MS risk genes identified

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Postby Nemotoday » Mon Jul 30, 2007 1:44 pm

another Cambridge breakthrough...........

New MS genes after 30 year hunt

Many genes are thought to play a role in MS
The first new genes for three decades linked to multiple sclerosis have been
identified by UK and US researchers.
Approximately 60,000 people in the UK suffer from the incurable disease of
the nervous system.

The finding, published in two journals, will not lead directly to new tests
or treatments, as experts say as many as 100 more genes may play a role in
MS.

However, a Cambridge University researcher said he now expected swifter
progress to reveal them all.

The joint project used the latest genome-scanning technology to look at the
genetic make-up of thousands of MS patients, looking for signs of tiny
genetic differences which might mean a greater risk of developing the
illness.

It concluded that people carrying either of two genetic variants, called
IL7R-alpha and IL2R-alpha, had an increased risk of between 20% and 30%.

No test

Dr Stephen Sawcer, from Cambridge University, said that even though this
only represented a tiny increase in risk, it was a "landmark" discovery.

"This ends 30 years of complete frustration," he said. "But now we finally
have the technology we need to help us find these genes."


These finds are the first of many, and after three decades finding nothing,
we would expect to find many more of these genes over the next few years
Dr Stephen Sawcer, Cambridge University

A test for this gene alone would reveal nothing about a person's chances of
developing MS later in life, he said, as only one in 10 people in the UK did
not carry it.

"We estimate that there are between 50 and 100 other genes which carry an
additional risk.

"These finds are the first of many, and after three decades finding nothing,
we would expect to find many more of these genes over the next few years."

It was only once many more "MS genes" were revealed, he said, that
scientists would then be able to identify people carrying large numbers of
them and examine what other factors might be triggering their illness.

Both of the genes identified by the research are known to have a role in the
body's immune responses.

MS is caused when the immune system wrongly attacks the sheaths surrounding
the nerves, destroying them and the body's ability to send signals along
them.

This leads to muscle weakness, difficulties with balance and speech and
vision problems.

Joint effort

The Harvard Center for Neurodegeneration and Repair was one of several US
universities and research institutes which worked together on the project.

Adrian Ivinson, its director, said: "This study illustrates the power of
collaboration - individually, none of us could have completed a study of
this scale and complexity."

Dr Lee Dunster, head of research and information at the MS Society, welcomed
the publication of the studies in the journals Nature Genetics and the New
England Journal of Medicine

He said: "One of the great unknowns about MS is what causes it and this
looks like a welcome breakthrough in getting to grips with the genetics
behind the disease.

"People with MS often worry about what caused it, and particularly whether
it will affect their children, so a better understanding of the role of
certain genes is good news.

"These latest findings will be of great interest to researchers trying to
develop future treatments."

The research is published in the New England Journal of Medicine and Nature Genetics.
Keep smiling as who knows what good things might be around the corner and if the road snakes a bit keep going.
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Postby bromley » Tue Jul 31, 2007 2:59 am

The Accelerated Cure Project has produced a summary of what this all means (and some conclusions).

http://www.acceleratedcure.org:8080/node/2783
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Postby viper498 » Tue Jul 31, 2007 6:30 am

Ian,

What a fantastic Data Miner you are!!!

Brock
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Postby HarryZ » Tue Jul 31, 2007 6:38 am

One point that may be missed in some of the news reports describing these studies is that the variants that were associated with MS are very common in the general population. Also, the frequencies in the people with MS were not that much higher than in the controls. For instance, one of the papers (Gregory et al) reports that the IL7R variant associated with MS was found in 76-78% of the MS subjects vs. 72-73% of the control subjects. This is still a statistically significant difference, but not a large one in absolute terms.


You have to wonder why this information didn't make it into a number of different versions of the press release. While the gene discovery was significant for the genetic scientists, I'm still trying to figure out what it really means for MS patients.

Also, for those (such as us at Accelerated Cure Project) who are looking for the gene-gene and gene-environment interactions that are necessary in the development of MS, these results signify good starting points.


Like I said yesterday, there is a huge amount of work involved in making this discovery work in solving the mystery of MS.

Harry
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Postby dignan » Tue Jul 31, 2007 9:17 am

Here are a couple of Pubmed abstracts on these studies:


Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis.

Nat Genet. 2007 Jul 29;
Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallström E, Khademi M, Oturai A, Ryder LP, Saarela J, Harbo HF, Celius EG, Salter H, Olsson T, Hillert J.
Division of Neurology, Department of Clinical Neuroscience, Karolinska Institutet at Karolinska University Hospital–Huddinge, SE-141 86 Stockholm, Sweden.

Multiple sclerosis is a chronic, often disabling, disease of the central nervous system affecting more than 1 in 1,000 people in most western countries. The inflammatory lesions typical of multiple sclerosis show autoimmune features and depend partly on genetic factors. Of these genetic factors, only the HLA gene complex has been repeatedly confirmed to be associated with multiple sclerosis, despite considerable efforts. Polymorphisms in a number of non-HLA genes have been reported to be associated with multiple sclerosis, but so far confirmation has been difficult. Here, we report compelling evidence that polymorphisms in IL7R, which encodes the interleukin 7 receptor alpha chain (IL7Ralpha), indeed contribute to the non-HLA genetic risk in multiple sclerosis, demonstrating a role for this pathway in the pathophysiology of this disease. In addition, we report altered expression of the genes encoding IL7Ralpha and its ligand, IL7, in the cerebrospinal fluid compartment of individuals with multiple sclerosis.

Pubmed link



Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis.

Nat Genet. 2007 Jul 29;
Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, Lincoln R, McCauley JL, Sawcer SJ, Compston DA, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, Haines JL; for the Multiple Sclerosis Genetics Group.
[1] Center for Human Genetics, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, USA. [2] These two authors contributed equally to this work.

Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.

Pubmed link
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What does this discovery mean to me?

Postby Smilingface » Tue Jul 31, 2007 6:07 pm

This is an amazing discovery to me because it has a significant impact for my nine and fifteen year-old. That means a lot to me.
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Postby Frank » Thu Aug 02, 2007 2:26 pm

In fact the comparison between MS patients and healthy controls isnt that convincing.

Several associations were found in the initial analysis (as you would expect given the large number of genes investigated), but the authors narrowed the field down further and highlighted two genes in particular (IL7RA and IL2RA).


That part made me think on what criteria the authors narrowed the field.
Did they maybe just go after genes that would fit the autoimmune hypothesis.

If these findings (together with the known MHC HLA2/4 variants) really represent the genetic profile that makes one predestinated to MS it would point towards an aberrence of the immune system, rather than an metabolic defect or a susceptibility to infections.
In that way might be a contribution to the inflamation vs. neurodegeneration debate.

Do you agree with me about that?

--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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Postby finn » Fri Aug 03, 2007 4:44 am

Frank wrote:Did they maybe just go after genes that would fit the autoimmune hypothesis.

Good question, Frank. IMO, the study setting seems to have been biased towards autoimmune theory. In any case, I personally don't think this study will make that much difference.

-finn
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley
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Postby HarryZ » Fri Aug 03, 2007 6:50 am

H Finn,

finn wrote:
Frank wrote:Did they maybe just go after genes that would fit the autoimmune hypothesis.

Good question, Frank. IMO, the study setting seems to have been biased towards autoimmune theory. In any case, I personally don't think this study will make that much difference.

-finn


I agree with you 100% on this comment!

If these scientists had published the genetic information discovery on its own, it would have likely gone unnoticed. Add that it could be a major breakthrough for MS, every major newswire in the world will pick it up.

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I still think it is an amazing discovery.

Postby Smilingface » Fri Aug 03, 2007 1:37 pm

Researchers went looking for a genetic marker and found it. It is a diagnostic marker, that is it. It does not mean MS is an autoimmune disease or it is not. It means if you test a child and find this marker, that child is predisposed to contracting MS. It may not be a major marker but it is still a marker.

I am willing to bet Biogen is excited that their pipeline drug zenapax targets
IL2RA. They didn't pay for the study, did they?

I'm still smiling about this discovery.
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Postby SarahLonglands » Fri Aug 03, 2007 2:56 pm

So am I! :wink:
An Itinerary in Light and Shadow Completed Dr Charles Stratton / Dr David Wheldon abx regime for aggressive secondary progressive MS in June 2007, after four years. Still improving with no relapses since starting. Can't run but can paint all day.
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Postby Frank » Fri Aug 03, 2007 3:24 pm

Smilingface,

you are right about the genes impact on predisposition.

But as the genetic configuration determins how processes in our body take place, one will know in which way MS patients act different than healthy controls.

If one thinks that IL2 (Treg cells) and IL7 (T- / B-cell proliferation) are the crucial genetic factors, one would come to the point that there is something wrong with the immunesystems regulartion.
And this could point towards the autoimmune hypothesis, wouldnt it?

In that way, understanding the genetic difference (the way MS patients program is different from healthy controls) will enhance our understanding of what causes MS.

--Frank
Treatment: Gilenya since 01/2011, CCSVI both IJV ballooned 09/2010, Tysabri stopped after 24 Infusions and positive JCV antibody test, after LDN, ABX Wheldon Regime for 1 year.
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I love thinking about genes

Postby Smilingface » Fri Aug 03, 2007 6:50 pm

Frank,

You are most definitely correct about genetic configuration determining how processes in our body take place. All life processes --- disease, normal neurological process, metabolic process, growth, healing, etc. are determined by our genes being turned off or on. Genes do a lot more than just regulate our immune system! The gene study from three different research teams was empirical, that is the study was derived from scientific data unbiased from any particular theory. It does not conclude anything about the disease process, though. It also does not mean that these two newly discovered genes are the only genes involved, or the most important genes involved.
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Postby gwa » Sat Aug 04, 2007 6:31 am

Why are some of you smiling about this discovery? Do you think it is pretty useless for the most part?


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Postby dignan » Sat Aug 04, 2007 10:13 am

I feel compelled to repost this info that I put in an earlier post in this thread. It covers the importance of this discovery quite neatly I think. I read a lot of media coverage about these studies and this "Time" story was the only one I saw that included this info about the significance of the findings. We should all be shaking our heads at the shoddy quality of medical journalism around the world.



As exciting as the discovery is, it's a small part of the story: the new genes account for less than 1% of the risk of developing MS. In addition, about 70% of the normal, non-MS affected population has the same variants. "Every single time we have looked for genes for MS, the genes turn out to have a very small effect," says Dr. Moses Rodriguez, professor of immunology at the Mayo Clinic and a leading MS researcher." That suggests that either the disease is not genetically controlled in a significant way, or that if it is, that there are at least a 100 or so more genes that account for the entire disease process."

Hafler acknowledges that these findings are only the first step. Uncovering additional genes will require analyzing an even larger pool of MS patients and their families — Hafler is hoping to find at least 9,000 more patients. He calculates that with that much DNA, he'll be able to tease out 90% of the genetic culprits involved in MS. "These first genes give us a working hypothesis for what may be causing MS," says Hafler, "and a lot more work needs to be done. But we have finally begun."

http://www.time.com/time/health/article ... 40,00.html
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