Mendelian randomization study reveals opposing roles for IL6 and IL6R in long-term mortality
· News-MedicalUsing 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.
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