Two-Sample Bidirectional Mendelian Randomization Analysis of the Causal Relationship Between Immune Cell Phenotypes...

Area of Science:

• Immunology
• Genetics
• Autoimmune Diseases

Background:

• Systemic lupus erythematosus (SLE) is a complex autoimmune disease with critical, yet poorly defined, roles for immune cells.
• Understanding the genetic basis of immune cell involvement is crucial for elucidating SLE pathogenesis.
• Identifying immune biomarkers could reveal pathogenic or protective mechanisms in SLE.

Purpose of the Study:

• To systematically evaluate potential causal relationships between 731 immune cell phenotypes and SLE at the genetic level.
• To identify immune biomarkers associated with SLE using Mendelian randomization (MR).
• To explore potential pathogenic or protective immune cell phenotypes in SLE.

Main Methods:

• Utilized genome-wide association study (GWAS) summary statistics for 731 immune cell phenotypes and SLE.
• Employed Mendelian randomization (MR) with inverse variance weighted (IVW) as the primary method, validated by multiple sensitivity analyses.
• Conducted reverse MR analysis to investigate bidirectional causal effects between SLE and immune cell phenotypes.

Main Results:

• Identified 24 immune cell phenotypes with significant causal associations with SLE (6 positive, 18 negative).
• Key associated immune molecules include HLA-DR, CD25, CD45/CD45RA, CD8, BAFF-R, CD24, CD14, CX3CR1, CD28, CD11b, CD4, CD3, CD27, and CD16.
• Discovered a bidirectional causal relationship between SLE and IgD⁺ CD24^- %B cells.

Conclusions:

• Immune cell phenotypes contribute to SLE pathogenesis via immune tolerance regulation, self-antigen recognition, and inflammation amplification.
• Phenotypes like HLA-DR, CD3, CD24, CD25, CX3CR1, and CD8 warrant further mechanistic investigation for therapeutic potential.
• Findings offer promising targets for future basic and clinical research in SLE, with translational value for treatment development.