is implicated in inflammation and cardiovascular disease.
• The causal impact of IL6 on long-term mortality is not fully understood.
• Investigating IL6 and its receptor (IL6R) offers insights into mortality regulation.

Purpose of the Study:

• To determine the causal effects of genetically proxied IL6, IL6R, C-reactive protein (CRP), and growth differentiation factor-15 (GDF15) on long-term all-cause mortality.
• To explore potential opposing roles of IL6 and IL6R in mortality.
• To assess associations with cardiovascular events and other conditions.

Main Methods:

• Utilized Mendelian randomization (MR) with genome-wide association study data from over 750,000 individuals.
• Primary outcome: all-cause mortality over an 11.7-year median follow-up.
• Employed multiple sensitivity analyses to ensure result robustness and directionality.

Main Results:

• Higher genetically predicted IL6R levels were associated with significantly reduced mortality (OR: 0.95; 95% CI: 0.91-0.98) and lower risks 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).
• No significant causal effects were found for CRP or GDF-15; findings were consistent across sensitivity analyses.

Conclusions:

• IL6 and IL6R act as opposing causal regulators of human survival.
• IL6 increases mortality, while IL6R reduces it, primarily through cardiovascular pathways.
• Results support IL6R antagonism as a potential strategy for cardiovascular disease prevention.