Navigation Links
Unlocking the genetics and biology of ankylosing spondylitis
Date:7/10/2011

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
c.brierley@wellcome.ac.uk
44-207-611-7329
Wellcome Trust
Source:Eurekalert

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:
*Name:
*Comment:
*Email:
(Date:2/3/2016)... , February 4, 2016 --> ... SEK 1,351.5 M (105.0), up 1,187% compared with fourth quarter of 2014. ... to SEK 517.6 M (loss: 30.0). Earnings per share increased ... was SEK 537.4 M (neg: 74.7). , ... Revenues amounted to SEK 2,900.5 M (233.6), up 1,142% compared with 2014. ...
(Date:2/3/2016)... , Feb. 3, 2016 Vigilant Solutions announces ... Department in Missouri solved two ... reader (LPR) data from Vigilant Solutions. Brian ... in which the victim was walking out of a convenience store and witnessed ... next to his vehicle, striking his vehicle and leaving ...
(Date:2/2/2016)... Feb. 2, 2016  BioMEMS devices deployed ... focused on medical screening and diagnostic applications, ... Wearable devices that facilitate and assure continuous ... movement are being bolstered through new opportunities ... signal acquisition coupled with wireless connectivity and ...
Breaking Biology News(10 mins):
(Date:2/12/2016)... SAN DIEGO , Feb. 12, 2016 Biocom, ... life science community, took a group of San ... as part of its 2016 Precision Medicine Advocacy Fly-In. ... at the Food and Drug Administration (FDA), the Centers for ... (NIH), as well as San Diego U.S. Representatives Susan ...
(Date:2/11/2016)... , February 11, 2016 Non-profit Consortium ... Genetic Understanding to Support Research and Discovery ... today announced an ambitious plan to sequence 100,000 individuals. It ... countries and at least 7 of North and East Asian ... the first phase, the project will focus on creating phased ...
(Date:2/11/2016)... 2016  Spectra BioPharma Selling Solutions (Spectra) is ... biopharma companies the experience, expertise, operational delivery and ... sales teams. Created in concert with industry leading ... strategic and tactical needs of its clients by ... both personal and non-personal promotion. ...
(Date:2/11/2016)...   BioInformant announces the February 2016 release ... Opportunities, Tools, and Technologies – Market Size, Segments, Trends, ... The first and only market ... BioInformant has more than a decade of historical information ... stem cell type. This powerful 175 page global strategic ...
Breaking Biology Technology: