Navigation Links
Unlocking the genetics and biology of ankylosing spondylitis

A study involving over 5,000 people living with the joint disorder ankylosing spondylitis has identified 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.

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.

The study also provided clues as to why a particular genetic variant known as HLA-B27 is associated with the disease. Scientists have known for almost forty years that this variant significantly increases the risk of developing the disease. Nine out of ten people with ankylosing spondylitis carry the variant. Whilst not everyone with the variant develops the condition, those who carry the variant are up to eighty times more likely to develop it than non-carriers. Yet despite this knowledge, the mechanism by which the variant causes the disease is still unknown.

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.

ERAP1 plays a role in breaking down proteins within the body into smaller molecules known as peptides. The gene interacts with HLA-B27 to affect how these peptides are presented to the immune system. This is an essential process for mounting an immune response to invading pathogens, but when it goes awry it can result in the immune system causing inflammation and damaging tissue. The researchers found that some variants of ERAP1 protect against the development of ankylosing spondylitis by reducing the amount of peptide available to HLA-B27 within cells. The researchers believe that inhibiting ERAP1 may help treat the condition.

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".


Contact: Craig Brierley
Wellcome Trust

Related biology news :

1. Unlocking the secret(ase) of building neural circuits
2. Unlocking the secrets of a plants light sensitivity
3. Unlocking the secrets of a plant’s light sensitivity
4. Unlocking the secrets of RNA biology with WIREs
5. Unlocking the opium poppys biggest secret
6. Unlocking mysteries of the brain with PET
7. Unlocking the secret of the bladders bouncers
8. Adult stem cells carry their own baggage: Epigenetics guides stem cell fate
9. Genetics of melanoma chemoresistance
10. Population genetics reveals shared ancestries
11. MARC travel awards announced for GSA Mouse Genetics Conference
Post Your Comments:
(Date:11/18/2015)... --> --> ... report titled  Gesture Recognition Market - Global Industry Analysis, ... to the report, the global gesture recognition market was valued at ... US$29.1 bn by 2021, at a CAGR of 20.3% ... dominated the global gesture recognition market in ...
(Date:11/17/2015)... Nov. 17, 2015  Vigilant Solutions announces today that ... Board of Directors. --> ... retiring from the partnership at TPG Capital, one of ... over $140 Billion in revenue.  He founded and led ... the TPG companies, from 1997 to 2013.  In his ...
(Date:11/12/2015)... BOSTON , Nov. 12, 2015  A golden ... for Duchenne muscular dystrophy (DMD) has provided a new ... Boston Children,s Hospital, the Broad Institute of MIT and ... Brazil . Cell, ... some dogs "escape" the disease,s effects. The Boston Children,s ...
Breaking Biology News(10 mins):
(Date:12/1/2015)... Harry Lander , President of Regen, expands his role to ... and recruits five distinguished scientists to join advisory ... expands his role to include serving as ... scientists to join advisory team --> Dr. Harry Lander ... serving as Chief Science Officer and ...
(Date:11/30/2015)... ... 2015 , ... Global Stem Cells Group Chile ... Central America and abroad for the first Iberoamerican Convention on Aesthetic Medicine, Cosmetology ... Testart will present and discuss new trends in anti-aging stem cell treatments, regenerative ...
(Date:11/30/2015)... 2015  An interventional radiology technique shows promise for helping ... of a study being presented today at the annual meeting ... (RSNA). --> --> ... interventional radiologists as a way to stop bleeding in emergency ... means of treating obesity is new. Mubin Syed ...
(Date:11/30/2015)... HOLLISTON, Mass. , Nov. 30, 2015 /PRNewswire/ ... HART ), a biotechnology company developing bioengineered ... has received written notification from The NASDAQ Stock ... minimum bid price requirements. The letter noted that ... of HART,s common stock having exceeded $1.00 per ...
Breaking Biology Technology: