Mendelian randomization analysis links HLA-DR+ CD14- CD16+ monocytes to CCL19-driven ankylosing spondylitis risk.

Ankylosing spondylitis (AS), strongly linked to human leukocyte antigen (HLA)-B27, lacks effective treatments for many patients despite biologics. This study investigated causal links between immune cells, inflammatory proteins, and AS to identify new therapeutic targets using genetic methods. Mendelian randomization (MR) analysis was applied using large-scale genetic data. Immune cell data came from Vuckovic et al and Orrù et al, AS data from FinnGen, and inflammatory protein data from Zhao et al. Two-sample MR explored causal relationships, and mediation analysis assessed whether proteins mediated immune cell effects on AS. MR analysis identified 26 immune cell phenotypes associated with AS, with HLA DR+ CD14- CD16+ monocytes showing the strongest protective effect (odds ratio = 0.6423). Among the 5 associated inflammatory proteins, C-C motif chemokine 19 (CCL19) had the most substantial effect on AS risk (odds ratio = 2.4234). Mediation analysis revealed that HLA DR+ CD14- CD16+ monocytes influence AS risk by reducing CCL19 levels, with the proportion of the mediated effect was 17.98% (95% confidence interval = 8.23%-27.72%). Our findings suggest that HLA DR+ CD14- CD16+ monocytes are associated with a reduced risk of AS, as indicated by a negative causal effect (β = -0.4426). This protective effect is partially mediated by a decrease in CCL19 levels, a chemokine that, when elevated, increases AS risk. These results identify CCL19 and this monocyte subset as potential key players in AS pathogenesis and highlight them as promising targets for more effective, personalized therapies.