Association of genetic variants with extra-vascular complications and cytokine production in Takayasu arteritis: a cross-sectional study

Objective Genetic variants in the chromosome 21q22 (chr21q22) region are shared among patients with Takayasu arteritis (TAK), inflammatory bowel disease (IBD), and spondyloarthritis (SpA), contributing to specific macrophage inflammation. This study aims to clarify the impact of this region on the clinical and molecular phenotypes of TAK. Methods In this cross-sectional study, seventy-one TAK patients from Keio University Hospital were included. Single nucleotide polymorphisms (SNPs) in the chr21q22 region were identified through genomic DNA sequencing in 25 patients, and serum proteome analysis was conducted in 17 patients. Interleukin (IL)-17C-induced cytokine production was measured via whole blood cytometry by Time of Flight (CyTOF) in five patients with chr21q22 SNP accumulation and five without. Results Among the 71 patients, 11% had IBD and 8.5% had SpA. Complications of IBD and SpA were strongly associated with chr21q22 SNP accumulation such as rs2242944, rs9808651, and rs2836882. Serum proteomic analysis revealed significantly elevated levels of IL-17C in TAK patients with chr21q22 SNP accumulation. IL-17C stimulation of whole blood from patients with chr21q22 SNP accumulation resulted in increased IL-6- and tumor necrosis factor-α-producing cells compared with those without SNP accumulation. Conclusion SNPs in the chr21q22 region and elevated IL-17C levels may contribute to the pathophysiology of TAK-IBD-SpA comorbidity. These insights advance our understanding of the genetic and inflammatory mechanisms underlying extra-vascular complications in TAK.