P2X7 receptor polymorphism linked to Bipolar Disorder

[pattismith]

Bipolar disorder and 1513A>C P2RX7 polymorphism frequency


Highlights


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BD patients presents a decrease in 1513C allele frequency compared to controls.

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BD patients has a potential increase in 1513 A A and in 1513 A A/AC genotype frequency.

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BD patients presents a state of disadvantage of pro-inflammatory receptor activity.

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P2 × 7R is a possible important mediator to the pathophysiology of bipolar disorder.

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P2 × 7R is a potential biomarker for prediction and diagnosis of BD.



Abstract
Although the etiology of Bipolar Disorder (BD) remains unknown, a strong genetic component to the pathogenesis and risk for this disorder has been widely hypothesized. Several risk genes for BD have been identified; of these, the purinergic P2 × 7 receptor (P2 × 7R) constitutes a pro-inflammatory receptor and a potential risk gene candidate. The purpose of the present study was to assess the frequency of the 1513 A > C P2RX7 polymorphism (rs3751143; Glu496Ala), which leads to receptor loss-of-function, in 154 BD patients versus 184 control subjects. The existence of a differential modulation of P2 × 7R was also analyzed in 22 euthymic BD patients, in comparison to 18 healthy controls.

Our data show a decrease in 1513C allele frequency (p = 0.045) and a potential increase in 1513 A A/AC (p = 0.055) genotype frequency in BD patients, compared to controls, indicating an enhanced function of the pro-inflammatory P2 × 7 receptor in BD subjects. Interestingly, no differences in P2RX7 gene and protein expression were found between euthymic BD patients and matched healthy controls.

In conclusion, our results suggest that P2 × 7R might play a role in the pathophysiology of BD and add new information regarding this receptor as a potential biomarker for the prediction and diagnosis of the disorder.



Sex-specific effects of gain-of-function P2RX7 variation on bipolar disorder


Highlights


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rs1621388 and rs2230912 in P2RX7 were associated with bipolar disorder in females.

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These P2RX7 variants were not associated with bipolar disorder in males.

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P2RX7 variants were not associated with rapid cycling.



Abstract
Background
Patients with bipolar disorder demonstrate sex differences in clinical presentation, particularly in the sub-phenotypes related to periodicity of mood episodes, such as rapid cycling. Additionally, recent studies have linked P2RX7 gene variants with the risk of rapid cycling in clinical cohorts of patients with bipolar disorder, as well as other mood disorders. However, little is known about potential sex differences in the relationship between variants in P2RX7 and bipolar disorder.

Methods
We investigated sex-specific genetic associations between variants of P2RX7 (rs1621388 and rs2230912) in 756 patients with bipolar disorder and 787 control patients matched on age, sex, and ancestry. We examined sex-specific genetic associations with bipolar disorder by comparing cases and controls, as well as rapid cycling of mood episodes in cases. Findings were replicated in an independent dataset.

Results
P2RX7 variants implying an increased pore activity were more common in bipolar disorder, in females but not in males.
Neither P2RX7 variants associated with rapid cycling among bipolar patients.

Limitations
Low sample size limited power for tests of SNP by sex interaction, and data about the onset of rapid cycling and the timing of medication use were not available.

Conclusion
The effects of P2RX7 variants on bipolar disorder may be sex-specific, with increased P2X7 activity potentially elevating risk for bipolar disorder in females. Future research to examine the effect of P2RX7 on bipolar disorder should consider sex-specific effects.

 

[pattismith]

at the opposite of bipolar disorder, chronic Q fever is favored by P2X7R variants with loss of function:


Genetic variations in innate immunity genes affect response to Coxiella burnetii and are associated with susceptibility to chronic Q fever
2019

Abstract
Objectives
Chronic Q fever is a persistent infection, mostly of aortic aneurysms, vascular prostheses or damaged heart valves caused by the intracellular bacterium Coxiella burnetii. Only a fraction of C. burnetii-infected individuals at risk develops chronic Q fever. In these individuals, a defective innate immune response may contribute to the development of chronic Q fever. We assessed whether genetic variations in genes involved in the killing machinery for C. burnetii by macrophages, contribute to the progression to chronic Q fever.

Methods
The prevalence of 66 single nucleotide polymorphisms (SNPs) in 31 genes pivotal in phagolysosomal maturation, bacterial killing and autophagy, was determined in 173 chronic Q fever patients and 184 controls with risk-factors for chronic Q fever and serological evidence of a C. burnetii infection. Associations were detected with univariate logistic regression models. To assess the effect of these SNPs on innate responses to C. burnetii, C. burnetii-induced cytokine production and basal ROS production of healthy volunteers was determined.

Results
RAB7A (rs13081864) and P2RX7 loss-of-function SNP (rs3751143) were more common in chronic Q fever patients than in controls.

RAB5A (rs8682), P2RX7 gain-of-function SNP (rs1718119), MAP1LC3A (rs1040747) and ATG5 (rs2245214) were more common in controls.

In healthy volunteers, RAB7A (rs13081864) and MAP1LC3A (rs1040747) influenced the C. burnetii-induced cytokine production. RAB7A (rs13081864) modulated basal ROS production.

Conclusions
RAB7A (rs13081864) and P2RX7 (rs3751143) are associated with the development of chronic Q fever, whereas RAB5A (rs8682), P2RX7 (rs1718119), MAP1LC3A (rs1040747) and ATG5 (rs2245214) may have protective effects.

 

[nandixon]

For the past couple of weeks I've been experimenting with various ways of trying to Inhibit the NLRP3 inflammasome, which is just downstream of P2X7 and is involved in the production of the proinflammatory cytokine IL-1 beta in response to various danger signals.

P2X7 appears to be somewhat difficult to Inhibit, absent using suramin or Brilliant Blue G (BBG).

Whereas NLRP3 is potentially (theoretically) able to be inhibited by a variety of herbs (e.g., andrographis, curcumin, etc), although probably weakly, and medicines, including the “antibiotic” minocycline and the anti-diabetes drug glibenclamide (aka glyburide). I'm particularly interested in trying the glyburide as it may be the most potent readily available inhibitor of NLRP3 and my blood sugar levels have been tending to be borderline high anyway.

I’m homozygous (AA) for what appears to be a gain of function SNP on NLRP3, rs10733113, and I'm trying to figure out if at least part of the reason why certain foods (milk products, chocolate/cocoa/cacao, and some others) severely exacerbate my fatigue and are also migraine triggers (for which NLRP3 is implicated when trigeminal nerve-related) are related to an increased production of IL-1 beta.

Also, one of the ways NLRP3 is activated is by an outflow of intracellular potassium, and I've found that cutting by half (0.1 -> 0.05 mg) the amount of fludrocortisone (Florinef) I've been taking has been helpful as well. I may try to discontinue it entirely. The Florinef seemed helpful the first several years I took it but now I'm suspicious it's possibly exacerbating things in a proinflammatory way through NLRP3.

 

[dreampop]

I'm A/A for rs3751143 (development of q/fever p2x7 variant).

 

[pattismith]

I have double A allele (gain of function) at rs1718119 (frequency 35.8%)

This one is not associated with bipolar disorder, but with neuropathic pain in diabete/women


For rs3751143, I have AA (= ancestral allele = high functioning receptor). This allele is associated to BP in the first study.



If Naviaux is right about P2X7 activation in CFS/ME, I guess we should find association with gain of function P2X7R variants, don't you think so?

 

[Sidereal]

I’m homozygous (AA) for what appears to be a gain of function SNP on NLRP3, rs10733113, and I'm trying to figure out if at least part of the reason why certain foods (milk products, chocolate/cocoa/cacao, and some others) severely exacerbate my fatigue

I'm GG but have severe fatigue, somnolence and brain fog reactions to dairy, chocolate/cocoa/cacao and any kind of caffeine-containing products like tea, coffee, coca cola etc.

 

[nandixon]

I'm GG but have severe fatigue, somnolence and brain fog reactions to dairy, chocolate/cocoa/cacao and any kind of caffeine-containing products like tea, coffee, coca cola etc.

@Sidereal, There are several other gain of function mutations on NLRP3, some of which 23andMe tests for but some they don't.

One in particular I remember seeing that 23andMe tests for that you can also check is rs35829419. (You would only be heterozygous for that one if it's present.

How soon after eating the milk or cacao products would your worsening symptoms occur? Mine would typically happen about 2 days later, plus or minus half a day.

That's interesting about caffeine products also causing a problem for you. I actually use pure 200 mg caffeine tablets that I cut in half and take a total of 300-400 mg per day to help alleviate a little of the fatigue. I've never drank coffee, and tea doesn't seem to be very good for me either (hence the use of the caffeine tablets instead).

 

[Sidereal]

One in particular I remember seeing that 23andMe tests for that you can also check is rs35829419. (You would only be heterozygous for that one if it's present.

CC on that one.

How soon after eating the milk or cacao products would your worsening symptoms occur? Mine would typically happen about 2 days later, plus or minus half a day.

Interesting. Mine would occur pretty much right away.

 

[M Nosson]

@nandixon I have been looking into Glyburide for a few weeks. I made a case to my GP to prescribe it to me based on the evidence that it can inhibit the release of interleukin-1 beta and is somewhat neuroprotective, and can reduce neuroinflammation. I took my first dose 2 days ago, and had some really bad hypoglycemia about 5 hours afterwards. Hot and cold sweating, visual disturbances and extreme shakiness. Thought I might faint.

I got through that, but it's my only experience so far with this drug. I am pausing it until I can get a glucose tolerance test to figure out if there's some kind of borderline diabetes issue going on. I'm wondering if I might have a type of MODY (maturity onset diabetes of the young), as a result of problems absorbing glucose from my small intestine because it is so inflamed. I have been curious to see whether the Glyburide would it help with my neurological symptoms, and whatever else is being affected by high levels of interleukin-1 beta. Now I'm curious if it may also help me with whatever blood sugar issues might be going on.

I have been taking andrographis for a few months. Not sure if it's helping much, but probably it is on some level!

 

[nandixon]

@nandixon I have been looking into Glyburide for a few weeks. I made a case to my GP to prescribe it to me based on the evidence that it can inhibit the release of interleukin-1 beta and is somewhat neuroprotective, and can reduce neuroinflammation. I took my first dose 2 days ago, and had some really bad hypoglycemia about 5 hours afterwards. Hot and cold sweating, visual disturbances and extreme shakiness. Thought I might faint.

How many mg did you start with? Glyburide (glibenclamide) at the usual dose (~2.5 - 5.0 mg) seems likely to me to cause hypoglycemia in anyone with normal blood sugar levels. When this drug was in development, healthy volunteers were infused with glucose in order to maintain their blood sugar levels after just a 5 mg dose (I believe).

Glibenclamide is also both a substrate for and an inhibitor of the p-glycoprotein transporter (ABCB1 gene).

I'm really sensitive to any drugs that use p-gp (which is a lot of them), and even more so to ones that also inhibit p-gp. So I always start with no more than 1/4 of the smallest available dosage, and in this case I’m planning to start with only 1/8 of a 1.25 mg glibenclamide tablet, or 0.16mg. (My blood sugar has been running at the top of the normal range for a while so I'm hoping that might eventually help me tolerate a higher dose.)

I have been taking andrographis for a few months. Not sure if it's helping much, but probably it is on some level!

I've also been trying andrographis for several weeks, and from the beginning I've noticed only a small positive effect, I think. So far it seems worth continuing to take though.

Everything I'm trying right now is just an attempt to dampen down “inflammation” (i.e., modulate pro- and anti-inflammatory cytokines in a hopefully favorable direction) as a prelude to trying to do a reset of the HPA axis with mifepristone (RU486) per Nancy Klimas's work.

Thanks for posting your experiences.

 

[Jackb23]

Has anyone tried allopurinol? I am about to try it and I think it is pertinent to this conversation. It has been studied in the use of bipolar disorder and they found it to be an effective add on to lithium and depakote. The study I linked below found that it may block the NLRP3 inflammatory response.

“Our results show that XO inhibition attenuates NLRP3 inflammasome activation, as evidenced by impaired caspase1 and IL1β secretion in macrophages in vitro and in vivo.”


https://www.nature.com/articles/ncomms7555

 

[Sidereal]

I tried allopurinol a few years back. Made me feel noticeably better for a few days, which I must say I did not expect at all since nearly all meds either make me worse or no better. The effect disappeared after a few days.

 

[Jackb23]

Sorry to hear that the benefits didn’t persist. I am going to take the first one tonight and I’ll report back in a week or so. @Sidereal

 

[pattismith]

Has anyone tried allopurinol? I am about to try it and I think it is pertinent to this conversation. It has been studied in the use of bipolar disorder and they found it to be an effective add on to lithium and depakote. The study I linked below found that it may block the NLRP3 inflammatory response.

“Our results show that XO inhibition attenuates NLRP3 inflammasome activation, as evidenced by impaired caspase1 and IL1β secretion in macrophages in vitro and in vivo.”


https://www.nature.com/articles/ncomms7555

I tryed it! And the very first day, only a few hours after the intake, I add acute scleritis in my eye, a very painful and scary condition that need quick treatment with cortisone drops.
Needless to say that I will never take it again.

Why not trying Inositol instead?

 

[Jackb23]

Today is my third day. Too soon to tell if the effects will hold, but I have noticed a significant improvement in my mood/motivation. I also feel less wired and tired. It has been so noticeable that I would definitely put it down as one of the more positive aids I have found so far, along with maybe 3 or 4 other things.
I have not seen any effects in my sleep, but am working on some other things to address that.

 

[S-VV]

@Jackb23 how's that purinol experiment going? I'm thinking of trying it myself

 

[S-VV]

I tryed it! And the very first day, only a few hours after the intake, I add acute scleritis in my eye, a very painful and scary condition that need quick treatment with cortisone drops.

Lol you know more medicine than most "doctors".

Is acute scleritis a known side effect of allopurinol?

 

[pattismith]

Lol you know more medicine than most "doctors".

Is acute scleritis a known side effect of allopurinol?

lol, I made the story short, but it was not so simple…
My eye started to acutely hurt and become red, just a few minutes/hours after allopurinol intake. The day after, the eye was still red and painful, so I rushed into an ophtalmologist and he did the scleritis diagnosis and gave me the treatment.

Scleritis is not a known side effect of Allopurinol, but I can't see anything else that could have caused it.
I never experienced eye inflammation before taking Allopurinol, nor after.
I don't have any known rhumatologic condition, nor any auto-immune disease, nor gout.
I was not taking any other drug, and it happened very quickly after the first intake, so an allergic reaction is the only explanation I found.
Allopurinol is known for hypersensitivity vasculitis reactions.

 

[S-VV]

Thanks! I'm glad you caught it on time

 

[SlamDancin]

@pattismith Hey just stumbled on this thread and wanted to suggest IP-6/Inositol as both inhibit XO. I also take a product called Cardenosine (that includes 100mg Inosine) that you should google to further attempt to compensate for lack of ATP production.