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NET (Norepi Transporter) SNPs?

xks201

Senior Member
Messages
740
Does anyone know them so I can search for possible NET mutations in my 23andme data?
 
Messages
15,786
Does anyone know them so I can search for possible NET mutations in my 23andme data?
The proper annotation for the NET gene is SLC6A2 and according to http://www.ncbi.nlm.nih.gov/gene/6530 it's located between 55689542 and 55740104 on chromosome 16. So the following 23andMe SNPs are included, and probably a few before and after them:
rs168924
rs2242446
rs36030
rs9937434
rs17841327
rs17307096
rs12232407
rs3785143
rs1532701
rs17247999
rs734980
rs41154
rs17841329
rs13306041
rs187715
rs36026
rs36024
rs187714
rs36023
rs9925429
rs3785151
rs36020
rs16955591
rs3785152
rs40147
rs1814270
rs12443955
rs1805066
rs36016
rs10521329
rs1345429
rs880711
rs16955619
rs11862589
rs879519
rs4564560
rs36013
rs5563
rs5564
rs11568324
rs5566
rs5567
rs3785157
rs5568
rs36011
rs1566652
rs8047672
rs5569
rs5570
rs998424
rs36009
rs5558
rs1800887
rs5559
rs3743788
rs36007
rs2242447
rs15534
rs42460
rs7194256
 
Messages
15,786
But norepinephrine problems in ME patients might be accounted for by our ADRA2A gene becoming upregulated after exertion (it's normal prior to exertion). This upregulation can result in norepinephrine being suppressed, hypotension, and slow gut motility.
 

xks201

Senior Member
Messages
740
Wow. I would bet just about everyone walking the earth has at least one mutation across those snps? Lol
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
I too are very interested in this area. Im cutting and pasting some info on NET and exactly what it is here (which Im still trying to get my head around)

Norepinephrine, also known as noradrenaline, is a neurotransmitter found in the sympathetic nervous system and biosynthesized from the amino acid tyrosine, which is sequentially hydroxylated to generate dihydroxyphenylallanine (Dopa), decarboxylated to produce dopamine, and hydroxylated to form NE (19).

As one of the crucial neurochemical messengers in the CNS, NE plays an important role in human physiology and pathology, and is involved in mood regulation, sleep regulation, expression of behavior and the general degree of alertness and arousal (20). Norepinephrine also exerts central control over the endocrine system and autonomic nervous system. Outside the CNS and adrenal glands, NE is located in the sympathetic nerve endings, and the NE content of a particular tissue reflects the extent of its sympathetic innervation (21).

The NET is located in the plasma membrane of noradrenergic neurons, where it functions to take up synaptically released NE. The NET thus serves as the primary mechanism for the inactivation of noradrenergic signaling (22-24). Reuptake of NE by the NET protein (also known as uptake 1) is the primary mechanism by which the biological effects of NE in the synapse are terminated (Fig. 2). The inactivation process through the NET is critical in preventing an excessive increase in the NE concentrations in the synaptic cleft, which regulate adrenergic neurotransmission in the brain, as well as the removal of NE from the heart and other peripheral organs (21, 25). Reuptake of NE is competitive with a variety of naturally occurring amines and drugs.

Drugs of abuse (e.g., cocaine) and antidepressants (e.g., desipramine, venlafaxine, reboxetine, bupropion) block the transport of NE and thereby cause an elevation in the synaptic concentrations of NE and potentiation of the activation of postsynaptic receptors (21, 26, 27). The above neurobiology of the NE system and other accumulating evidence support the view that NE plays an important role in the CNS

Okay Im confused.. when they say somehing like cocaine and antidepressants block to transport of NE and thereby cause an elevation in the synaptic concentrations of NE, does that mean they help lower NE in the body? The whole article is here http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1518795/ (im really struggling to get my head around things).

I want to work out what NET mutations I have as my hyperadrenalic POTS is being shocking.. my orthostatic hypertension is shooting my BP up to almost 180. Something is very wrong with my noradrenaline.
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
For anyone else who has hyperadrenalic POTS or orthostatic hypertension before caused by noradrenaline.. and wants to compare results, Here are the mutations I could see I have from 23andME in which one copy has shifted (unfortunately I know no way to see the abnormal ones when two copies of the SNP mutation are abnormal)

my obvious (+-) NET gene mutations (noradrenaline transport)
SLC6A2 55720458 rs10521329 A or C AC
SLC6A2 55716550 rs3785152 C or T CT
SLC6A2 55723381 rs880711 A or G AG
SLC6A2 55729836 rs3785157 C or T CT
SLC6A2 55731735 rs8047672 A or G AG
SLC6A2 55731835 rs5569 A or G AG
SLC6A2 55731946 rs998424 A or G AG

......................

Taking a closer look at these SLC6A2 genes.

With the rs10521329 there have been several studies done on that. Ones who have this mutation get more high on amphetamines and hence more at risk of developing a drug issue. http://www.ncbi.nlm.nih.gov/pubmed/19727679?dopt=Abstract

........................

Females who have SLC6A2 mutations (as far as I see it doesnt specify exact mutations in this area) are more at risk for ADHD.

" A growing body of literature finds gender differences in ADHD. However, little is known about the causes of these differences. One possibility is that ADHD risk genes have sexually dimorphic effects. We have investigated four ADHD candidate genes (COMT, SLC6A2, MAOA, SLC6A4) for which there is evidence of sexually dimorphic effects. Past neurobiological and genetic studies suggest that COMT, and SLC6A4 variants may have a greater influence on males and that SLC6A2, and MAOA variants may have a greater influence on females. Our results indicate that genetic associations are stronger when stratified by sex and in the same direction as the previous neurobiological studies indicate: associations were stronger in males for COMT, SLC6A4 and stronger in females for SLC6A2, MAOA " http://www.ncbi.nlm.nih.gov/pubmed/18937309?dopt=Abstract

.........................

Rs3785152 ..only has had one study done on it..
"Clinical efficacy of atomoxetine treatment in ADHD shows potential dependence upon a series of genetic polymorphisms of its mechanistic target, the norepinephrine transporter"

....................

rs880711 .. no research has been done on it.

..................

Rs3785157
"Support for association between ADHD and two candidate genes: NET1 and DRD1.[PMID 15717291]

[PMID 18937296] Replication of a rare protective allele in the noradrenaline transporter gene and ADHD. "
....................
Rs8047672 . .. has had no research done on it
.................
Rs5569 ... has a bit of research on it. http://snpedia.com/index.php/Rs5569 (none of which I found interesting.. some investigating if there is a possible link between this and depression)

.....................

Rs998424.. has a bit of research on it http://snpedia.com/index.php/Rs998424 (none of which I found interesting).
.......
Maybe we can share results and discover something new.
 
Messages
15,786
Okay Im confused.. when they say somehing like cocaine and antidepressants block to transport of NE and thereby cause an elevation in the synaptic concentrations of NE, does that mean they help lower NE in the body? The whole article is here http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1518795/ (im really struggling to get my head around things).
If the norepinephrine is elevated in the synapses, then that means the existing levels are basically staying the same, but are being used more effectively.

Have you ever had norepinephrine levels tested? There's been a very recent study of ME patients showing that a gene which blocks norepinephrine production is 3x more active after exertion compared to sedentary controls.

Hence if your norepinephrine is low and you have OI symptoms (like me!), the upregulation of that ADRA2A gene could explain it. There are a couple drugs when can help suppress it, thereby raising norepinephrine levels. The most potent and specific is a natural bark extract, Yohimbe, which might be available via prescription in Australia, but not over-the-counter. The 2nd best bet is probably Mianserin, and then there's also mirtazapine.
 
Messages
15,786
Maybe we can share results and discover something new.
Some of us have been doing that, but with much more with this one gene.

My fiance made a program to pull out rare results at http://sourceforge.net/projects/analyzemygenes/ . It can also make a bigger list of rare homozygous results using ten_percent.zip from https://sourceforge.net/projects/analyzemygenes/files/Databases/

There are explanations of how to use it on the wiki on those pages. And if you still run into troubles, I can run it for you if you send me your 23andMe file. If you PM me with your results, I can compare your ten_percent rare results to that of myself and a few other ME/CFS patients who have sent them thus far. Then we can see if there's anything similar :)
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
If the norepinephrine is elevated in the synapses, then that means the existing levels are basically staying the same, but are being used more effectively.

oh now Im even more confused. So this all doesnt affect a persons test result levels at all??


Have you ever had norepinephrine levels tested? There's been a very recent study of ME patients showing that a gene which blocks norepinephrine production is 3x more active after exertion compared to sedentary controls.

Hence if your norepinephrine is low and you have OI symptoms (like me!), the upregulation of that ADRA2A gene could explain it. There are a couple drugs when can help suppress it, thereby raising norepinephrine levels.

Yes I have had my neorephinehrine levels tested at least 4 (I think it was 5) times. My results were so abnormal that the labs were finding them hard to believe and kept getting me to do the test again and again even once saying I must of spilt the perservative..which I didnt. Another time they said the test bottle most of not have the right amount of perservative..but it looked the same as the others which I got from different places. (I went throu different labs and the same thing happened.. I even took in my pee and got the test bottles with perservative from different medical clinics to it wasnt something going on there which was causing the labs to keep rejecting my results). My noradrenaline on my tests is abnormally high hence why I have the bad orthostatic hypertension and the hyperPOTS. In the end after 4-5 tries I did finally get a result (I even had a lab ring me to ask me what I was doing with my samples!! I was doing nothing wrong with them).. not normal, high.

I take a drug to try to keep my noradrenaline down (I was getting woken by noradreanline rushes too during the middle of the night.. waking in a flushed sweat due to them ..and once my noradrenaline goes up very high, it doesnt come down very easily, it takes quite a while). Im on Clonidine (a hypertension drug) for my orthostatic issues as it specifically works on the noradrenaline and helps drop it so aids my BP orthostatic reactions
...................

Now Im heaps more confused as you've been speaking of the opposite.. can you explain how all the stuff would reate to me ..what is going on with my noradrenaline as far as genes go?
 
Messages
15,786
oh now Im even more confused. So this all doesnt affect a persons test result levels at all??
Substances which keep norepinephrine in the synapses shouldn't affect norepinephrine levels much.
Now Im heaps more confused as you've been speaking of the opposite.. can you explain how all the stuff would reate to me ..what is going on with my noradrenaline as far as genes go?
The stuff I said about ADRA2A might not apply to you - you obviously don't want to be repressing the gene which is lowering your norepinephrine levels! There must be something else (additional?) going in the ME patients with hypertensive POTS.
 

Sushi

Moderation Resource Albuquerque
Messages
19,934
Location
Albuquerque
Does anyone know them so I can search for possible NET mutations in my 23andme data?


Just a note--I believe the autonomic nervous system research bunch at Vanderbilt have done a fair amount of research on SNPs in NET. Sorry I don't have links.

Sushi