Potential Key Genes for Giant Cell Arteritis Revealed Based on Single-Cell Sequencing and Mendelian Randomization...

Area of Science:

• Immunology
• Genetics
• Vascular Biology

Background:

• Giant cell arteritis (GCA) is an autoimmune vasculitis affecting medium to large arteries.
• GCA presents heterogeneously, with potential for serious complications including blindness and aneurysms.
• The underlying pathogenesis of GCA remains incompletely understood.

Purpose of the Study:

• To identify key genes associated with GCA.
• To investigate potential pathogenic mechanisms in GCA development.
• To explore the causal relationship between specific genes and GCA risk.

Main Methods:

• Integrated single-cell RNA sequencing, expression quantitative trait loci (eQTL), and genome-wide association study (GWAS) data.
• Employed two-sample Mendelian randomization (MR) to assess causal effects of CD4+ T cell marker genes on GCA.
• Conducted colocalization analysis to identify shared causal variants.

Main Results:

• Identified RCAN3, RPS6, and HLA-DQB1 as genes causally associated with reduced GCA risk.
• RCAN3 (OR=0.49), RPS6 (OR=0.21), and HLA-DQB1 (OR=0.76) showed inverse associations with GCA.
• Sensitivity analyses confirmed robustness, ruling out heterogeneity, pleiotropy, and reverse causality.

Conclusions:

• Identified RCAN3, RPS6, and HLA-DQB1 as potential key genes in GCA causality.
• These findings offer novel insights into GCA pathogenesis.
• Provides new avenues for developing therapeutic strategies for GCA.