Research funded by the Wellcome Trust and the Arthritis Research Campaign has identified two genes implicated in the disease ankylosing spondylitis, a common disease primarily causing back pain and progressive stiffness. The research, published online today in Nature Genetics, suggests that a treatment currently being trialled for Crohn's disease may also be applied to this disease.
Ankylosing spondylitis affects as many as 1 in 200 men and 1 in 500 women in the UK, typically striking people in their late teens and twenties. Whilst it mainly affects the spine, it can also affect other joints, tendons and ligaments. More rarely, it can affect other areas, such as the eyes, lungs, bowel and heart.† High-profile sufferers of the condition include former England cricket captain Mike Atherton.
Now, using a technique known as genome-wide association scanning, researchers led by Professors Lon Cardon, Matthew Brown and Paul Wordsworth, from the Wellcome Trust Centre for Human Genetics at the University of Oxford have analysed DNA samples from 1,000 patients with ankylosing spondylitis and a further 1,500 people unaffected by the disease in search of genetic mutations which, if present, increase a person's risk of developing the disease. The findings from this study were then confirmed by a team at University of Texas (Houston) led by Professor John Reveille.
"Ankylosing spondylitis is a painful and often very disabling disease," says Professor Brown. "Yet, our understanding of the causes of the disease, and hence our ability to treat it effectively, is relatively poor."
The researchers have identified two genes, ARTS1 and IL23R, which increase the risk of developing the disease. Together with the genetic variant HLA-B27, this takes the number of genes definitely known to be involved in the disease to three. A person carrying all three variants would be expected to have a one in four chance of developing the disease.
The IL23R gene plays a role in the immune response to infection, providing instructions for making a receptor present on the surface of several types of immune system cells. The receptor is involved in triggering certain chemical signals inside the cell that promote inflammation and help coordinate the immune system's response to infection. It is already recognised as playing a role in a number of autoimmune diseases, such as Crohn's disease (a type of inflammatory bowel disease) and psoriasis (a skin disease). Ankylosing spondylitis, Crohn’s disease and psoriasis are known to often occur together, and this genetic finding goes a long way to explain why.
Professor Brown believes that the unexpected involvement of IL23R in ankylosing spondylitis provides a major step towards being able to treat the disease.
"We already know that IL23R is involved in inflammation, but no one had ever thought it was involved in ankylosing spondylitis," says Professor Brown. "A treatment for Crohn's disease that inhibits the activity of this gene is already undergoing human trials. This looks very promising as a potential treatment for ankylosing spondylitis."
Scientists have known that there is a genetic component to ankylosing spondylitis for 37 years, since the discovery of the gene HLA-B27. However, how this gene led to disease is not known. Professor Brown believes that the gene ARTS1 may hold the answer.
A protein created by the HLA-B27 gene takes fragments of pathogens and displays them on the outside of immune cells. These fragments then trigger the immune system to fight against the pathogen. ARTS1 is involved in breaking up the pathogen into "bite-size chunks" that can be displayed by HLA-B27.
"This strongly suggests that in ankylosing spondylitis, there are problems with the information that the HLA-B27 protein receives, thereby causing the disease," says Professor Brown.
Scientists believe that ankylosing spondylitis may be triggered in genetically-susceptible people by bacteria commonly found in the gut. Why this should be the case is unclear, but it is hoped that the new genetic discoveries will help answer this question.
"These findings are very exciting and show the value of exploring the genetics of disease," says Dr Mark Walport, Director of the Wellcome Trust. "It usually takes many years between genetic discoveries and new treatments for disease. In this case the two genes discovered to be associated with ankylosing spondylitis provide striking insights into the mechanisms of the disease and offer a possible new pathway for treatment."
The study is a collaboration between the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
“These genetic studies involve large patient samples and require expertise over a wide range of scientific specialities”, says Professor Cardon. “Bringing together these two consortia was the final key that enabled these exciting discoveries.”
Recruitment and collection of samples of patients with ankylosing spondylitis was assisted by the National Ankylosing Spondylitis Society.