Background: Giant cell arteritis (GCA) is a vasculitis characterised by persistent inflammation of medium and large-sized arteries, particularly the aorta and its branches. This disease is associated with significant morbidity and mortality, including the risk of vision loss and stroke. Despite the need to unravel GCA pathogenesis, the mechanisms underlying its development remain incompletely elucidated. Epigenetic modifications, such as DNA methylation, play a crucial role in regulating gene expression and can be profoundly altered in the context of disease. Studying DNA methylation patterns in GCA-affected tissue can provide valuable insights into the molecular underpinnings of the disease and potentially identify novel therapeutic targets.

Objectives: To gain insights into the pathogenesis of GCA by identifying specific DNA methylation signatures in the arterial tissue of GCA patients.

Methods: DNA methylation levels were studied in 81 samples, including 69 from GCA patients (inflamed temporal artery) and 12 samples from controls (non-inflamed temporal artery). Genome-wide DNA methylation profiling was performed using the Infinium MethylationEPIC Bead Chip array. Statistical comparisons were conducted to identify significant differences in methylation levels between GCA patients and controls. Significant methylation alterations were further investigated using bioinformatic functional tools, such as gene ontology (GO) term enrichment analysis, to elucidate their potential biological roles.

Results: Genome-wide DNA methylation profiling identified 211,610 significantly hypermethylated and 217,080 hypomethylated CpG sites associated with GCA. Among these alterations, the set composed of the most significant CpGs (|logFC| > 1.5) was annotated to 24 genes, exhibiting a significant association with aortic dilation (FDR<7.62×10 ^-17 ). GO term enrichment analysis revealed a strong connection to immune system involvement, including myeloid cell differentiation and CD4 ⁺ T cell regulation, as well as structural pathways related to extracellular matrix organisation and angiogenesis. These findings underscore the critical role of epigenetic regulation in GCA pathogenesis, offering valuable insights into the pathogenic mechanisms of this disease.

Conclusion: Our study identified GCA-specific DNA methylation signatures present in the primary tissue affected by the disease, which were linked to fundamental pathways driving the development of this vasculitis.

REFERENCES: NIL.

Acknowledgements: This project was funded by the Foundation for Research in Rheumatology (FOREUM) ( https://www.foreum.org/projects.cfm?projectid=142 ).

Disclosure of Interests: None declared.