Genetic variations with CCSVI

L · Post by L » Sat Aug 14, 2010 2:43 am

Here is a paper from the university of Ferrara on the subject of genetic variations and venous malformations.

They conclude:

The CNVs [copy number variations] contained in the HLA locus region in patients with the novel phenotype of CCSVI/VM and MS were mapped in detail, demonstrating a significant correlation between the number of known CNVs found in the HLA region and the number of CCSVI-VMs identified in patients. Pathway analysis revealed common routes of interaction of several of the genes involved in angiogenesis and immunity contained within this region. Despite the small sample size in this pilot study, it does suggest that the number of multiple polymorphic CNVs in the HLA locus deserves further study, owing to their possible involvement in susceptibility to this novel MS/VM plus phenotype, and perhaps even other types of the disease.

1eye · Post by **1eye** » Sat Aug 14, 2010 9:46 am

Did you tell cheerleader/alliance about it? sounds like one for the books.

L · Post by L » Sat Aug 14, 2010 10:17 am

1eye wrote:Did you tell cheerleader/alliance about it? sounds like one for the books.

Perhaps I should. It's a few months old mind you.

Cece · Post by **Cece** » Sat Aug 14, 2010 10:52 am

Cheer herself posted this a while back. It's huge, in my opinion! A genetic assocation between MS and vascular malformations. Maybe it should be our number one response to all the naysayers.

cheerleader · Post by **cheerleader** » Sat Aug 14, 2010 11:47 am

Yup--thanks for reposting, L. It's on the Alliance website. I agree, Cece, this is the most compelling evidence out there.

I actually heard Dr. Ferlini speak in Bologna regarding this study last September. She totally talked over my head....but I was happy to hear from doctors in attendance that hers was the most complex presentation. It's very interesting to see venous malformations and MS share copy number variants on the HLA locus already definitively associated with MS.

Here's the whole paper for DNA geeks --

http://www.fondazionehilarescere.org/pd ... -final.pdf

cheerleader · Post by **cheerleader** » Sat Aug 14, 2010 12:02 pm

Here are my notes from Dr. Ferlini's presentation last September in Bologna.
http://www.facebook.com/note.php?note_id=131482162210

Dr. Alessandra Ferlini- geneticist at Universite deglie Studi di Ferrara
SNPs are single nucleotide polymorphisms- and they reveal a multi-loci susceptibility to MS. The 4 specific loci are MS1, MS3, MS4, MS2. These are the chromosomes most linked to MS

Genetics is still questioned in this research, since there are undefined environmental factors.

Genome inflation- a characteristic of SNPs may hamper the true definition of identified genetic loci by SNP association. More studies are needed.

Interactome- the interaction of phonemics, genomics, preteomic, metabolic studies- all together-
This is done in genomic studies using CGH array rather than SNPs

The Ferrara study looked at CNVs (copy number variations) of chromosome 6p21.32 (HLA locus) in CCSVI patients.
CGH verified the occurrence of CNVs in the major locus of MS patients.
15 unrelated CCSVI patients were tested. No relation between the topography of CNVs and phenotype were shown....
but there was a significant relation between the number of extragenic CNVs and the phenotype correlated with venous malformations.

HSPAIL, HSPIA, HSPIB (heat shock proteins) were related to angiogeniesis and immunity. HLADLAZ and CD4 are involved in proinflammatory disease and tumor angiogensis. There are multiple gene disorders, and environment has a large influence.

The genome imbalance may be sensitive to environmental factors.

There was a significant correlation between the number of CNVs and the number of venous malformations. The number of polymorphic CNVs in the HLa region linked to MS does correlate with the number of venous malformations in MS patients.

This is a new way to study genetic disorders- to look for mutations on more than one genome. It is a very complex system, and cannot be narrowed to one genome.

Dr. Frohman asks if this has been tested in families? Are there genes affected in relatives with other autoimmune diseases?

Dr. Ferlini answers that this is a pilot study, and it is the first time looking at this paradigm. Future testing will look at families.

Dr. Lee comments that we have much genetic data on lymphatic malformation, yet no studies on the genetics of venous malformation. The veno-lymphatic systems need to be brought together. They have been separated and we need more venous information.

Dr. Ferlini comments that a similar phenotype can involve many genes, it depends on how they interact in the pathway. We need to locate many genes and understand how they interrelate, when they switch on and off, and how they interact in polygenetic disorders.

selkie · Post by **selkie** » Sat Aug 14, 2010 12:23 pm

I'm sorry this is way over my head - (thanks CeCe for putting it in plain English).

Is this discovery the beginning of proof that MS & CCSVI are genetically inherited disorders? Or am I completely misunderstanding the significance?

I'd wondered if CCSVI birth defects were the cause of something that happens to the fetus in the womb, like say having a mother that smokes or has a nutritional deficiency or whatever else causes birth defects. But does this mean it's actually inherited thru ancestry?

And what does this imply for gene therapy (another topic I know zero about but am wondering).

Sorry for being thick & asking stupid questions - MS brain here.

L · Post by L » Sat Aug 14, 2010 12:23 pm

I knew you'd have read it! I saw it on a blog and the author must have reposted from your Facebook post,,

cheerleader · Post by **cheerleader** » Sat Aug 14, 2010 12:35 pm

selkie wrote:I'm sorry this is way over my head - (thanks CeCe for putting it in plain English).

Is this discovery the beginning of proof that MS & CCSVI are genetically inherited disorders? Or am I completely misunderstanding the significance?

I'd wondered if CCSVI birth defects were the cause of something that happens to the fetus in the womb, like say having a mother that smokes or has a nutritional deficiency or whatever else causes birth defects. But does this mean it's actually inherited thru ancestry?

And what does this imply for gene therapy (another topic I know zero about but am wondering).

Sorry for being thick & asking stupid questions - MS brain here.

Selkie--it's WAY over my head, too....but I wanted to post it here, so that the folks that do understand this, have it.

Basically, Dr. Ferlini and her team found a very strong association between MS and venous malformations. Dr. Zamboni and vascular specialists from 47 nations, headed up by Dr. B.B. Lee of Georgetown University, have written a consensus document, stating that the venous malformations found in pw CCSVI look to be truncular venous malformations. These are congenital, meaning you are born this way.

Dr. Ferlini's research adds to this. It shows that MS and venous malformations are related, in fact, the mutation in genes associated with both happens on the same locus (place) in the same gene....one that is already associated with MS --chromosome 6p21.32 (HLA locus)

So....what this genetic research is doing is confirming the link between people who develop MS, and people who are born with venous malformations. This may be a coincidence, or it may be much more. We currently do not have any procedures that can address venous malformations in utero, or any genetic treatments. BUT we know how to take care of truncular venous malformations in other parts of the body (like those found in Budd Chiari), with angioplasty and venous surgery.

L---it's been surreal seeing my writing show up on random blogs and websites, always uncredited, and in some cases other people putting their names on it. Whatever. As long as the info gets out there, I guess. I ain't getting paid anyway

cheer

1eye · Post by **1eye** » Sat Aug 14, 2010 12:57 pm

cheerleader wrote: L---it's been surreal seeing my writing show up on random blogs and websites, always uncredited, and in some cases other people putting their names on it. Whatever. As long as the info gets out there, I guess. I ain't getting paid anyway
cheer

It means you have joined the immortals. Your work will be in many dictionaries, encyclopedias, and anthologies, always listed as 'unattributed'.

But a select few will know.

L · Post by L » Sat Aug 14, 2010 1:26 pm

cheerleader wrote:L---it's been surreal seeing my writing show up on random blogs and websites, always uncredited, and in some cases other people putting their names on it. Whatever. As long as the info gets out there, I guess. I ain't getting paid anyway
cheer

Well, you are doing a fantastic job. If it weren't for your efforts news of Zamboni's work would not have reached as many people, perhaps none of us, at least not this fast, so thank you.

orion98665 · Post by **orion98665** » Sat Aug 14, 2010 2:38 pm

Cheerleader, i can't thank you enough for being such a supporter
of this forum and the CCSVI alliance; your work is greatly appreciated.

Cece · Post by **Cece** » Sat Aug 14, 2010 3:11 pm

I wish I knew how to make this a 'shortened url', I will figure that out.

<shortened url>

This is a link to the internation ms genetic consortium project. They gathered data on the entire genome of many MS patients and families (3000 subjects total). Dr. Stephen Hauser was one of the principal investigators. If ccsvi researchers could use this data to add to the proof of the vascular nature of CCSVI in MS patients that would be lovely lovely irony.

Part of why we can't just toss out the autoimmune hypothesis altogether is because there is evidence that people with MS have abnormalities in areas of the genome known to be associated with the immune system. But now with the paper L posted, there is the double-edged sword for anyone holding too tightly to the autoimmune hypothesis alone: evidence that people with MS also have abnormalities in the HLA area known to be responsible for vascular formation. It's huge.

CureIous · Post by **CureIous** » Sat Aug 14, 2010 6:10 pm

My Dr. has a part time assistant with twins, one with MS. Both full grown adults. The other has suddenly begun (not sure how long the first has had MS) to develop neurological symptoms.

What I wouldn't give for a full set of scans on both of them, including SWI, might just see CCSVI in progress...

Hopefully the Mom will contact me soon so I can at least point her in the right direction(s). Loved my Dr's comment on Thursday, he said, "well I can see you here right now, I SEE the difference from last year, it's incredible!". My Dr. is cool like that, pretty much seen it all so when something like this comes along he gets a bit excited...

I hope that someday at least 85-90% of PWMS can be easily classified into different diseases, some strictly genetic, some in the structural defect category inc. valves and vetebrae impingment. Combo's of both.

Thinking of what they may be able to do with a mouth swab on a youngster years before the damage is done...

selkie · Post by **selkie** » Sat Aug 14, 2010 7:43 pm

Thank you Cheerleader, that helped me understand much better and I do appreciate you taking the time to break it down for me.

I find this fascinating - and I'm only sorry I didn't take more interest in the biological sciences when I was in college.

I'm wondering if they'll be able to pinpoint if this is a defect that develops while the fetus is in the womb or are the genetic defects hereditary, or possibly both. I have high hopes that someday - most likely after my time on this planet - gene therapy will be come a reality.

In the meantime, I'm hoping this will support the evidence that CCSVI liberation treatment is a reasonable option for people with these malformations - and that our various country's healthcare plans should pay for that treatment as they do for any other medical intervention.

Thank you again - exciting information!

selkie