Progress in ankylosing spondylitis genetics

Published on 01 April 2010
Source: Arthritis Today

X-ray of the lumbar and sacral spine showing ankylosing spondylitis

Ankylosing spondylitis expert Matt Brown outlines exciting new genetic breakthroughs that could transform treatment of this common type of inflammatory arthritis.

We’ve known for decades that ankylosing spondylitis (AS) runs in families, and for nearly four decades that HLA-B27 is the major gene that causes the disease. However, only about five per cent of people who carry HLA-B27 develop AS, and so our group has been researching what it is that causes this minority to develop the disease. We know from studies of twins and families with AS that it is an individual’s genetic makeup that explains this, and that nearly all of the differences between individuals in their risk of developing AS is genetic. Progress in identifying those genes has to date been slow, as it has been with all common human diseases.

Major advances

However, in the past three years major advances have been made in the ability to identify genes that cause common human diseases, such as arthritis, diabetes, obesity and so on. Studying thousands of individuals for hundreds of thousands of genetic markers each, we can now identify many, but not all, of the genes that influence the risk of developing conditions. These studies are expensive (minimum cost at least $1million per study), complex, and generally involve multinational consortia to ensure the skills and patient cohorts are available to complete the studies.

In AS there has always been good international collaboration between the main genetics research groups in North American and Britain. In 2007 Paul Wordsworth (Oxford), John Reveille (Houston) and I (in Brisbane) formalised this collaboration by establishing the ‘Australo- Anglo-American Spondyloarthritis Consortium’ (TASC), funded mainly by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases and other agencies, with support for the British component from Arthritis Research UK. Its principal aim is to identify genes involved in the disease, and also non-genetic factors, such as work, lifestyle and psychological factors which influence the severity of the condition and how it affects patients. We have now completed two major
studies which have identified four definite new genes/genetic regions involved in AS, and several others that are very likely to be true AS genes.

The first big breakthrough

The first big breakthrough came in 2007, when in collaboration with
another group (the Wellcome Trust Case Control Consortium) TASC
identified two genes, called IL23R and ERAP1, as being involved in AS. These were really exciting findings because of the known function of the genes, and neither had been suspected as having been involved in AS previously. Both tell us a lot about the processes which lead to AS developing. The IL23R gene produces a protein that helps to stimulate a type of immune cell, the TH17 lymphocyte. These cells help to protect us against infections in the lining of the bowel. Since the discovery of the association of IL23R with AS, several other genes that influence the activity of TH17 lymphocytes have also been found to be linked with either AS or its related conditions, inflammatory bowel disease (IBD) and psoriasis. This tells us that this type of immune cell is really important in the process by which AS develops.

Targeting is effective

Pharmaceutical companies have found that targeting this system is effective at treating IBD and psoriasis. Trials of antibodies which block the proteins important in this system have been shown to be very effective in these two conditions and are in the process of being licensed for use in Europe and America. Disappointingly, the company involved, Centocor, has not yet initiated trials in AS, even though they are very likely to be effective in this condition,
and we are obviously in desperate need of new treatments for AS at least as alternatives to anti-TNF. Thankfully, other companies are also active in this area, and trials of antibodies blocking other parts of the system are underway.

This is a remarkably rapid turn of events, and shows that the strategy of working on AS to identify genes other than HLA-B27, essentially leaving it in the ‘too hard basket’, is a productive one. Despite years of research, we still don’t really know how HLA-B27 causes AS. But recent work tells us that our other important candidate gene, ERAP1, may work together with HLA-B27 to
make some T-lymphocytes – immune cells that normally help us fight off infections – ‘turn’ on the body and cause inflammation themselves. There are other ways that ERAP1 may cause AS, but this is the most likely. If proven to be true, this would represent a major advance in working out how the biggest AS gene, HLA-B27, causes the disease.

‘Gene deserts’

The other two genetic regions we have shown to be involved in AS are what we call ‘gene deserts’, which are regions of the genome where the DNA contains no genes. These regions used to be called ‘junk DNA’, but are now known to contain areas which control the expression of other genes. We don’t yet know what the other genes are that these gene deserts control, but we are working at it, and hope that by working this out, we can use the information to develop new therapies for AS.

Genetic tests

One other area in which you can use genes is to help with diagnosing AS. At the moment, it takes on average approximately eight years between onset of AS symptoms and a diagnosis being made. This is obviously way too long and in the UK has actually increased over the past 30 years. As a clinician I often see people who have had inappropriate surgery and other treatments because their AS has not yet been diagnosed. Our genetic tests are now very good at diagnosing the condition (at least as good as an MRI scan), and we are testing them out to see if we can use them to screen the general community to identify people at high risk of developing AS, so that they can get treatment early on if and when they develop signs of the condition. We have also shown that by using a test for which genes are being expressed in blood, we can accurately distinguish between patients with AS and healthy people. This test is now being developed to help in early AS diagnosis. Using these tests we hope to be able to pick up AS early on, help avoid inappropriate treatment, and instead allow treatment to prevent the damage that joint inflammation in AS leads to.

Other studies underway

Many more genes have yet to be identified which cause AS, and there are other large studies underway in Europe, Canada and China that will report findings in the next 12–18 months which will increase this list further. In particular, the International Genetics of AS consortium (IGAS) will be performing a study with about 13,000 samples from all over the world. So the next two years will be a very exciting time for discovering genes in AS.

The challenge is now before us to translate these genetic findings into diagnostic, treatment and preventative approaches for patients. As you can see we are already making progress on that front and, given adequate resources, I think we can expect that this translational research will make a substantial difference to the diagnosis and management of AS in the near future.

Matt Brown

Former Arthritis Research UK Senior Research Fellow Matt Brown is now Professor of Immunogenetics at the University of Queensland.

For more information on ankylosing spondylitis you can read our new booklet online (PDF version): Ankylosing spondylitis

Alternatively please call 0300 790 0400 or email us at enquiries@arthritisresearchuk.org for a free paper version.