A series of genetic variants associated with increased susceptibility to the condition as well as providing new clues to how the condition may be treated in the future has been identified in a study involving over 5,000 people living with the joint disorder ankylosing spondylitis. The study, a collaboration between the Australo-Anglo-American Spondyloarthritis Consortium and the Wellcome Trust Case Control Consortium, also provides one of the first confirmed examples of gene-gene interaction seen in humans.
Ankylosing spondylitis is an autoimmune disease that affects as many as one in 200 men and one in 500 women in the UK, typically striking people in their late teens and twenties. While 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.
Now, a study carried out in the UK, Australia and North America comparing the genomes of 3,023 cases against those of 8,779 healthy controls has identified a series of genetic regions newly implicated in the disease. The findings were confirmed in an independent cohort of 2,111 cases and 4,483 controls. The results are published in the journal Nature Genetics.
Professor Peter Donnelly from the University of Oxford, Chair of the Wellcome Trust Case Control Consortium says: "Thanks to over 5,000 people with ankylosing spondylitis who have provided DNA samples, we were able to undertake the largest study of the genetics of this painful and often disabling disease. It revealed important, and in some cases surprising, new insights into the disease."
The study identified three regions of the genome – RUNX3, LTBR and TNFRSF1A – in which genetic variants were strongly associated with ankylosing spondylitis. In addition, they found a further four which are likely candidates: PTGER4, TBKBP1, ANTXR2 and CARD9.
As well as furthering our understanding of the genetics underlying the condition, the findings also strengthen evidence that a particular process by which signals are transmitted within cells – known as the IL-23R pathway – is involved in the disorder and could be a target for drugs.
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The researchers found that variants of the gene ERAP1 interact with HLA-B27 to affect disease susceptibility – one of the first confirmed examples of gene-gene interaction seen in humans. For individuals who carry HLA-B27, their risk of developing ankylosing spondylitis decreases by a factor of four if they also carry two copies of the protective variants of ERAP1.
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The researchers also analysed the genetic make-up of individuals with ankylosing spondylitis who did not carry the HLA-B27 variant and found associations with several genetic regions, the first time that associations have been found in HLA-B27 negative individuals. These findings indicate considerable similarity between the way HLA-B27 positive and negative ankylosing spondylitis develop.
Professor Matt Brown from the University of Queensland, Australia, says: "Our work shows the great value of partnering genetics research with functional investigations to determine the basic biology which leads to common diseases such as ankylosing spondylitis, the causes of which have remained an enigma for so long.
"At the moment, whilst we have effective treatments to suppress the inflammation in ankylosing spondylitis, we have no treatment to substantially improve its long-term outcome, particularly the chronic pain, marked loss of movement and disability and that are common consequences of this disease. We must be cautious about the promise that these findings offer, but they are a promising step in the right direction."
Professor Alan Silman, Medical Director of Arthritis Research UK , which funded the preliminary work for the genetics research said the study was important, but added that it needed to be followed up before its significance could be measured clinically. "We're supporting further intensive work needed to investigate whether these genetic targets could offer scope for novel treatment approaches," he said.
Debbie Cook, Director of The National Ankylosing Spondylitis Society (UK) added: "We are delighted with the results of these genetic studies in ankylosing spondylitis which will help us to understand the causes of the disease better, and hopefully to develop new ideas about its treatment. Our members have been heavily involved in these studies with scientists at the University of Oxford over the past 10 years and it is good to see the progress that has been made. It has long been recognised that there is a genetic element to the condition and that it has a tendency to run in families. The identification of 14 genes involved in this process clearly helps to understand the reasons for this. "Over the past ten years our members have been donating blood or saliva samples so that their DNA can be analysed. It is good to see that this truly global collaboration, involving teams in Australia and USA as well as the UK has been so worthwhile. We look forward to further developments in the future towards preventing or curing this persistent and painful disease that affects about 200,000 people in the UK alone".
Source-Eurekalert