Elevated levels of interleukin-6 are correlated with diseases such as cancer, autoimmune diseases and infections. IL-6 receptor inhibitors (IL-6Ri), used for rheumatoid arthritis and COVID-19, may have wider uses.
The authors applied Mendelian randomisation (MR) to study the effects of IL-6Ri. To simulate the effects of IL-6R gene blockade, they selected single nucleotide polymorphisms (SNPs) within or near the IL6R gene that show genome-wide significant associations with C-reactive protein. Using rheumatoid arthritis and COVID-19 as positive controls, key outcomes included risk of asthma, asthmatic pneumonitis, small cell lung cancer, Parkinson's disease, Alzheimer's disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type 1 diabetes and type 2 diabetes. The IVW (Inverse Variance Weighted) method was their main analytical approach, with MR hypotheses assessed by sensitivity and colocalization analyses. In addition, they performed Bayesian Mendelian randomisation analyses to minimise confounding and reverse causality biases as much as possible.
Bayesian Mendelian randomisation analyses were performed to minimise confounding and reverse causality bias.
IL-6 inhibitors significantly reduced the risk of idiopathic pulmonary fibrosis (OR = 0.278, 95% [CI], 0.138-0.558; P <0.001), Parkinson's disease (OR = 0.354, 95% CI, 0.215-0.582; P <0.001) and positively influenced the causal relationship with type 2 diabetes (OR = 0.759, 95% CI, 0.637-0.905; P = 0.002).
However, these inhibitors increased the risk of asthma (OR = 1.327, 95% CI 1.118-1.576; P = 0.001) and asthmatic pneumonia (OR = 1.823, 95% CI 1.246-2.666; P = 0.002). The causal effect estimates obtained using the BWMR method are consistent with those based on the IVW approach. Similarly, IL-6R also exerts a significant influence on these diseases.
Diseases such as Alzheimer's disease, Crohn's disease, pulmonary heart disease, systemic lupus erythematosus, type 1 diabetes, non-small cell lung cancer and ulcerative colitis showed non-significant associations (p > 0.05) and were excluded from further analysis. Similarly, small cell lung cancer was excluded due to inconsistent results.
Conclusion: IL-6Ri may represent a promising therapeutic pathway for idiopathic pulmonary fibrosis, Parkinson's disease and type 2 diabetes.
