Zamboni research: genetic difference in PPMS compared to RR

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Zamboni research: genetic difference in PPMS compared to RR

Postby Cece » Sat Aug 11, 2012 10:07 am

http://www.biomedcentral.com/content/pd ... -13-70.pdf
Polymorphisms in the genes coding for iron binding and transporting proteins are associated with disability, severity, and early progression in multiple sclerosis

Donato Gemmati, Giulia Zeri, Elisa Orioli, Francesca E De Gaetano, Fabrizio Salvi, Ilaria Bartolomei, Sandra D’Alfonso, Claudia Dall’Osso, Maurizio A Leone, Ajay V Singh, Rosanna Asselta and Paolo Zamboni

BMC Medical Genetics 2012, 13:70 doi:10.1186/1471-2350-13-70
Published: 10 August 2012
Abstract (provisional)

Background

Iron involvement/imbalance is strongly suspected in multiple sclerosis (MS) etiopathogenesis, but its role is quite debated. Iron deposits encircle the veins in brain MS lesions, increasing local metal concentrations in brain parenchyma as documented by magnetic resonance imaging and histochemical studies. Conversely, systemic iron overload is not always observed. We explored the role of common single nucleotide polymorphisms (SNPs) in the main iron homeostasis genes in MS patients.

Methods

By the pyrosequencing technique, we investigated 414 MS cases [Relapsing-remitting (RR), n=273; Progressive, n=141, of which: Secondary (SP), n=103 and Primary (PP), n=38], and 414 matched healthy controls. Five SNPs in 4 genes were assessed: hemochromatosis (HFE: C282Y, H63D), ferroportin (FPN1: -8CG), hepcidin (HEPC: -582AG), and transferrin (TF: P570S).

Results

The FPN1-8GG genotype was overrepresented in the whole MS population (OR=4.38; 95%CI, 1.89-10.1; P<0.0001) and a similar risk was found among patients with progressive forms. Conversely, the HEPC -582GG genotype was overrepresented only in progressive forms (OR=2.53; 95%CI, 1.34-4.78; P=0.006) so that SP and PP versus RR yielded significant outputs (P=0.009). For almost all SNPs, MS disability score (EDSS), severity score (MSSS), as well as progression index (PI) showed a significant increase when comparing homozygotes versus individuals carrying other genotypes: HEPC -582GG (EDSS, 4.24+/-2.87 vs 2.78+/-2.1; P=0.003; MSSS, 5.6+/-3.06 vs 3.79+/-2.6; P=0.001); FPN1-8GG (PI, 1.11+/-2.01 vs 0.6+/-1.31; P=0.01; MSSS, 5.08+/-2.98 vs 3.85+/-2.8; P=0.01); HFE 63DD (PI, 1.63+/-2.6 vs 0.6+/-0.86; P=0.009). Finally, HEPC -582G-carriers had a significantly higher chance to switch into the progressive form (HR=3.55; 1.83-6.84; log-rank P=0.00006).

Conclusions

Polymorphisms in the genes coding for iron binding and transporting proteins, in the presence of local iron overload, might be responsible for suboptimal iron handling. This might account for the significant variability peculiar to MS phenotypes, particularly affecting MS risk and progression paving the way for personalized pharmacogenetic applications in the clinical practice.
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Re: Zamboni research: genetic difference in PPMS compared to

Postby cheerleader » Sat Aug 11, 2012 11:09 am

It's really an interesting study, isn't it? It may give us more insight into why PPMS has more neurodegeneration and iron deposition than RRMS.

PPMS had varients in the hepcidin promoter--582AG--also implicated in iron overload in thalassemia major.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738723/
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Re: Zamboni research: genetic difference in PPMS compared to

Postby Daisy3 » Sat Aug 11, 2012 1:51 pm

Can we do something to reduce the iron load? Is that possible? I know that people with Thallasemia do it all the time..
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Re: Zamboni research: genetic difference in PPMS compared to

Postby Cece » Sat Aug 11, 2012 2:06 pm

What do people with thallesemia do? I know for MS some people have donated blood regularly or have it drawn and discarded, and drinking green tea or taking supplements for its iron-chelating properties and ability to cross the blood brain barrier.

Definitely an interesting study. I am still thinking it through! The differences in disease course between people with RR and SP and PP is so fundamental to this disease, and little to nothing is known as to why we get which one we get.
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Re: Zamboni research: genetic difference in PPMS compared to

Postby Daisy3 » Sat Aug 11, 2012 3:41 pm

People with Thalassaemia major have blood Transfusions on a very regular basis. Too cope with the iron overload that the transfusions cause these patients remove iron from their body using medication.
The iron overload has to be managed or it kills organs in the body.

Really wonder if this could help:-/
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Re: Zamboni research: genetic difference in PPMS compared to

Postby Cece » Sat Aug 11, 2012 5:24 pm

ok, looking up on wikipedia, this brings us back to beet juice or deferoxamine, an iron chelator.
http://en.wikipedia.org/wiki/Thalassemia
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Re: Zamboni research: genetic difference in PPMS compared to

Postby Daisy3 » Sat Aug 11, 2012 5:30 pm

Hi Cece,
I have just been reading about bloodletting as a way of controlling iron overload and also testing for the faulty gene-genetic test-
Iron chelation would not be enough.
I know some people on this site were using Phlebotomy to control their MS. Maybe they can chime in about their experiences?
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Re: Zamboni research: genetic difference in PPMS compared to

Postby CureOrBust » Sat Aug 11, 2012 6:57 pm

OK, so in this study the find a strong correlation between these gene's (controlling Iron in the body) and MS type (ie RR, SP & PP), while in his previous study (we all know) there was a correlation between venous flow irregularities and MS type. I would be interested to see a cross over study between the two, and see what / if happens when you get someone with PP type genes, but an RR style flow irregularity. :?
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Re: Zamboni research: genetic difference in PPMS compared to

Postby Cece » Sat Aug 11, 2012 7:09 pm

First we need to see another study reproducing that correlation between venous flow irregularities and MS type. It was very interesting but we have not heard anything more along those lines in a long time.
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Re: Zamboni research: genetic difference in PPMS compared to

Postby cheerleader » Sun Aug 12, 2012 10:09 am

Cece wrote:First we need to see another study reproducing that correlation between venous flow irregularities and MS type. It was very interesting but we have not heard anything more along those lines in a long time.


This is a great point, Cece. I think that maybe the failure to replicate Dr. Zamboni's findings of correlation of MS type to venous irregularities may have promted this genetic study. Those with PPMS appear to have a variety of locations for stenosis. In the past, Zamboni has posited that iron dysregulation is implicated in some cases of CCSVI.

Here's a paper he co-authored with Singh from 2009 where he discusses iron overload and genetics--referencing Stys' research, as well. (unable to copy and paste, but suggest you read page 3) He refers to 0% of iron deficient mice developing EAE. (Grant et al, 2003) and other studies in humans.

http://members.sirweb.org/members/misc/Singh.pdf

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Re: Zamboni research: genetic difference in PPMS compared to

Postby Liberation » Sun Aug 12, 2012 2:16 pm

CureOrBust wrote:there was a correlation between venous flow irregularities and MS type.


I haven't followed this section lately. Can anyone tell me where I can find this study?

If someone is prone to restenosis is there any other way than angioplasty to fix his bloodflow?

Are we getting closer to a consnsus within the medical community about the role of CCSVI?

Thank,
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Re: Zamboni research: genetic difference in PPMS compared to

Postby CureIous » Mon Aug 13, 2012 11:05 pm

I'd be more interested in finding out if serum iron levels do, or do not play a role.

I'm not sure if we can say "iron dysregulation" on the one hand, and "serum levels are irrelevant" on the other. If people with "iron overload" receive benefit from bloodletting, how do we not say that CCSVI would not benefit from the same thing?
RRMS Dx'd 2007, first episode 2004. Bilateral stent placement, 3 on left, 1 stent on right, at Stanford August 2009. Watch my operation video: http://www.youtube.com/watch?v=cwc6QlLVtko, Virtually symptom free since, no relap
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Re: Zamboni research: genetic difference in PPMS compared to

Postby Cece » Tue Aug 14, 2012 7:40 am

For serum levels of iron, there is also the concern about free iron, such as is added to cereal, being worse than iron that is naturally occurring. But I've understood it to be hemosiderin iron that is the culprit in CCSVI, following the leakage of red blood cells across the blood-brain barrier.

A benefit from bloodletting in CCSVI could also be due to the retirement of older blood cells that are banged up, and the production of new blood cells that might function better in conditions of turbulent flow and/or stasis.
Conclusions

Polymorphisms in the genes coding for iron binding and transporting proteins, in the presence of local iron overload, might be responsible for suboptimal iron handling. This might account for the significant variability peculiar to MS phenotypes, particularly affecting MS risk and progression paving the way for personalized pharmacogenetic applications in the clinical practice.

Genetically some of us are better and some of us are worse at iron binding and transporting iron out of our brains. The local iron overload is in the brain as a result of hemosiderin leakage (CCSVI theory) or neuron degeneration (MS theory) but both theories agree that there is iron overload in the brain. Because people with progressive disease are genetically worse at removing iron from their brains, it might be that this ability is among the determinants of whether we have a relapsing-remitting course or a progressive course. This is a very fundamental difference and, if we are RR, we want to stay RR as long as possible and not go SP; and maybe there are strategies such as blood-letting or iron chelation by taking green tea supplements or the deferoxamine as used in thalessemia.

The difference is to stop looking at iron accumulation in the brain as a side-effect of neurodegeneration (MS theory), and start looking at it as a contributor to damage. And if CCSVI is contributing to the iron accumulation, then getting CCSVI venoplasty is a great start.
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Re: Zamboni research: genetic difference in PPMS compared to

Postby cheerleader » Tue Aug 14, 2012 1:35 pm

CureIous wrote:I'd be more interested in finding out if serum iron levels do, or do not play a role.
I'm not sure if we can say "iron dysregulation" on the one hand, and "serum levels are irrelevant" on the other. If people with "iron overload" receive benefit from bloodletting, how do we not say that CCSVI would not benefit from the same thing?


Mark---I think this is going to be a situation that will be best dealt with on an individual patient/doctor basis. Note that those with RRMS (like you and Jeff) did not have the genotype associated with the most serious iron dysregulation. Jeff has his iron levels checked and his serum results have remained all normal. But he also has taken EGCG for four years now. EGCG can pass thru the blood brain barrier and chelate iron and metals from the brain.
http://www.ncbi.nlm.nih.gov/pubmed/17447435

If Jeff had progressive MS, you can bet we'd be getting his iron metabolism checked out further. And if you haven't looked into your own iron levels, I think that would be a good idea. That's what the "personal pharmacological" reference in the abstract is suggesting.
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Re: Zamboni research: genetic difference in PPMS compared to

Postby Daisy3 » Fri Aug 17, 2012 3:23 am

Cheer,

Even if we did a blood test that showed iron levels to be say,for arguments sake,high,what other tests would we need to do?
Would it just be a plain old blood test,measuring ferritin?
I also doubt that we would convince anyone to give us medication for high iron. it would have to be plain old fashioned bloodletting or chelation.
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