CCSVI not associated with HLA DRB1*1501 status?

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

CCSVI not associated with HLA DRB1*1501 status?

Postby MSUK » Tue Feb 15, 2011 9:02 am

Study suggests CCSVI not associated with HLA DRB1*1501 status in MS patients

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Abstract

Background
Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients.... Read More - http://www.msrc.co.uk/index.cfm/fuseact ... ageid/2944
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Postby cheerleader » Tue Feb 15, 2011 9:50 am

Here's the abstract-


Background
Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients.

Methodology/Principal Findings
This study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR = 4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group. The 51.9% frequency of HLA DRB1*1501 positivity (HLA+) in MS was higher compared (OR = 2.33, p<0.001) to 31.6% to controls. The HLA+ frequency in the non-progressive (51.6%) and progressive MS groups (52.3%) was similar. The frequency of HLA+ CCSVI+ was 40.7% in progressive MS, 27.5% in non-progressive MS and 8.4% in controls. The presence of CCSVI was independent of HLA DRB1*1501 status in MS patients.

Conclusions/Significance
The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS.


I find this abstract to be a bit misleading. There was a correlation with HLA frequency in MS and CCSVI ....53% in MS and around 40% in CCSVI. What I find incredibly odd is that the HLA % is HIGHER in controls (32%) than CCSVI is in controls (21%)...yet they have no problem stating the HLA is associated with MS, but CCSVI is not (?)

The title of the abstract is CCSVI is NOT associated with HLA DRB 1501 status
This is a very conclusive statement, for inconclusive results. And what I fear is that it will be taken as another negative study to add to the neurological pile, when actually, the information and complete paper was more nuanced than the abstract.

Here's more from the paper---
Other than the report of Ferlini et al. [13], who conducted preliminary analysis of copy number variations associated with CCSVI in a group of 15 MS patients, no information is available on the role of genetic factors in CCSVI. These authors reported that CCSVI was associated of copy number variations in the HLA region for a small group of 15 MS patients [13]. In other diseases with venous pathophysiologies, a role for gender, and environmental and genetic factors is suggested. Female gender, older age, and pregnancy are risk factors for chronic venous diseases [24] and women have greater frequency of variant hepatic veins [25]. Women have also been reported to have a smaller internal jugular vein size than men (1.48 for men vs. 1.27 in women) [26]. Venous malformations may have genetic contributions and a “double-hit” mechanism has been invoked to explain incomplete penetrance and variability [27], [28]. The R849W substitution in the angiopoietin receptor Tie2 [29], an endothelial receptor tyrosine kinase, has been linked to familial venous malformations and results in variable thickness or lack of smooth-muscle cells in the veins of patient lesions. Interestingly Tie2 activates Stat1, which is also critical in interferon signaling. We did not observe, age, gender or disease duration differences in the occurrence of CCSVI (results not shown) in MS. However, a more detailed analysis of candidate gender-dimorphic factors, e.g., vein diameters and autoimmune factors, is warranted as these could strongly interact with changes in cerebral venous outflow.

Here's the complete paper:
http://www.plosone.org/article/info:doi ... ne.0016802

Here's Ferlini's independent research showing correlation of copy number variations in MS and venous malformations on the HLA locus--

The CNVs 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.

http://www.biomedcentral.com/content/pd ... -11-64.pdf
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Postby scorpion » Tue Feb 15, 2011 11:41 am

I am not sure why you consider this study to be misleading. The researchers tested a large number of people and concluded from the data that CCSVI is NOT associated with HLA DRB 1501 status. Study after study continues to call into question Zamboni's original CCSVI hypothesis and certainly brings into doubt his original findings which no study has even gottn close to validating. Instead of skepticim these studies seem to continually elicite "damage control" which is unfortunate for all of us trying to make sense of this chaos. If anyone can break down, in layman terms, what this study actually proves without throwing in their own "spin" it would be greatly appreciated. Patientx?? Any objective science buffs out there???
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Postby cheerleader » Tue Feb 15, 2011 1:25 pm

scorpion wrote:I am not sure why you consider this study to be misleading. The researchers tested a large number of people and concluded from the data that CCSVI is NOT associated with HLA DRB 1501 status. Study after study continues to call into question Zamboni's original CCSVI hypothesis and certainly brings into doubt his original findings which no study has even gottn close to validating. Instead of skepticim these studies seem to continually elicite "damage control" which is unfortunate for all of us trying to make sense of this chaos. If anyone can break down, in layman terms, what this study actually proves without throwing in their own "spin" it would be greatly appreciated. Patientx?? Any objective science buffs out there???


Scorpion-
I know you don't like me, or my scientific "spin", and I could frankly care less, but the final paragraph and the last sentence I highlighted is not the same thing as the title of this paper. And that is an objective observation. Read the entire paper, like I did.

Dr. Zamboni did not test for HLA DRB 1501, he found venous malformations and reflux in vivo. Dr. Ferlini tested venous malformations and the HLA locus, and found a correlation in CNVs.

If the specific loci of HLA DRB 1501 is only found in 53% of pwMS anyway....why is this even an issue?
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Numbers

Postby fiddler » Tue Feb 15, 2011 1:41 pm

Scorpion, the numbers provided in the paper contradict its title. The correlation of HLA DRB 1501 status with CCSVI is almost 5 times as high as for normals (40.7% versus 8.4%). Therefore the title is COMPLETELY misleading and cheerleader is right. If you are going to be a skeptic, great, but then at least do your homework. You get an "F" for this one, as should the authors and/or the journal editor.
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Postby cheerleader » Tue Feb 15, 2011 1:43 pm

Here, in layman's terms-- I'll make it clear.

Having HLA-DRB 1501, which is a genetic marker that shows up in northern Europeans, increases your risk for having MS by three-fold.

A region at or near the HLA-DRB1 locus in the MHC influences the risk of MS. HLA-DRB1 has over 400 different alleles. The dominant haplotype of Northern Europe, marked by the presence of DRB1*1501, increases risk of MS by 3-fold. The environment also plays a key role in MS. The most striking illustration of this is the geographical distribution of the disease in populations matched for ethnicity.


http://www.plosgenetics.org/article/inf ... en.1000369

This means that this locus is associated with risk of getting MS. It doesn't mean it causes MS, or it's always found in pwMS....it just means that this particular allele makes you more susceptible to getting MS. And lots of things come into play, like environmental issues, or where you live.

It's like saying, (and this is a made up, for-instance) people from northern Europe have 3 times the risk of getting MS than people from Central America. That doesn't mean you can't get MS if you live in Brazil, and it doesn't mean you will get MS if you live in Ireland. It's just a way of looking at the genome and MS risk. OK?

OK, are we clear so far?...so, the Buffalo doctors looked for this particular genetic marker in their patients. They found it in 53% of the pwMS they tested. They found it in 33% of the people with CCSVI. They also found it in a third of the normal population.

So? So what? They found a marker that is associated with northern Europeans that can increase risk of MS. It was more prevalent in pwMS than pwCCSVI by 20%. But, it was also found in 30% of normals....

this is not a negative study that disproves anything about CCSVI, this is an interesting study that needs more research, according to the last paragraph of the paper.

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Re: Numbers

Postby scorpion » Tue Feb 15, 2011 2:09 pm

fiddler wrote:Scorpion, the numbers provided in the paper contradict its title. The correlation of HLA DRB 1501 status with CCSVI is almost 5 times as high as for normals (40.7% versus 8.4%). Therefore the title is COMPLETELY misleading and cheerleader is right. If you are going to be a skeptic, great, but then at least do your homework. You get an "F" for this one, as should the authors and/or the journal editor.
...Ted


If you would have taken the time to fully read my post you would see I was asking someone to explain this study since I was not familar with some of the terminology. I would work harder at doing my homework but I am afraid if I did not give the answers the teacher wanted to hear I would get my knuckels smacked.
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Students who don't work

Postby fiddler » Tue Feb 15, 2011 2:47 pm

Yes, I've heard that excuse for not doing homework before... pretty sad, really.
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Postby cheerleader » Tue Feb 15, 2011 3:21 pm

For those not familiar with the genetic markers for MS--who would like to learn more-- this is a good paper explaining how the HLA -DRB allele shows up in different genetic populations, and doesn't always correspond with MS rates in that population.

For instance, from the paper: The island of Sicily has high MS rates, but low rates of HLA-DRB 1501 frequency. Malta has high HLA-DRB 1501 rates, yet low prevelance of MS.

link

Genetics and MS is a very complex issue. The Buffalo study was looking at American patients, a very ethnically and genetically diverse population. It strikes me as odd that the title and conclusion of this study are so decisively negative in nature as to CCSVI and MS correlation, when the science is inconclusive, at best.

After reading all of the above, I again submit, the conclusion in the abstract of the study (which is all many doctors read) is incredibly misleading:
The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution.
Last edited by cheerleader on Tue Feb 15, 2011 5:10 pm, edited 1 time in total.
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Re: Students who don't work

Postby scorpion » Tue Feb 15, 2011 4:40 pm

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Last edited by scorpion on Tue Feb 15, 2011 4:58 pm, edited 1 time in total.
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Postby MrSuccess » Tue Feb 15, 2011 4:53 pm

so .... a well explained answer ... is considered going into ''an attack mode '' .


Go figure . Thanks for bringing Ringleaders methods to light ...... :wink:







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Postby scorpion » Tue Feb 15, 2011 5:03 pm

It seems that what pretty much is being established is that CCSVI does not cause MS. Noooooo I am not saying that conclusively but that seems to be what studies are pointing towards. So if CCSVI is a result of MS the question that should be asked is whether treating it has any impact on symptoms.
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Re: Students who don't work

Postby cheerleader » Tue Feb 15, 2011 5:06 pm

scorpion wrote:The study above is another study that did not find the results one would expect if Zamboni's original hypothesis is correct and prior to that there were three or four studies calling into question his hypothesis.


Your statement is not true.

This study has nothing to do with his hypothesis, which is that CCSVI is found in pwMS.
The allele HLA-DRB 1501 is a gene related to northern Europeans genetic make-up.
It is an MS susceptibility gene and an immune response gene. It does not cause MS. It only increases susceptibility. Why should it be directly related to CCSVI?

People who live in Sardinia have MS, but do not have the specific allele HLA-DRB 1501. Does that mean people in Sardinia do not have MS? No, it means this gene is only ONE factor in susceptability.

47% of the pwMS screened in Buffalo did not have this allele. Does that mean they do not have MS? No.

The study doesn't prove anything about CCSVI. It is not a negative study against the viability of CCSVI. It is only more smoke.
Last edited by cheerleader on Tue Feb 15, 2011 5:27 pm, edited 1 time in total.
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Re: Students who don't work

Postby scorpion » Tue Feb 15, 2011 5:23 pm

cheerleader wrote:
scorpion wrote:The study above is another study that did not find the results one would expect if Zamboni's original hypothesis is correct and prior to that there were three or four studies calling into question his hypothesis.


Your statement is not true.

This study has nothing to do with his hypothesis, which is that CCSVI is found in pwMS.
The allele HLA-DRB 1501 is a gene related to northern Europeans genetic make-up.
It is an MS susceptibility gene. It does not cause MS. It only increases susceptibility. Why should it be directly related to CCSVI?

People who live in Sardinia have MS, but do not have the specific allele HLA-DRB 1501. Does that mean people in Sardinia do not have MS? No, it means this gene is only ONE factor in susceptability.

47% of the pwMS screened in Buffalo did not have this allele. Does that mean they do not have MS? No.

The study doesn't prove anything about CCSVI. It is not a negative study against the viability of CCSVI. It is only more smoke.


This ONE study may not disprove some things about CCSVI but it adds to the growing evidence that shows there is not a strong relationship between early MS/CIS and CCSVI and it certainly starts to make it look like CCSVI is secondary to MS. To disregard this and other trials as "smokescreens" does not help us get to the truth about the real role CCSVI does or does not play in MS. Has it become more important to prove only what you want to believe(CCSVI causes MS.period) than to get to the truth?
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Postby thornyrose76 » Tue Feb 15, 2011 7:52 pm

In other words we need to find out why an individual goes from being unable to walk and stand, or walk properly and then post anngioplasty walks normally like Denise Manley, Linda Rousey. And placebo is a cop out in regards to these results.
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