Taking it cell by cell…
Ankylosing spondylitis (AS) is the prototypic member of a family of related diseases known as the Spondyloarthritides. Spondyloarthritides also include inflammatory bowel disease (IBD) associated arthritis, psoriatic arthritis and reactive arthritis. The initial stages of AS involves inflammation of the spine and sacroiliac joints of the pelvis, which may then lead to bony ankylosis (fusion of the joint).
Early studies showed that AS is a highly heritable disease, and extensive genetic studies have been carried out on AS cohorts. Currently there are 113 loci associated with AS, many in immune genes including: HLA-B27, components of HLA class I antigen processing, and components of the IL-23 immune signalling pathway. These 113 loci account for 27.82% of AS heritability, with HLA-B27 contributing 20.1% of that heritability.
Unfortunately the mechanism through which these loci cause the immune changes that lead to AS is still unknown.
Pairing gene expression (transcriptomics) and methylation (methylomics) information with genotype information can reveal genetic variants that alter gene expression and methylation, known as expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL). Polymorphisms that disrupt DNA motifs that are used by cellular machinery for mRNA production and processing can interfere with the expression of near (cis-) and network associated (trans-) genes.
It is the aim of this project to investigate if genetic changes at these AS associated loci alter gene expression or methylation, either in cis or trans, to elucidate the mechanism through which these genetic changes alter immune function and lead to AS. Unlike past studies, which have investigated expression signals in pooled populations of cells, we are specifically studying immune cell subtypes in isolation to determine genetic variants that act on these specific cells, and isolate cell-type contributions to altered biological processes. A range of immune cells are under scrutiny (CD4+ T-cells, CD8+ T-cells, monocytes, NK cells and gamma-delta T-cells). This will be the largest RNA sequencing and paired methylation project of its kind in AS.