Kickas.org Forums Ankylosing Spondylitis General Discussion #1 AS Web Support Group New genes linked to AS

Rheumatologists Discover Two Genes Related to Disabling Form of Arthritis

Work done in part by researchers at The University of Texas Medical School at Houston has led to the discovery of two genes that cause ankylosing spondylitis, an inflammatory and potentially disabling disease. The findings are published in the Oct. 21 online edition of Nature Genetics, a journal that emphasizes research on the genetic basis for common and complex diseases.

John D. Reveille, M.D., professor and director of the Division of Rheumatology and Clinical Immunogenetics, in conjunction with Matthew A. Brown, M.D., professor of immunogenetics at Australia’s University of Queensland, led research done by the Triple “A” Spondylitis Consortium Genetic Study (i.e. the TASC or Australo-Anglo-American Spondylitis Consortium).

The international team of researchers worked with investigators from the British Wellcome Trust Case Control Consortium, and together they made the genetic discovery.

Reveille, chief of rheumatology at Memorial Hermann – Texas Medical Center, said the discovery of genes ARTS1 and IL23R brings the scientific community two steps closer to fully understanding ankylosing spondylitis or AS, a chronic form of arthritis that attacks the spine and also can target other joints and organs in the body.

“We’ve long known that the HLA-B27 gene accounts for 40 percent of the overall cause of AS,” said Reveille, the principal investigator of TASC. “Now we have found two new genes. Together with HLA-B27, these genes account for roughly 70 percent of the overall cause. That means we’ve almost nailed this disease. Within the next year, I predict we will have identified all the genes that play a role in this insidious disease. There is more exciting news to come.”

The recent discovery is based on work from the largest and most comprehensive genome-wide association scan conducted to date. In this part of the research project, investigators were searching for genetic information related to AS, as well as autoimmune thyroid disease/Graves’ Disease, breast cancer and multiple sclerosis. Reveille, the George S. Bruce, Jr. Professor in Arthritis and Other Rheumatic Diseases, said the most significant findings were in AS, a disease that generally strikes patients in their teens, 20s or 30s.

ARTS1 and IL23R show a new pathway of causation, Reveille said, and this could lead to new therapies for the arthritic condition, which can cause a complete fusion of the spine, leaving patients unable to straighten and bend.

The identification of the two new genes also could help physicians identify patients who are at the highest risk for developing AS.

“For example, if you have a family member with AS, a simple blood test would be able to tell us if you are also at risk,” Reveille said. “We could offer screenings for people with back pain. In the past, the HLA-B27 test was all we had. Now we potentially have more tests.”

Steve Haskew, who has lived with AS for thirty years, said the genetic discovery offers hope to patients – especially those who are newly diagnosed.

“When I first started experiencing problems – lower back pain, the aching joints – no one could tell me what was wrong,” said Haskew, 59, co-leader of an AS support group that meets every other month at the UT Medical School at Houston. “It took 10 years before a rheumatologist diagnosed me with AS. Back then, there weren’t many options. I was told to take anti-inflammatories and stay as active as possible. It’s fascinating to see how far we’ve come and how much has been learned about the disease since then.”

The research done by Reveille and his colleague Xiaodong Zhou, M.D., associate professor of medicine in Division of Rheumatology and Clinical Immunogenetics, was supported in part by the Center for Clinical and Translational Sciences (CCTS) at The University of Texas Health Science Center at Houston.

“This is a success story for genetics work, and I think it will lead the way for other work to be done,” Reveille said.

The Spondylitis Association of America (SAA) oversaw the nationwide recruitment of patients and families for the study.

“This is the most significant breakthrough in AS genetic research since HLA-B27 was uncovered 34 years ago, and SAA played a significant role in making the study possible,” said SAA Associate Executive Director Laurie Savage, who is co-principal investigator for TASC’s administrative core.-University of Texas Health Science Center at Houston

Hey Fishy! Thank you for your update. Back in '98 I was a participant in a similar attempted genetic study with Dr. Yu of UCLA ---the actual study was being done in China with a budget of $2,000, imagine that. It's great to see we've come a long way in such a short time. Thanks again, Warmest, Teresa

Hi, thanks for posting this!

there' been a fair few announcements in the past. MA Brown was involved at the welcome trust in the UK.

The research also was taken on Anglo American patients, there's often a difference in gene studies and other causing genes......

Welcome Trust have the press release and a bit more, especially IL23R!

http://www.wellcome.ac.uk/ extract
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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 were 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."


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they seem to like the IL23R, as it is known to be involved in Chron's.

Apparently some variations in this gene are assoc with UC, in childhood but it's not so clear cut and may just some variations.




IL23R

IL23R is involved in Interleukin 23

http://en.wikipedia.org/wiki/Interleukin_23

<===+++++++++++++++++++=====>

ARTS1

The info on this gene is all sciency.......

comments TNF and Zinc keep coming up. Maybe that's why chick peas seem to help!

http://www.ncbi.nlm.nih.gov/sites/entrez...om_uid=38438333

I was watching the baseball playoffs the other night and they were in the stretch so I thought I'd channel surf. Never made if back to the game because I found a documentary on epigentics and its effect on DNA.
The epigenome, from what I could gather, is a wrapper on the DNA which has the ability to turn off or turn on certain genes, depending on whether the come from the father or mother. Fascinating.
Remember all the stories of identical twins where one gets a disease and the other does not? That's the epigenome acting for either parent on the same gene with totally different outcomes.
I started thinking that maybe fixing AS could be as easy as flipping an epigenetic switch on these 2 genes that have been identified.

Thanks for posting this information Fishy!
I just sent it to Art so he can print it out. I'm going to drop it off at my rheumy's office tomorrow and see what he thinks. Very interesting and better hope than to have to wait 5, 10, 15 years before a clear dx and the damage is already done.

Take care...

Bugs,

how you keeping?

Prof Brown is a bit fixated with B27....which is probably a good thing!!!

The IL23R seems to need one of the NOD/CARD genes implicated in Chron's as well so .....

What about UC what about idiopathic AS so I'm not getting too excited......




Some time back 4 areas were Associated with IBD and as far as I know are still being pursued:

NOD / CARD same place in the genome but they changed the naming convention so

NOD1 = CARD4
NOD2 = CARD15

I'm not sure about these and duse to renaming in the gene mapping process I get lost quickly
I think
NOD3 = CARD16:1 or CLR16:1
NOD4 = CARD16:2 or CLR:16:2


not sure what has happened to the other NOD GENES which I think are 3 and 4

NOD3 is involved with capase-11

http://en.wikipedia.org/wiki/Caspase

NOD4

searching ..................


So did some googling, lots of studies and it seems that ethnicity seems to play a factor....if IBD is associated with the NOD2 variations......Colitis seems to be more weakly associated than Chron's....



So it's not a clear cut answer for all folk!

Tim,

they found something in Australia a year or so back where a family had a high incidence of cancer. when they tested the family they found a strong assoc with a gene but not in all cases where cancer was present. Eventually they found a protein sheath over the gene stopping it from being detected in those that had the cancer but tested negative for the gene.

I've wondered a few times if this might be the case in AS with B27 negatives....wish I had a few hundred thousand spare ( after a few remicade infusions )


zzyzx,

Prof David Yu ? , has gone a bit quiet. My last trace of him was announcing that he found a heavy chain protein that was n't expressed in the guts of Spondy patients. Since then he's gone off my radar a bit.

But I did find this:...........

http://www.medscape.com/viewarticle/561929

Mr Brown's and Yu were top of my watch list when I was more active on the board! All good signs....

In general, if you look at the other common diseases associated with these genes it's no wonder we have a real mixture of auto immune diseases, there are clear associations with LUPUS thyroid etc Diabetes ...

Bugs, Latex allergy is associated with HLA-DR4 ..... I think that goes with Rheumatoid A as well....

David

this seems to have more specific info

http://www.digitaljournal.com/article/24...ing_Spondylitis

NOD 1 /2 at least both implicated in IBD and their role in detecting infection

http://www.hhmi.org/research/scholars/philpott.html


NOD1 and 2 sense the presence of bacteria by Detecting Proteins

some of this seems very simple and it looks for patterns in the protein.....

much like a network sniffer looks for specific parts of an network packet


Extract on NOD1 and Sensing Gram Negative Bugs
===============================================
Our recent studies focused on identifying the bacterial ligands or PAMPs that activate Nod1 and Nod2. Both proteins sense PG fragments released from the cell wall of bacteria. For Nod1, we identified a naturally occurring PG fragment of N-acetyl glucosamine-N-acetyl muramic acid linked to a tripeptide, in which the terminal amino acid is meso-diaminopilemic acid (meso-DAP). The presence of DAP in PG can be considered as a general signature of Gram-negative bacterial infection.

Extract on NOD2
================================================
Nod2 also senses a PG fragment; however, Nod2 is specific for muramyl dipeptide or MDP. MDP is the minimal bioactive PG fragment from both Gram-positive and Gram-negative bacteria, rendering Nod2 a general sensor of bacterial infection.

Freund's complete adjuvant
=============================

this is mentioned in relation to NOD2, it's not good for human's/ not that good for mice either!!!

http://en.wikipedia.org/wiki/Freund's_adjuvant


Bit More Extracted
=====================
The most common mutation in the Nod2 gene associated with Crohn's disease is an insertion mutation at nucleotide position 3020, which leads to the deletion of the terminal LRR of the protein. Using in vitro studies, we showed that mutated Nod2 protein is unable to detect MDP to initiate NF-&#954;B activation. Moreover, peripheral blood mononuclear cells isolated from patients with Crohn's disease cannot respond to MDP in terms of NF-&#954;B activation and cytokine induction. The implications of these findings therefore suggest that the defect in Crohn's disease patients may stem from the inability to respond normally to bacterial products. How this then initiates the development of disease remains unknown.


Dave

This is very exciting! Thank you for posting it.

Many hugs,

Timo, I have found the work in epigenomics extremely interesting. Seems our DNA does not stop developing upon birth, as has always been believed. What we ingest in childhood will have an effect on our epigenome and, in fact, can impact several generations of our descendants.

Here's an article from Discover Magazine that I read on the subject last year.

DNA Is Not Destiny

Happy reading!

Many hugs,