NEW YORK – A team led by researchers at the University of Oxford has untangled gene expression and regulation features involved in a common and highly heritable inflammatory spinal arthritis condition called ankylosing spondylitis (AS), suggesting new genes and pathways to pursue for drug discovery.
AS, which affects about 200,000 people in the UK, is marked by inflammation at tendon or ligament insertion sites at the spine and sacroiliac joints that leads to pain, new bone formation, and spinal vertebral fusions.
The study, published in Cell Genomics on Monday, "underlines how we need to look for functional effects of disease-associated genetic variants in the appropriate cellular and disease contexts, in ankylosing spondylitis and other immune-mediated conditions," senior and corresponding author Julian Knight, a professor of genomic medicine at the University of Oxford, said in a statement.
For the study, the researchers relied on RNA sequencing, the assay for transposase-accessible chromatin using sequencing (ATAC-seq), high-resolution chromosomal conformation capture (Capture-C), and chromatin immunoprecipitation sequencing coupled with tagmentation-based library preparation (ChIPmentation) to profile gene expression, chromatin accessibility, chromatin interactions, and promoter/enhancer histone modifications, respectively, in immune cells found in blood samples from 20 individuals with AS who had not yet received biologic therapy and 35 unaffected control individuals.
Based on data for immune cells isolated by immunomagnetic cell separation from peripheral blood samples, the team tracked AS-associated transcriptomic and epigenomic changes, bringing in a priority index algorithm and data from prior AS-focused genome-wide association studies to focus in on disease-related cell types, pathogenic features, and potential treatment targets.
The investigators tracked down transcript changes in CD4-positive T cells, CD8-positive T cells, and CD14-positive monocytes from individuals with AS, along with epigenomic changes falling at loci previously linked to AS by GWAS in monocytes. The available GWAS variant data also helped to narrow in on risk SNPs with functional ties to specific genes or enhancers within a chromatin architecture associated with AS in monocytes.
Their results pointed to the potential importance of the ETS proto-oncogene 1 (ETS1) transcription factor and the immune-related prostaglandin E receptor 4 (PTGER4) gene, for example, as well as pathways involved in NOTCH signaling, chemokine receptor signaling, and other processes.
Together, the team noted, the results may provide an avenue for finding new treatment targets for AS, since a significant subset of individuals with the condition do not show a lasting response to available biologic treatments.
"The outlook for patients with more severe forms of AS has been greatly improved in recent years by the introduction of new biologic treatments inhibiting the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and IL-17A," the authors explained. "Nevertheless, fewer than half are likely to achieve sustained remission even within these targeted therapies, highlighting the need for patient stratification of potential responders and new therapeutic targets in AS."
More generally, the authors suggested that the current findings "show how functional genomic evidence can be integrated with GWAS data through [a priority index algorithm] to identify candidate therapeutic targets for future study."