Study Finds An Epigenetic Mechanism Effecting Net Function In Pots

[ramakentesh]

Finally published and this work was once described by a leading researcher while attempting to get published as 'the most exciting work in recent times':

Objective—The postural tachycardia syndrome (POTS) has multiple symptoms, chief among which are tachycardia, weakness, and recurrent blackouts while standing. Previous research has implicated dysfunction of the norepinephrine transporter. A coding mutation in the norepinephrine transporter gene (SLC6A2) sequence has been reported in 1 family kindred only. The goal of the present study was to further characterize the role and regulation of the SLC6A2 gene in POTS.

Methods and Results—Sympathetic nervous system responses to head-up tilt were examined by combining norepinephrine plasma kinetics measurements and muscle sympathetic nerve activity recordings in patients with POTS compared with that in controls. The SLC6A2 gene sequence was investigated in leukocytes from POTS patients and healthy controls using single nucleotide polymorphisms genotyping, bisulphite sequencing, and chromatin immunoprecipitation assays for histone modifications and binding of the transcriptional regulatory complex, methyl-CpG binding protein 2. The expression of norepinephrine transporter was lower in POTS patients compared with healthy volunteers. In the absence of altered SLC6A2 gene sequence or promoter methylation, this reduced expression was directly correlated with chromatin modifications.

Conclusion—We propose that chromatin-modifying events associated with SLC6A2 gene suppression may constitute a mechanism of POTS

http://atvb.ahajournals.org/content/early/2012/06/21/ATVBAHA.111.244343.abstract

[ramakentesh]

To explain this complex mechanism, NE at autonomic ganglia is not recycled by NET protein back out of the synaptic cleft, rather it leaks into plasma.

[sue1234]

Really interesting. Do they have any clue to what they can do about it or is it something that can be addressed?

[Birdlady]

Rama I have seen this. Thanks for posting.

You figure if I have a mutation on this gene that decreases function AND something else triggered this chromatin modifying event, then this very well could be the cause of my POTS.

[ramakentesh]

its not actually a mutation as such - the gene itself is fine, but epigenetic regulatory mechanisms are turing the gene off.

[bellgirl]

So how do we turn it back ON....this is a great discovery. I want to know what we can do!!

[ramakentesh]

When this stuff first came out it was regarded as a very important study, now many haev returned to other hypothesis - Ben Levine raised the possibility of intact autonomic control and deconditioning, Stewart and Medows suggest low flow states with impaired ANG II and neuronal nitric oxide and importantly demontrated that POTS is dominated by cerebral autoregulation problems rather than traditional low blood pressure. Mayo's work on the AAG in POTS which was originally thought as important by some has also had somewhat of a resurgence, although the neuropathy associated with most POTS is not specific to a3 receptors, but small fibres.

Now that its published it will be interesting to see what they find. Evidence is strong given the MIBG results from germany and the fact that the proband with NET deficiency has symptoms identical to most POTS patients.

it could even explain hypovolumia.

At the moment it seems that most of the research groups are looking at ery different areas - blood volume regulation, central control of autonomic function, etc.

And yes it will be fixable if its the primary mechanism. If its counter-regulatory then SNRIs might be employed, etc. But im just speculting.

[ramakentesh]

I would suggest anyone with an interest in POTS to consider buying this article. I have just read it in its entirety and this is an important article! Please PM me for specifics as I dont want to publish them here. Lets just say this article says a lot more than just what is written in the synopsis.

To me this is probably one of the most interesting articles on POTS in the last five years. Between this and Ang II we are getting there!

Edited July 4, 2012 by corina

[bellgirl]

Rama,

Your personal messages are full. I already tried to PM you. Could you please send me that whole article on SLC6A2 Gene suppression in POTS. I would like to bring it with me to my neurologist in September.

Thanks, and appreciate all your medical knowledge. So glad that you are on the DINET site to educate us all!!

Joy, Kim

[jangle]

Rama I believe I have access to this journal through my university. I will go tomorrow and read the full article, this is indeed very exciting news. I know technically we can't post details or anything but just in generalities if the gene is indeed intact and it is an epigenetic phenomenon then that increases the likelihood of being able to treat it.

Although from the abstract they make it sound like it is chromatin level abnormalities. That seems difficult to treat, I hope they proposed some idea to treat it in that article haha!

[issie]

Jangle, Please let us all know what you find. Rama, still no room in your PM box.

Issie

[ramakentesh]

Indeed. The paper speculates that the abnormal histone modifications may relate to how cytokines effect the amounts of certain regulatory molecules like Hand2 which was associated with this promotor binding if I remember correctly.

Check out the study below: These researchers looked at what NET inhibition did to syncope from abnormal gravitational pull, thinking it might improve resistance to syncope (because SNRIs have been found to improve NCS) but what they found was that it actually made hemodynamics worse and created a phenotype similar to POTS - with peripheral vasonstriction and tachycardia, but reduced central sympathetic activity, reduced vasoconstrictive responses and delayed baroreflex activation (set to a higher point of BP).

http://jap.physiolog.../3/756.full.pdf

What this means is NET inhibition can create a phenotype identical to POTS. It effects cerebral autoregulation. it could account for tachycardia. And perhaps even cytokine regulation of epigenetic controls of NET expression might suggest a connection between inflammatory illness and eventual lack of NET expression. NET even accounts for around 20% of peripheral dopamine reuptake so if its faulty, extra dopamine in the peripheral plasma could potentially effect D1 kidney dopamine receptors and reduce blood volume via salt loss.

If this does indeed prove to be a causal factor and I assume further studies are on the way, its very exciting because there are medications already that can effect histone modifications and that can regulate epigenetic expression. And perhaps at least for some of us there could be the possibility of future hope.

And diet can effect inflammation and can certainly have minor effects on histone activity.

[jangle]

Rama have you taken these studies to your rheumatologist? If so what did they say?

If this is true, then would biologics be effective in treating POTS based on the fact that the biologics suppress cytokine activity.

There might be other drugs to target cytokines, either way it is a question for a rheumatologist to answer.

[jangle]

Nevermind, my Rheumatologist's office called to refer me. Though they did say they've heard of medicines to treat the cytokines? I don't know if the medicines they were referring to were the standard treatments or rheumatological treatments I was asking about. Guess I'll ask the guy I'm getting referred to.

Hey Rama can you PM me your email.

[issie]

Jangle, There's herbals that can affect this too.

Issie

[Mytwogirlsrox]

I read that NSAIDs affect cytokines and they basically cancel out SSRIs in rats

[Mytwogirlsrox]

http://scientopia.org/blogs/scicurious/2011/08/10/another-reason-those-antidepressants-might-not-be-working-taken-aspirin-lately/

[Chaos]

Mytwogrilsrox- Reading that study it looks like the NSAIDS decreased the effectiveness (but didn't cancel out completely the effectiveness) of the SSRIs but it noted that the Wellbutrin/Bupropion was actually slightly MORE effective with the NSAIDS.

[Mytwogirlsrox]

I was just generalizing, so for the misinformation...

[issie]

Jangle, There's herbals that can affect this too.

Issie

Look into ginger and tumeric - they will affect certain cytokines. There is a new article in the latest Life Extension magazine about them and the affects they have on this.

Issie

[ramakentesh]

As stated previously there are 100s of cytokines and not all of them are inflammatory - some are antiinflammatory, others regulate totally different functions in the body. Ginger and tumeric suppress TNF alpha - which is just one cytokine. Ginger also lowers blood pressure.

[Chaos]

Ginger also lowers blood pressure.

Ha! Thanks for giving me ammo for refusing to use ginger. It's never worked well for me and gives me nasty side effects but lots of well meaning friends keep pushing it on me.

Never know what handy tidbits I will get from surfing around here.

[issie]

Ginger also lowers blood pressure.

Ha! Thanks for giving me ammo for refusing to use ginger. It's never worked well for me and gives me nasty side effects but lots of well meaning friends keep pushing it on me.

Never know what handy tidbits I will get from surfing around here.

Yeah, some POTS people do horrible with Tumeric too. So, just goes to show what makes one person feel good - can make another SICK!

Issie

[jangle]

While I have found some evidence that CNTF could be a cause of the NET deficiency, some things I have found disturb me.

1.) Patients with other conditions treated with CNTF infusions did not to my knowledge develop POTS like symptoms.

However, I want to write this as a caveat. The studies I read found mostly nausea/anorexia associated with dosages of CNTF 0-30 mcg/kg.

At 30 mcg/kg symptoms of fatigue began to set in on patients. We all know fatigue is a major symptom of POTS.

There was a study that brought the dose of CNTF to 100 mcg/kg, but I don't have access to that article and they didn't list lightheadedness, palpitation, or anything like that on their abstract.

Granted the side effects of postural tachycardia would probably only be listed on these studies if they were actively searched for, which they were most certainly not. Given that many of us went years with postural tachycardia undiagnosed.

Has anyone gotten their serum IL-6 levels measured?

--------------------------------------------------

I guess a question to you all is that if it is methylation of the gene (and I'm assuming that's what they found as they talk about the methylation) that is causing the suppression, what options do we have? I noticed the authors did a study on using valproic acid and found that could boost NET expression, but that drug seems depressing to take as its side effect profile is almost as bad if not worse than POTS itself.

Would the methylation be reversible by some other means?

[issie]

My PCP is looking into doing testing for some of these cytokines. It can be gotten without a Dr.'s script through Life Extension - but, is rather pricey and they don't take insurance.

What I'm learning about the methylation mutations - yes, there is things you can do about it. What I have found is there are certain foods and substances that my body won't use properly or break down properly and they were things I've been doing all the time. For example ---I found out there is a dysfunction in sulfites and sulfur. I used to eat cabbage, brocolli, califlower etc. all the time. Also, I found that even though I need more NO and l-arginine should provide that - because of my mutations my body doesn't break down l-arginine and use it to make NO - what it does is turn it into a free radical -----which is not good. There are things we can do if there is mutations in the genes that affect the methylation pathways. We just have to figure it out. I'm still learning and about this and can't really answer questions about it ----Cause I have tons of them myself.

Issie