Understanding 3D genome organization in ankylosing spondylitis

Background: Ankylosing spondylitis (AS) is a common form of arthritis primarily affecting the spine (~200,000 individuals in the UK), characterised by inflammation at stress-bearing sites where soft tissues such as tendons are attached to bones.

It causes high levels of disability with chronic pain and stiffness due to bony fusion affecting the whole spine in some cases.

AS has a very strong genetic component but susceptibility to the disease is complex and determined by contributions from at least 100 different genetic factors.

Individual genes are made of packages of DNA that contains the code for the manufacture of proteins (molecules that form the structures and perform the everyday cells' functions).

Some of the genetic variants associated with increased risk of AS alter the structure and function of these proteins but, more commonly, the alterations are in bits of DNA that affect the activity of individual genes in particular types of cells (eg. skin, immune, bone) in response to specific stimuli, such as infections.

From our previous work we suspect that these regulatory alterations in DNA are particularly important in susceptibility to AS, probably because they cause genes to be switched on inappropriately (wrong time or place).

What is known?: Large-scale genetic studies (called Genome Wide Association Studies) involving thousands of individuals have shown that genetic variation in the RUNX3 gene are not only linked to AS but also to other diseases where the immune system is involved, including psoriatic arthritis, and gut disorders, such as inflammatory bowel disease (IBD).

People with AS or their relatives often have these related conditions as well (30% of those with AS may also have psoriasis and/or IBD). People with IBD are particularly prone to AS and the majority of people with AS have low-grade gut inflammation.

The relationship between this gut inflammation (and the immune cells involved) and AS is poorly understood but may be crucial to understanding the processes underlying the spinal inflammation of AS.

Why is this research needed?: Although we now have substantial information about the specific DNA alterations that increase the risk of AS not much is yet known about the precise functional consequences of these changes or the cell types in which they exert their most important effects.

I will therefore evaluate differences and similarities between particular immune cells called CD8+ T-cells from the blood and gut of people with AS compared to healthy volunteers and people with IBD.

I will compare the DNA in these gene regulators and how they alter the activity of nearby genes, including RUNX3, and exactly how this might change the behaviour of the CD8+cells.

This work will be an important step to defining the contribution of RUNX3 to AS and how this might influence the activity and function of other genes with a view to identifying plausible new targets for drug treatment in AS. Where will the work be done?: The work will be done in the University of Oxford Wellcome Centre for Human Genetics