Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis

Abstract

ObjectiveMultiple lines of evidence indicate that ankylosing spondylitis (AS) is a lymphocyte-driven disease. However, which lymphocyte populations are critical in AS pathogenesis is not known. In this study, we aimed to identify the key cell types mediating the genetic risk in AS using an unbiased integrative functional genomics approach.MethodsWe integrated GWAS data with epigenomic and transcriptomic datasets of immune cells in healthy humans. To quantify enrichment of cell type-specific open chromatin regions or gene expression in AS risk loci, we used three published methods which have identified cell types for other diseases. Additionally, we performed co-localization analyses between GWAS risk loci and genetic variants associated with gene expression (eQTL) to find putative target genes of AS risk variants.ResultsNatural killer (NK) cell-specific open chromatin regions are significantly enriched in heritability for AS, compared to other immune cell types such as T cells, B cells, and monocytes. This finding was consistent between two AS GWAS. Using RNA-seq data, we validated that genes in AS risk loci are enriched in NK cell-specific gene expression. Expression levels of AS-associated genes, such asRUNX3,TBX21,TNFRSF1A, andNPEPPS, were found to be highest in NK cells compared to five T cell subsets. Using the human Space-Time Gut Cell Atlas we found significant upregulation of AS-associated genes predominantly in NK cells. Co-localization analysis revealed four AS risk loci affecting regulation of candidate target genes in NK cells: two known loci,ERAP1 and TNFRSF1A, and two under-studied loci,ENTR1(akaSDCCAG3) andB3GNT2.ConclusionOur results point to NK cells as potential key drivers in the development of AS and highlight four putative target genes for functional follow-up in NK cells.

Unraveling New Therapeutic Targets in Ankylosing Spondylitis: Multi-Omics Mendelian Randomization on Immune Cells, Metabolites, and Inflammation Proteins

“…Advances in immunology have emphasized the roles of regulatory T cells (Treg), Natural Killer (NK) cells, and Mesenchymal Stem Cells (MSCs). Additionally, the involvement of IL-22-producing cells, Gamma Delta T cells, and Regulatory B cells (Bregs) has been recognized, shedding new light on AS's immune dynamics and unveiling potential therapeutic targets (9)(10)(11)(12)(13)(14)(15).…”