This Is MS Multiple Sclerosis Knowledge & Support Community

The Letter in Nature that the CTV News item refers to is entitled "Genetic risk and a primary role for cell-mediated immune mechanissms in multiple sclerosis" (Nature, 476, 11 Aug 2011, pp214 - 219) summarizes the findings of this large genome study as follows:

"More generally, our study reinforces the view that the GWAS design, combined with very large experimental sample sizes and careful statistical analysis, provides valuable insights into the genetic architecture of common complex diseases. Here, this approach has identified many associated genetic variants close to genes, which are both individually interesting and collectively illuminate the roles of key biological pathways. It also provides indirect evidence that many more common variants of small effect contribute to genetic susceptibility for multiple sclerosis. Simple models, in which the previously known and newly identified variants affect risk multiplicatively, both within and across loci, explain a meaningful proportion (~20%, see Supplementary Information) of genetic risk for the disease. Important challenges lie ahead in understanding overlap between the genetic basis for susceptibility in the context of different autoimmune diseases, and in uncovering the functional mechanisms underlying these associations."

I leave it to the reader to determine if the CTV News item reflects this summary. I could find no reference in the Nature article to vein obstruction clearance.

indirect evidence that many more common variants of small effect contribute to genetic susceptibility for multiple sclerosis. Simple models, in which the previously known and newly identified variants affect risk multiplicatively, both within and across loci, explain a meaningful proportion (~20%, see Supplementary Information) of genetic risk for the disease

I'm still convinced about venoplasty, and don't want to wait for someone to figure out how to change my (maybe) contributing genetics.

Does that mean 80% of genetic risk remains unexplained?

I posted these in the other thread on this Nature research, it's initial genetics research in CCSVI and MS.

http://ccsvism.xoom.it/ISNVD/Abstract-Gemmati.pdf

www.biomedcentral.com/1471-2350/11/64

There has long been a link (albeit perhaps a weak one) associating genetics to MS. The language in the Nature Letter earlier this week doesn't seem to run counter to that. It may simply be that some dedicated Neurologists pick up a new bit of scientific evidence and interpret the results in a black and white frame. On the other hand there are many Neurologists who suspect MS etiology is a consequence of a number of contributing factors. That the media picks up a black and white interpretation and perhaps accentuates it further may simply be a part of the media process.

ttucker

I want to pick up on your comment:

There has long been a link (albeit perhaps a weak one) associating genetics to MS

I quite agree with you. I don’t post often anymore but I feel compelled to post my nonscientific perspective on the relative importance of genetics in determining who actually develops MS. I do believe that there is a genetic susceptibility to MS, however, what I want to know: does that genetic susceptibility play a relatively small or relatively large role in determining who actually develops MS?

The most recent research (abstract here) according to two MS experts proves the cause of MS. I seriously doubt that.

From the abstract:

Within the MHC we have refined the identity of the HLA-DRB1 risk alleles…….Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

That’s all well and good and I understand that this most recent research confirmed the HLA DRB1 risk alleles as still being the most important genetic susceptibility risk factor(s) for MS identified thus far.

Just how important is HLA DRB1? According to one expert in a model of genetic susceptibility to MS, the HLA DRB1 locus may not be nearly as important as most people think.
The genetic basis of multiple sclerosis: a model for MS susceptibility

The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed.

Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility" at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't.

Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction (≤ 5.2%) are even susceptible to getting MS.

I would add, that doesn’t mean they are ever diagnosed with MS, only that about 5% of people with HLA DRB1are susceptible to being diagnosed with MS.

Further, the NMSS write up on the most recent research states in part: here

…They also identified 29 new genetic variants associated with MS risk albeit with small effects (as well as five variants with a suspected association with MS).

In addition, last October, before this most recent research was published, there was this perspective:
Genes associated with MS: 15 and counting

in a study by the International Multiple Sclerosis Genetics Consortium, the classic MS risk locus, HLA-DRB1, stood out with remarkably strong statistical significance, but they also identified 12 other loci and/or genes associated with MS. However, all of these alleles have a very modest odds ratio and they explain approximately 3% of the variance in MS risk.

There’s also this from the International Consortium of Genetics in MS from 2010,
Evidence for polygenic susceptibility to multiple sclerosis--the shape of things to come

The collective effect of 12,627 SNPs…..in our discovery GWAS set optimally explains approximately 3% of the variance in MS risk in our independent target GWAS set, suggest that the risk alleles identified to date represent just the tip of an iceberg of risk variants likely to include hundreds of modest effects and possibly thousands of very small effects

My point is really, genetic susceptibility to MS is but one, and in my opinion, thus far, even with the new research, a relatively small risk factor in determining who actually is diagnosed with MS.

It’s also interesting to note (from the actual research article itself),

We found no evidence for genetic associations with clinical course, severity of disease or month of birth, and no evidence of interaction with gender or DRB1*15:01 in any part of the genome

If the genetic susceptibility immunity genes for MS are not associated with clinical course, severity of disease, month of birth or interact with gender, one has to ask how relevant are these newly discovered immunity MS genes to the MS disease process? I mean really, if they don’t impact clinical course, severity of disease, or interact with gender, and it seems to be fact that MS is overwhelmingly a disease of women…2 or 3 to 1 depending on who you read and increasing in women, common sense makes me ask: how can you argue that there’s a significant relationship of these new immune genes to the disease of MS? And don’t forget even the NMSS noted these new genes have a small effect.

Further, according the NMSS, at least 1/3, are not specific to MS.

Most of the genes implicated in the study were related to immune function, and more than one-third have previously been confirmed to be associated with autoimmune diseases. In a second study published in PLoS Genetics (2011;7[8]),

1/3rd related to other autoimmune diseases and this makes MS autoimmune, really? A 1/3rd non specific disease association makes MS autoimmune?

Enough of my soap box on this and of course there's the info from Cheer on the overlap of immune genes with vascular issues. I just think it’s important to have a broader perspective on these research findings and I must say it seems to me that the genetic susceptibility risk for MS, albeit present, really seems to be a rather small segment of the overall risk for MS.

You may be right ttucker, perhaps it's all part of the media process.

Take care all…rock on.

Sharon

Shayk, I am going to read through all that in the morning, it looks good....

That the media picks up a black and white interpretation and perhaps accentuates it further may simply be a part of the media process.

I wanted to respond to this, since I first learned of CCSVI at around the time of the CTV special in Canada (which I remember watching in shock), that it has been an education seeing how the media has dealt with CCSVI.