A Mendelian randomization study of IL6 signaling in cardiovascular diseases, immune-related disorders and longevity

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Cardiovascular Medicine

Background:

• Inflammation is increasingly recognized as a key factor in the development of various cardiovascular diseases (CVDs).
• The soluble IL6 receptor (sIL6R) acts as a negative regulator of IL6 signaling, a pathway implicated in inflammatory processes.
• Understanding the causal relationships between sIL6R, IL6 signaling, and disease is crucial for therapeutic development.

Purpose of the Study:

• To investigate the causal inference between plasma levels of soluble IL6 receptor (sIL6R) and the risk of cardiovascular and immune-related disorders.
• To explore the association of genetically determined sIL6R levels with longevity.
• To correlate gene expression data with Mendelian randomization findings to validate IL6 signaling effects.

Main Methods:

• Mendelian randomization (MR) analysis using multiple instrumental variables to assess causal effects of sIL6R on various diseases.
• Analysis of associations between genetically determined sIL6R and longevity traits (parental age at death).
• Gene-based association analysis using S-PrediXcan with GTExV7 tissue expression data.

Main Results:

• Inverse associations were found between sIL6R and rheumatoid arthritis, atrial fibrillation, stroke, coronary artery disease, and abdominal aortic aneurysm.
• Positive associations were observed between genetically determined sIL6R levels and atopic dermatitis and asthma.
• sIL6R levels showed an association with increased longevity, suggesting a complex role in aging and health.

Conclusions:

• Genetically determined reduction in IL6 signaling, mediated by sIL6R, is associated with a lower risk of multiple cardiovascular diseases and increased longevity.
• This reduction in IL6 signaling comes at the cost of an increased risk for atopic conditions.
• The findings highlight the dual role of IL6 signaling in cardiovascular health, longevity, and atopic disease susceptibility.