Pathway-Based Mendelian Randomization for Pre-Infection IL-6 Levels Highlights Its Role in Coronavirus Disease

Area of Science:

• Immunology
• Genetics
• Epidemiology

Background:

• Interleukin 6 (IL-6) is implicated in COVID-19 prognosis and treatment.
• The relationship between pre-existing IL-6 levels and severe COVID-19 risk is not well understood.

Purpose of the Study:

• To investigate the association between genetically predicted IL-6 pathway components and the risk of severe COVID-19.
• To explore potential pre-COVID-19 biomarkers for severe disease.

Main Methods:

• Two-sample Mendelian randomization study design.
• Utilized genetic instruments for IL-6, soluble IL-6 receptor, IL-6 signal transducer, and CRP from large GWASs.
• Analyzed data from Host Genetics Initiative and GenOMICC studies for COVID-19 outcomes.

Main Results:

• Inverse association found between genetically instrumented IL-6 levels and severe COVID-19 risk (OR = 0.60).
• Soluble IL-6 receptor showed an inverse association (OR = 0.94), while the soluble signal transducer showed a positive association (OR = 1.13).
• Only the association for IL-6 reached statistical significance for COVID-19 hospitalization and critical illness (p < 0.003).

Conclusions:

• Pre-COVID-19 IL-6 levels may have a causal relationship with severe COVID-19 risk.
• These findings suggest IL-6 could serve as a prognostic or preventive marker.
• Further research is needed to confirm these relationships and explore their relevance in other infectious diseases.