Functional Dissection of Genetic Signals for Ankylosing Spondylitis

From genes to function…

Multiple genome wide association studies have been conducted for the inflammatory spinal arthritis ankylosing spondylitis (AS) since 2007, and thus far at least 113 non-MHC AS associated variants across the genome have been identified as significantly contributing to risk of disease. Despite that, the underlying mechanisms of how genetic differences in AS patients operate to contribute to pathology remains largely unclear. Dissecting the functional consequences of genetic changes associated with AS is a key focus of the group.

The vast majority of AS associated genetic changes lie within non-coding region of the genomes (i.e not in genes that code for protein) and therefore raise a great challenge in unravelling the mechanisms through which they operate. Currently, we use computational approaches that leverage multiple ‘omics data to elucidate causative genes, pathways and critical cell types involved in AS pathogenesis. Recently we applied bioinformatic methods utilising epigenetic, gene transcript and protein expression data to identify the cell types through which AS-associated variants operate. Variants were enriched in transcriptionally regulated regions in monocytes, CD4+ and CD8+ T cells, natural killer cells, regulatory T cells and B cells and mucosa from the small intestine, sigmoid colon and rectum. Gene Ontology term enrichment analysis identified microbes and the gut in the aetiology of AS. These findings identify the key immune cell types that drive the disease, and further highlight the involvement of the gut microbiome in the pathogenesis of AS.

This work has been published here.