Potential key genes for giant cell arteritis revealed based on single-cell sequencing and Mendelian randomization analysis.

Introduction: Giant cell arteritis (GCA) is an autoimmune disease affecting medium and large arteries. It varies in presentation and often recurs, potentially leading to blindness and aneurysms. The pathogenesis of GCA is not well understood. This study aims to identify key genes linked to GCA and explore potential pathogenic mechanisms.

Methods: This study integrated single-cell RNA sequencing, expression quantitative trait loci, and genome-wide association study data, employing a two-sample Mendelian randomization (MR) method to explore the causal effects of marker genes in CD4+ T cells on the development of GCA. Additionally, colocalization analysis was conducted to determine whether there was a shared causal variant.

Results: Through single-cell RNA sequencing and MR analysis, we identified three key genes, RCAN3, RPS6, and HLA-DQB1, that had a causal relationship with a reduced risk of GCA. Specifically, RCAN3 (OR = 0.49, 95% CI = 0.26-0.93, p = 0.03), RPS6 (OR = 0.21, 95% CI = 0.06-0.73, p = 0.01), and HLA-DQB1 (OR = 0.76, 95% CI = 0.62-0.93, p = 0.01) were inversely associated with the disease. Multiple sensitivity analysis methods showed no heterogeneity and pleiotropy, and ruled out potential reverse causality, demonstrating the robustness of MR analysis results. Colocalization analysis revealed that HLA-DQB1 and GCA were related to SNPs within the same genomic region but involved different causal variants.

Conclusions: This study identified three potential key genes (RCAN3, RPS6, HLA-DQB1) linked to the causality of GCA, providing new perspectives on the pathogenesis of GCA and new avenues for therapeutic strategies.