Genetic perturbation of IL-6 receptor signaling pathway and risk of multiple respiratory diseases.

ABSTRACT

Dysregulation of inflammation can lead to multiple chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Interleukin-6 (IL6) is crucial in regulating the inflammatory cascade, but the causal link between IL6 signaling downregulation and respiratory diseases risk is unclear. This study uses Mendelian randomization to examine the effects of IL6R blockade on respiratory diseases. Analyzing data from 522,681 Europeans, 26 genetic variants were obtained to mimic IL6R inhibition. Our findings show that IL6R blockade significantly reduces the risk of COPD (OR = 0.71, 95% CI = 0.60-9.84) and asthma (OR = 0.82, 95% CI = 0.74-0.90), with protective trends for bronchitis, pulmonary embolism, and lung cancer. Results were consistent across methods, with no significant heterogeneity or pleiotropy. These insights suggest IL6R downregulation as a potential therapeutic target for respiratory diseases, meriting further clinical investigation.