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Genotypes (SNPs) to help determine Vitamin E supplementation - Relation to Inflammatory Cytokines

nandixon

Senior Member
Messages
1,092
Interesting article here that may have application to vitamin E supplementation in Chronic Fatigue Syndrome (CFS/ME):

"In healthy control subjects, the effect of α-tocopherol supplementation on the production of inflammatory cytokines appears to be dependent on an individual's genotype. These genotype-specific differences may help explain some of the discordant results in studies that used vitamin E."
http://www.ncbi.nlm.nih.gov/pubmed/22572643/

A related published U.S. patent application is here (METHODS FOR DETERMINING GENE-ALPHA TOCOPHEROL INTERACTIONS):
http://www.faqs.org/patents/app/20120064522

The authors found in a study of healthy males that alpha-tocopherol could have either anti-inflammatory OR pro-inflammatory cytokine activity based on a person's genotype. The SNPs used are available through 23andMe testing.

The most important SNP, among those looked at, seems to be glutathione-S-transferase pi, GSTP1 A316G (rs1695 in 23andMe). Persons having the alleles AA or AG had an increase in interleukin-6 (IL-6) upon supplementing alpha-tocopherol while those with GG saw a decrease (see Fig. 3A in the patent app; note that in the text of the app there is a typographical error in multiple places where GG should be AA).

(See here for more on IL-6:
http://en.wikipedia.org/wiki/Interleukin_6)

I found the article while trying to figure out why supplementing with 400iu of alpha-tocopherol (succinate form) worsened my fatigue. This might possibly explain it. To make it easier for others to determine their own status, here are my personal results for the above SNP and two others. Bottom line is - assuming I follow the pattern of the healthy test cases - all of my SNPs would seemingly dictate an increase in pro-inflammatory cytokines upon supplementing alpha-tocopherol - which I guess would be a bad thing:

GSTP1 A313G -/- AA (AA) rs1695
(See Fig. 3A for the changes in IL-6 levels for each SNP variant in response to alpha-tocopherol supplementation; Fig. 4A for IL-1)

TNF G(-238)A -/- GG (GG) rs361525
(Fig. 2B for TNF-alpha)

IL10 A(-1082)G +/- CT (TT) rs1800896
(Fig. 2* for TNF-alpha; Fig. 4D for IL-1)

*Figure "2" seems to be missing . . . the text says the "AG" (= CT for 23andMe) and "AA" (= TT) genotypes were associated with an increase in TNF-alpha levels.

I also feel almost as bad supplementing the gamma form of vitamin E. I always thought in either case it might be due to a blood pressure lowering effect. Now I'm not so sure, and am just going to stick to the amount in my multivitamin from now on. On the other hand, it seems people with the GG genotype for GSTP1, and/or the AG for TNF (and/or maybe CC for IL10), for example, might benefit from extra alpha-tocopherol, since those genotypes may have a decrease in their pro-inflammatory cytokine levels.
 
Messages
1
That is very interesting. I am also AA for rs1695 and have always felt worse after taking vitamin E. Thanks for sharing.
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
Interesting article here that may have application to vitamin E supplementation in Chronic Fatigue Syndrome (CFS/ME):

"In healthy control subjects, the effect of α-tocopherol supplementation on the production of inflammatory cytokines appears to be dependent on an individual's genotype. These genotype-specific differences may help explain some of the discordant results in studies that used vitamin E."
http://www.ncbi.nlm.nih.gov/pubmed/22572643/

A related published U.S. patent application is here (METHODS FOR DETERMINING GENE-ALPHA TOCOPHEROL INTERACTIONS):
http://www.faqs.org/patents/app/20120064522

The authors found in a study of healthy males that alpha-tocopherol could have either anti-inflammatory OR pro-inflammatory cytokine activity based on a person's genotype. The SNPs used are available through 23andMe testing.

The most important SNP, among those looked at, seems to be glutathione-S-transferase pi, GSTP1 A316G (rs1695 in 23andMe). Persons having the alleles AA or AG had an increase in interleukin-6 (IL-6) upon supplementing alpha-tocopherol while those with GG saw a decrease (see Fig. 3A in the patent app; note that in the text of the app there is a typographical error in multiple places where GG should be AA).

(See here for more on IL-6:
http://en.wikipedia.org/wiki/Interleukin_6)

I found the article while trying to figure out why supplementing with 400iu of alpha-tocopherol (succinate form) worsened my fatigue. This might possibly explain it. To make it easier for others to determine their own status, here are my personal results for the above SNP and two others. Bottom line is - assuming I follow the pattern of the healthy test cases - all of my SNPs would seemingly dictate an increase in pro-inflammatory cytokines upon supplementing alpha-tocopherol - which I guess would be a bad thing:

GSTP1 A313G -/- AA (AA) rs1695
(See Fig. 3A for the changes in IL-6 levels for each SNP variant in response to alpha-tocopherol supplementation; Fig. 4A for IL-1)

TNF G(-238)A -/- GG (GG) rs361525
(Fig. 2B for TNF-alpha)

IL10 A(-1082)G +/- CT (TT) rs1800896
(Fig. 2* for TNF-alpha; Fig. 4D for IL-1)

*Figure "2" seems to be missing . . . the text says the "AG" (= CT for 23andMe) and "AA" (= TT) genotypes were associated with an increase in TNF-alpha levels.

I also feel almost as bad supplementing the gamma form of vitamin E. I always thought in either case it might be due to a blood pressure lowering effect. Now I'm not so sure, and am just going to stick to the amount in my multivitamin from now on. On the other hand, it seems people with the GG genotype for GSTP1, and/or the AG for TNF (and/or maybe CC for IL10), for example, might benefit from extra alpha-tocopherol, since those genotypes may have a decrease in their pro-inflammatory cytokine levels.
This is really interesting. I take 1 d alpha-tocopherol and have for 35 years (b4 that 600mg for all the early years of my life). I have always felt it was a very important part of my health protocol along with 2g mineral ascorbates (and apparently / potentially calcium and magnesium citrates - someone sent me an article recently which seemed to think that keeping ones citrate level up was important to avoiding kidney stones...the kidney doctors are saying that >500mg C can cause kidney stones, but I have had no issue, perhaps because I take citrates...and I have always felt better with citrate forms that asporotate forms but could never really explain why).

I believe I am autistic but the lifelong high antioxidant dosage as well as wide ranging supplementation (such as lifelong multi and extra B100, etc) has saved me from the worst of it as a youngster. I wish I knew where to get such genes as above tested. In particular I have reason to suspect I have trouble breaking down B6 (I get short of breath if I stop my 50mg P5P) and also Vitamin A (despite taking beta carotene). I would like to be able to look at more of my genes. I have had the Yasko test and have 18 genetic defects out of 30. If anyone runs across any other good genetic panels I hope you will share!
 

roxie60

Senior Member
Messages
1,791
Location
Central Illinois, USA
This is really interesting. I take 1 d alpha-tocopherol and have for 35 years (b4 that 600mg for all the early years of my life). I have always felt it was a very important part of my health protocol along with 2g mineral ascorbates (and apparently / potentially calcium and magnesium citrates - someone sent me an article recently which seemed to think that keeping ones citrate level up was important to avoiding kidney stones...the kidney doctors are saying that >500mg C can cause kidney stones, but I have had no issue, perhaps because I take citrates...and I have always felt better with citrate forms that asporotate forms but could never really explain why).

I believe I am autistic but the lifelong high antioxidant dosage as well as wide ranging supplementation (such as lifelong multi and extra B100, etc) has saved me from the worst of it as a youngster. I wish I knew where to get such genes as above tested. In particular I have reason to suspect I have trouble breaking down B6 (I get short of breath if I stop my 50mg P5P) and also Vitamin A (despite taking beta carotene). I would like to be able to look at more of my genes. I have had the Yasko test and have 18 genetic defects out of 30. If anyone runs across any other good genetic panels I hope you will share!

Maybe 23andme???
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
Isn't 23andme the same as the Yasko panel but with fewer genes covered? I want to see genes governing breakdown of B6 to active P5P and breakdown of beta-carotene to active Vitamin A, for example, and I know these are not in that panel. It is disappointing how slowly genetic panels of wide scope are becoming available. The Yasko and 23andme panels have been available for 4 or more years and there have been no new wide scope panels developed since. Why??! Just when we have the tools to start making headway, science...stalls?!!
 

adreno

PR activist
Messages
4,841
Bump. I somehow missed this before - good information here.

I wish I knew more about the effects of SNPs on gamma-tocopherol.
 
Last edited:

nandixon

Senior Member
Messages
1,092
(My original post was a bit dense, so here is a simplification.)

Effect of supplementing alpha-tocopherol based on the following 23andMe SNPs*:

GSTP1 rs1695
AA or AG = pro-inflammatory (increases IL-6)
GG = anti-inflammatory (decreases IL-6)

TNF rs361525
GG = pro-inflammatory (increases TNF-α)
AG = anti-inflammatory (decreases TNF-α)
(AA is rare)

IL10 rs1800896
TT or CT = pro-inflammatory (increases IL-1β)
CC = anti-inflammatory (decreases IL-1β)

*Taken from Figure 1 (A, B & D) here.

(Note that only men were studied.)
 

aaron_c

Senior Member
Messages
691
Thanks for the work you put into this @nandixon. I was curious about how common these genotypes were. Here is what I found:

GSTP1 rs1695
AA or AG = pro-inflammatory (increases IL-6)
GG = anti-inflammatory (decreases IL-6)
AA:AG:GG = 43:43:13
EDIT: The PRO-inflammatory snps seem to be much more common.

TNF rs361525
GG = pro-inflammatory (increases TNF-α)
AG = anti-inflammatory (decreases TNF-α)
(AA is rare)
could not find data

IL10 rs1800896
TT or CT = pro-inflammatory (increases IL-1β)
CC = anti-inflammatory (decreases IL-1β)
TT:CT:CC = 58:37:9
Edit: Here too the PRO-inflammatory snps seem to be much more common.

(Assuming my dyslexia hasn't fooled me again) It seems like most people will react poorly to alpha tocopherol. I'm not sure what conclusion to draw, other than "huh."
 
Last edited:

Sidereal

Senior Member
Messages
4,856
Alpha tocopherol succinate made me feel more fatigued. Red palm oil extract made me feel great for a week followed by a severe inflammatory reaction in the joints lasting months.

GSTP1 rs1695
AA or AG = pro-inflammatory (increases IL-6)
GG = anti-inflammatory (decreases IL-6)

AA

TNF rs361525
GG = pro-inflammatory (increases TNF-α)
AG = anti-inflammatory (decreases TNF-α)
(AA is rare)

GG

IL10 rs1800896
TT or CT = pro-inflammatory (increases IL-1β)
CC = anti-inflammatory (decreases IL-1β)

CT

Well, that explains that mystery!

As always, fantastic information, @nandixon. Thanks.
 

Gondwanaland

Senior Member
Messages
5,092
GSTP1 rs1695
AA or AG = pro-inflammatory (increases IL-6)
GG = anti-inflammatory (decreases IL-6)
GG
TNF rs361525
GG = pro-inflammatory (increases TNF-α)
AG = anti-inflammatory (decreases TNF-α)
GG
IL10 rs1800896
TT or CT = pro-inflammatory (increases IL-1β)
CC = anti-inflammatory (decreases IL-1β)
I am TT and DH is CC

I took Gamma E continuously for 1.5 years, after taking warfarin for 1.5 years...

Now I know it worsened my K2 deficiency, in addition to my pro-inflammatory SNPs :ill:

Hopefully taking mixed tocopherols + mixed tocotrienols lessened the detrimental effects... At least no one beats my HDL -- it raised from the 70-80 range to 90-104, which is a good thing b/c the ratio total cholesterol/HDL has been between 2.5 and 3 (desirable <5).

Although it is good to know that my husband will better benefit from it than myself. In fact I started giving him Gamma E earlier this year when I first saw this thread (thanks @nandixon ).

Soon we are going to have his cholesterol retested, but he has been having so many other problems lately that I doubt this supplement had any significative positive outcome...
 

nandixon

Senior Member
Messages
1,092
(Assuming my dyslexia hasn't fooled me again) It seems like most people will react poorly to alpha tocopherol. I'm not sure what conclusion to draw, other than "huh."
Yes, the authors of the study indicate that it may be counterintuitive. As a general matter, you would seemingly want to have the SNPs that cause the pro-inflammatory response (from taking vitamin E), because those SNPs are apparently found in individuals with a higher antioxidant capacity.

As the authors state in the Discussion:
The data suggest that individuals with a lower antioxidant capacity might be those who would benefit the most from intake of α-tocopherol.


However, having ME/CFS may mess things up: Because our disease is associated with high levels of oxidative stress, it would seemingly be desirable to be able to supplement with vitamin E. But having those SNPs that are pro-inflammatory with respect to vitamin E (and which are actually normally the good SNPs) then becomes a problem for us. Because in the process of trying to lower the oxidative stress, the levels of the cytokines mentioned are being increased, and that increase (or change) may make us feel worse.

That's what I'm theorizing, anyway. Someone else may have a better idea.
 
Messages
7
Hi all,

I'm a bit confused....
So I am RS1695 AA and always tired, this was actually the reason to start genetic testing for me.
Should I avoid vitamine E? That seems counter-intuitive because it is in some of the most healthy foods.
What other dietary or supplement changes would the experts here recommend?

Thank you all in advance! :)
 
Messages
15,786
So I am RS1695 AA and always tired, this was actually the reason to start genetic testing for me.
Should I avoid vitamine E? That seems counter-intuitive because it is in some of the most healthy foods.
I doubt there is a connection between chronic fatigue, rs1695, and vitamin E. First of all, the study which people are relying upon is not very good. There is no effect size listed, so the actual impact might be tiny, if there really is an impact. There is no scatterpoint graph, so it's impossible to tell what the data actually looks like. There is probably a lot of overlap between the groups, based on the more basic graph which they created. The P-value is also very high for a SNP study. They used p<0.05, whereas most of these types of studies are using something closer to p<0.0001, or even lower. And the actual p-value for that relationship was p<0.019, which wouldn't even hold up to a basic p<0.01 threshold.

The other problem is that the "pro-inflammatory" allele for rs1695, according to that research, is "A". They found no difference between AA and AG genotypes. A is the more common allele for rs1695, with an allele frequency of 64.74%. This means that 41.9% of the general population has AA, and 45.7% have AG. The study therefore implies that 87.6% of the general population has an inflammatory response to vitamin E. Hence having AA or AG at rs1695 and an inflammatory response would be the normal situation, and it would be a small minority of 13.4% with GG who have an anti-inflammatory response to vitamin E.

So basically, your genotype makes you completely normal. It does not cause fatigue, since nearly 9 out of 10 people in the world are obviously not fatigued. And it's very unlikely that it would cause fatigue even in the presence of vitamin E, since nearly everyone taking vitamin E would experience and report the same fatigue.
 

nandixon

Senior Member
Messages
1,092
@Valentijn
Everything you wrote is basically correct, I think. Except, however, the issue I was looking at isn't whether supplementing with additional vitamin E might cause fatigue in normal healthy individuals. It's whether it might exacerbate existing abnormal fatigue (exhaustion, tiredness) in individuals with ME/CFS.

I know you often indicate that you don't suffer from any fatigue, so I can see where this concept might be unfamiliar.

Taking any significant amount of supplemental vitamin E certainly exacerbates my ME/CFS fatigue (as does vitamin D, DHA/EPA, and some other things).

Whether these particular SNPs are actually playing any role in that exacerbation of fatigue by vitamin E would obviously require additional study. It's just an interesting possibility.

@thevirusz
You would have to actually experiment with supplementing vitamin E to see whether it has any effect - bad, good, or none. And whatever your results, they may or may not be related to the SNPs that are the subject of this thread.

You're not likely to be able to predict ahead of time the personal significance of any common SNP (i.e., one having a minor allele frequency >1%). There are too many variables - other offsetting SNPs, rates of gene expression, epigenetic factors, comorbid disease, etc.
 
Messages
7
Hi all,

Thank you for the feedback.
It seems so hard to translate methylation and detox results in to actionable diet changes.
The goal is to positively impact our lives by doing these tests, but that is proving quite hard for me.

I opened a dedicated topic for my question btw :)

"A struggle through seemingly conflicting SNP outcomes. Help?"
 

TheChosenOne

Senior Member
Messages
209
I have all the risk alleles (AA, GG, TT) and I don't really have a negative reaction with regards to vitamin E.
I'll take a high dose tomorrow (1000 IU) to be sure.