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CYP2R1 SNP and Low Vitamin D

Peyt

Senior Member
Messages
678
Location
Southern California
Hello,

I have rs2060793(A;G) and I am usually low on Vitamin D especially in the winter time. Unfortunately, I am not able to tolerate Vitamin D supplements because it gives me really bad headaches. (I have tried at least 5 brands/ both capsule and tincture, all of which give me violent headaches).... So what I have noticed is every year, about 1 month into summer time, all the pain in my body reduces and goes away and again in November it comes back ... This has been happening all my life..

My question is: Is there any supplements that you know of that could benefit this SNP besides taking straight Vitamin D? I must add I have never tested low on Iron and my Iron has always been normal at least on the blood level.

Thank you so much in advance
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
The CYP2R1 gene provides instructions for making an enzyme called 25-hydroxylase. This enzyme carries out the first of two reaction steps needed to convert vitamin D to 25(OH)D and then to its active form, 1,25-dihydroxyvitamin D3, also known as calcitriol. Serum concentrations of 25(OH)D that most people test reflect vitamin D status, because 25(OH)D is the major circulating metabolite of vitamin D. CYP2R1 is the principal hepatic (liver) 25-hydroxylase responsible for the hydroxylation of parent vitamin D to the 25-hydroxyvitamin D [25(OH)D]. In the second step, the 1α-hydroxylation of 25(OH)D in the kidney by CYP27B1 generates the fully active vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25(OH)2D).

So that just means that if someone were to have numerous mutations in CYP2R1 that did not have other mutations to compensate elsewhere, there could be a lower level of 25(OH)D. If tested truly deficient such as under 10-12 ng/ml then taking a supplement may benefit that person which would bypass the conversion problem to 25(OH)D. That person however may have other mutations elsewhere to compensate such as CYP24A1 which normally breaks down active vitamin D might be mutated to increase levels as but one example. A couple snps also may not even have much effect so dont mess with things just because there are snps. This just suggests to listen to your body, if you get bad headaches taking it and you have snps, the likelihood is that you should not attempt to bypass mutations in those areas because the genes are mutated for a reason. Some people actually do better with lower vitamin D or at least taking less or only when inflammation is higher as too low inflammation is just as bad as too high. Blood type A's may be one of those groups I'm finding.

A level of 20-29 ng/ml is quite normal, in fact if its over 30 ng/ml magnesium helps lower the level back down to 30. Magnesium was found to have a regulating effect, raising and lowering vitamin D levels based on the original starting baseline 25(OH)D levels. In those people who had a baseline 25-D level of 30 ng/ml or below, magnesium supplementation raised up their 25-D level as expected. However, In those who started out with higher 25-D baseline levels starting around 30 ng/ml (75 nmol/L) up to 50 ng/ml (125 nmol/L), magnesium supplementation LOWERED THEIR 25-D levels back down, not raised 25-D levels to even higher levels. Magnesium regulates vitamin D levels, low magnesium impedes your body's ability to utilize vitamin D, even when it's present or taken by supplementation. Magnesium deficiency shuts down the vitamin D synthesis and metabolism pathways. https://academic.oup.com/ajcn/article/108/6/1249/5239886
 
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Judee

Psalm 46:1-3
Messages
4,395
Location
Great Lakes
Not sure about that particular snp but I just reading some things in the Coimbra MS group online.

I was searching for a different topic but read a post that mentioned progesterone upregulates VDR and as datadragon mentions also magnesium I believe was mentioned at some point. ??? (I would still say to be careful with experimenting with hormones though.)

I am also A,G on that gene.

That one wasn't on my Sterling's App download but several others were.
 

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Peyt

Senior Member
Messages
678
Location
Southern California
The thing that is a mystery to me is that every winter the pain in my body gets really bad and in the summer it gets much better... The only other thing that shows up on regular blood tests is high Uric Acid. I have had 1 episode of Gout as well.

Does anyone know if there is any correlation between winter time and uric acid going higher? Or maybe I should ask: Is there a correlation between low Vit D and High Uric Acid?
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
You might consider trying a bright light therapy box to see if it improves your condition in the winter and if the negative symptoms are the same as when taking vitamin D. 10,000 lux is the recommended amount for effective light therapy.
https://verilux.com/pages/10000-lux
https://www.amazon.com/s?k=10,000+lux+light

Yes there are certain times such as dealing with an infection or very high inflammation that additional vitamin D may be warranted. @Judee - The vitamin D binding protein (DBP) increased significantly after estrogen and there was a significant positive correlation between the plasma concentration of 1,25-(OH)2D (active Vitamin D) and DBP. https://www.researchgate.net/public...strogen_on_Vitamin_D_Metabolism_in_Tall_Girls Unlike vitamin A, which facilitates the hepatic secretion of the retinol-binding protein, vitamin D sterols or other calciotropic hormones do not regulate the plasma Vitamin D binding protein (DBP) concentration. Its hepatic synthesis is estrogen dependent and is significantly increased during pregnancy and estrogen therapy. https://www.sciencedirect.com/science/article/pii/B9780128000946000017
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
Does anyone know if there is any correlation between winter time and uric acid going higher? Or maybe I should ask: Is there a correlation between low Vit D and High Uric Acid?

Gout-associated uric acid crystals activate NLRP3 inflammasome (inflammation) so first thing would be to check inflammation levels including c-reactive protein to see if they are high and that might be one contributor of that inflammation. https://www.frontiersin.org/articles/10.3389/fimmu.2019.02538/full Fructose is known to increase serum uric acid and promote NLRP3 inflammasome activation, while also decreasing the active form of Vitamin D 1,25(OH)2D3 levels. Vitamin D can lower NLRP3 inflammasome but so can many other things you can use instead to try to rebalance inflammation lower if that is currently high besides only Vitamin D, or if something is needed to target lowering of uric acid.

Boron helps prevent the breakdown of vitamin D and increases the amount of available vitamin D in the body. Boron suppresses the activity of 24-hydroxylase encoded by CYP24A1, the microsomal enzyme primarily responsible for catabolism (breakdown) of 25(OH)D3 Another study mentioned that after only 1 week of boron supplementation of 6 mg/d all of the inflammatory biomarkers that were measured also decreased: (1) interleukin (IL) 6, from 1.55 pg/mL to 0.87 pg/mL; (2) high-sensitivity C-reactive protein (hs-CRP) by approximately 50%, a remarkable decrease, from 1460 ng/mL to 795 ng/mL; and (3) tumor necrosis factor (TNF-) by approximately 30%, from 12.32 to 9.97 pg/mL.
Levels of dihydrotestosterone, cortisol, and vitamin D increased slightly. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712861/ https://pubmed.ncbi.nlm.nih.gov/22100522/

Some of the studies if interested:
Fructose is known to induce uric acid production by increasing ATP degradation to AMP, a uric acid precursor and thus, within minutes after fructose infusion, serum uric acid levels rise https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197219/ Mechanistically, Fructose promoted the nuclear translocation of nuclear factor-kappa B (NF-κB) p65 to activate the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. https://pubmed.ncbi.nlm.nih.gov/35495917/

Chronic fructose intake decreases the active form of Vitamin D 1,25(OH)2D3 levels. Chronically high fructose intakes can decrease serum levels of 1,25(OH)2D3 in adult rodents experiencing no Ca2+ stress and fed sufficient levels of dietary Ca2+. This finding is highly significant because fructose constitutes a substantial portion of the average diet of Americans. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093611

vitamin D receptor (VDR) is a negative regulator of NLRP3 inflammasome activation (inhibits NLRP3 activation) https://www.frontiersin.org/articles/10.3389/fimmu.2019.02783/full
 
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Peyt

Senior Member
Messages
678
Location
Southern California
Gout-associated uric acid crystals activate NLRP3 inflammasome (inflammation) so first thing would be to check inflammation levels including c-reactive protein to see if they are high and that might be one contributor of that inflammation. https://www.frontiersin.org/articles/10.3389/fimmu.2019.02538/full Fructose is known to increase serum uric acid and promote NLRP3 inflammasome activation, while also decreasing the active form of Vitamin D 1,25(OH)2D3 levels. Vitamin D can lower NLRP3 inflammasome but so can many other things you can use instead to try to rebalance inflammation lower if that is currently high besides Vitamin D, or if needed to target lowering of uric acid.

Boron helps prevent the breakdown of vitamin D and increases the amount of available vitamin D in the body. Boron suppresses the activity of 24-hydroxylase encoded by CYP24A1, the microsomal enzyme primarily responsible for catabolism (breakdown) of 25(OH)D3 Another study mentioned that after only 1 week of boron supplementation of 6 mg/d all of the inflammatory biomarkers that were measured also decreased: (1) interleukin (IL) 6, from 1.55 pg/mL to 0.87 pg/mL; (2) high-sensitivity C-reactive protein (hs-CRP) by approximately 50%, a remarkable decrease, from 1460 ng/mL to 795 ng/mL; and (3) tumor necrosis factor (TNF-) by approximately 30%, from 12.32 to 9.97 pg/mL.
Levels of dihydrotestosterone, cortisol, and vitamin D increased slightly. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712861/ https://pubmed.ncbi.nlm.nih.gov/22100522/

Some of the studies if interested:
Fructose is known to induce uric acid production by increasing ATP degradation to AMP, a uric acid precursor and thus, within minutes after fructose infusion, serum uric acid levels rise https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197219/ Mechanistically, Fructose promoted the nuclear translocation of nuclear factor-kappa B (NF-κB) p65 to activate the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. https://pubmed.ncbi.nlm.nih.gov/35495917/

Chronic fructose intake decreases the active form of Vitamin D 1,25(OH)2D3 levels. Chronically high fructose intakes can decrease serum levels of 1,25(OH)2D3 in adult rodents experiencing no Ca2+ stress and fed sufficient levels of dietary Ca2+. This finding is highly significant because fructose constitutes a substantial portion of the average diet of Americans. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093611

vitamin D receptor (VDR) is a negative regulator of NLRP3 inflammasome activation (inhibits NLRP3 activation) https://www.frontiersin.org/articles/10.3389/fimmu.2019.02783/full
This is excellent information! Thanks so much.
As far as NLRP3 I have rs10733113(G;G) and rs4353135(G;T)
as far as VDR I have rs1544410 TT and rs731236 A,G

Thanks for letting me know about Fructuse. I was consuming a lot of red/black grapes up to about a month ago. But I stopped it because I was gaining weight fast. Ever since I stopped eating grapes the pain has reduced somehow. I have also lost the weight I had gained.
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
Thanks for letting me know about Fructose. I was consuming a lot of red/black grapes up to about a month ago. But I stopped it because I was gaining weight fast. Ever since I stopped eating grapes the pain has reduced somehow. I have also lost the weight I had gained.

Recent studies certainly indicate the relationship between fructose and elevated uric acid. Quercetin and Ascorbic Acid Suppress Fructose-Induced NLRP3 Inflammasome Activation by Blocking Intracellular Shuttling of TXNIP in Human Macrophage Cell Lines. This study revealed that intracellular TXNIP protein is a critical regulator of activation of the fructose-induced NLRP3 inflammasome, which can be effectively blocked by the antioxidants quercetin and ascorbic acid (Vitamin C). https://pubmed.ncbi.nlm.nih.gov/28326454/ Maybe quercetin would be helpful to try in your situation. Quercetin is also in red and yellow onions more than white, capers, asparagus, and apples (not apple juice).

You may find a lot of good information in this article trying to understand fructose intake and association with hyperuricemia. https://www.sciencedirect.com/science/article/pii/S0753332220309884

The Ginsenosides in Ginseng like panax ginseng (korean ginseng) promote the excretion of Uric Acid, and do so even better taken in combination with Anserine. https://pubmed.ncbi.nlm.nih.gov/31311296 Anserine is part of a group of Beta-Amino Acids and Derivatives. Anserine is beta-alanyl-1-methyl-L-histidine, and it is known to come from chicken, turkey, duck, rabbit, tuna and salmon.

at the site of dr. Perlmutter, he has several pages on UA, like www.drperlmutter.com/fructose-uric-acid-and-diabetes These are just some general ideas to discuss with your doctor or practitioner but it sounds like avoiding things that further contribute to your uric acid and inflammation should be more of the focus.
 
Last edited:

Peyt

Senior Member
Messages
678
Location
Southern California
Recent studies certainly indicate the relationship between fructose and elevated uric acid. Quercetin and Ascorbic Acid Suppress Fructose-Induced NLRP3 Inflammasome Activation by Blocking Intracellular Shuttling of TXNIP in Human Macrophage Cell Lines. This study revealed that intracellular TXNIP protein is a critical regulator of activation of the fructose-induced NLRP3 inflammasome, which can be effectively blocked by the antioxidants quercetin and ascorbic acid (Vitamin C). https://pubmed.ncbi.nlm.nih.gov/28326454/ Maybe quercetin would be helpful to try in your situation. Quercetin is also in red and yellow onions more than white, capers, asparagus, and apples (not apple juice).

You may find a lot of good information in this article trying to understand fructose intake and association with hyperuricemia. https://www.sciencedirect.com/science/article/pii/S0753332220309884

The Ginsenosides in Ginseng like panax ginseng (korean ginseng) promote the excretion of Uric Acid, and do so even better taken in combination with Anserine. https://pubmed.ncbi.nlm.nih.gov/31311296 Anserine is part of a group of Beta-Amino Acids and Derivatives. Anserine is beta-alanyl-1-methyl-L-histidine, and it is known to come from chicken, turkey, duck, rabbit, tuna and salmon.

at the site of dr. Perlmutter, he has several pages on UA, like www.drperlmutter.com/fructose-uric-acid-and-diabetes These are just some general ideas to discuss with your doctor or practitioner but it sounds like avoiding things that further contribute to your uric acid and inflammation should be more of the focus.
Thanks again for your great reply and information.
I have tried taking Quercetin before but I was not able to tolerate it . I have the CBS++ gene, I wonder if that's why. Is Quercetin considered a methyl donar?
 

datadragon

Senior Member
Messages
389
Location
East Coast, USA
Thanks again for your great reply and information.
I have tried taking Quercetin before but I was not able to tolerate it . I have the CBS++ gene, I wonder if that's why. Is Quercetin considered a methyl donar?

An “adaptogen” is a plant-based compound that promotes the body’s natural balance within a biochemical pathway, bringing the body back into homeostasis. The term “methylation adaptogen” was first coined by Dr. Michael Stone in Oregon and describes any compound that helps to restore methylation balance, both promoting appropriate methylation and inhibiting aberrant methylation.

Examples of methylation adaptogens include curcumin, betanin, anthocyanins, quercetin, rosmarinic acid, lycopene, and sulforaphane. These phytonutrients are found in abundance in a nutrient-dense diet, but additional supplementation may be helpful in some patients. https://kresserinstitute.com/treating-methylation-supplementing/

Its possible that it was due to over inhibiting inflammation at a time when your body was not currently under inflammation and having the pain. You can open the capsule and perhaps could try taking just a small amount if you want to test and see if you still have intolerance at the time you are experiencing pain and inflammation. I have taken 1/10 or less of a 500mg capsule,
 
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Messages
54
I have tried taking Quercetin before but I was not able to tolerate it
What symptoms did you get of intolerance? I've been trying to add in Quercetin and it's been helpful but when I try to increase to the recommended dose I get extreme tiredness and crash, then after letting it settle for week the next time I try to add it in at a smaller dose I get the crash symptoms earlier 🤦‍♀️
 

Peyt

Senior Member
Messages
678
Location
Southern California
Gout-associated uric acid crystals activate NLRP3 inflammasome (inflammation) so first thing would be to check inflammation levels including c-reactive protein to see if they are high and that might be one contributor of that inflammation. https://www.frontiersin.org/articles/10.3389/fimmu.2019.02538/full Fructose is known to increase serum uric acid and promote NLRP3 inflammasome activation, while also decreasing the active form of Vitamin D 1,25(OH)2D3 levels. Vitamin D can lower NLRP3 inflammasome but so can many other things you can use instead to try to rebalance inflammation lower if that is currently high besides only Vitamin D, or if something is needed to target lowering of uric acid.

Boron helps prevent the breakdown of vitamin D and increases the amount of available vitamin D in the body. Boron suppresses the activity of 24-hydroxylase encoded by CYP24A1, the microsomal enzyme primarily responsible for catabolism (breakdown) of 25(OH)D3 Another study mentioned that after only 1 week of boron supplementation of 6 mg/d all of the inflammatory biomarkers that were measured also decreased: (1) interleukin (IL) 6, from 1.55 pg/mL to 0.87 pg/mL; (2) high-sensitivity C-reactive protein (hs-CRP) by approximately 50%, a remarkable decrease, from 1460 ng/mL to 795 ng/mL; and (3) tumor necrosis factor (TNF-) by approximately 30%, from 12.32 to 9.97 pg/mL.
Levels of dihydrotestosterone, cortisol, and vitamin D increased slightly. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712861/ https://pubmed.ncbi.nlm.nih.gov/22100522/

Some of the studies if interested:
Fructose is known to induce uric acid production by increasing ATP degradation to AMP, a uric acid precursor and thus, within minutes after fructose infusion, serum uric acid levels rise https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3197219/ Mechanistically, Fructose promoted the nuclear translocation of nuclear factor-kappa B (NF-κB) p65 to activate the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome. https://pubmed.ncbi.nlm.nih.gov/35495917/

Chronic fructose intake decreases the active form of Vitamin D 1,25(OH)2D3 levels. Chronically high fructose intakes can decrease serum levels of 1,25(OH)2D3 in adult rodents experiencing no Ca2+ stress and fed sufficient levels of dietary Ca2+. This finding is highly significant because fructose constitutes a substantial portion of the average diet of Americans. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093611

vitamin D receptor (VDR) is a negative regulator of NLRP3 inflammasome activation (inhibits NLRP3 activation) https://www.frontiersin.org/articles/10.3389/fimmu.2019.02783/full
Just wanted to give a report back.

I have been using small amount of Boron Citrate for about 2 weeks now. I started with just 1mg and have increased it slowly to 3mg. I have noticed that for the first time I am sleeping 6 hours per night which is great. I have no side effects which is awesome.

I also started taking very small amount of Luteolin (I open the capsule and sprinkle a little on my food).. The first day I had a light headache, but it was tolerable, and yesterday I had no side effects and my afternoon headache that usually comes on did not... It's only been 2 days so I can't say much now, but I am very hopeful.

I have also been taking some Vitamin C (Ascorbic) hoping it will reduce the Uric Acid along with Luteolin but I have seen a bigger response from only 2 days of Luteolin than 10 days of Vitamin C.

Meanwhile the pain in my body has reduced although I still have a lot of low back pain. I am hopeful to see if my low back pain reduces after using Luteolin for 2 weeks or more.

Thank you so much for your recommendations.
 
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L'engle

moogle
Messages
3,167
Location
Canada
I also find luteolin is somewhat helpful. I've been trying the mast cell stabiizers. (luteolin, quercetin, resveratrol, Vit c)
 

L'engle

moogle
Messages
3,167
Location
Canada
What does resveratrol do exactly?
Is it to improve blood circulation?

Its in the list of mast cell stabilizers. I don't know in detail how it differs from the other ones as I'm just trying them out. There's a lot of info online about resveratrol.