Friday, 28 August 2015

ResearchSpeak: Vitamin D and MS risk

The best time to plant a tree is twenty years ago. The second best time is now. #ResearchSpeak #MSBlog #MSResearch

"The study below on vitamin D (vD) and MS risk confirms what we already know that low vD levels increase your risk of getting MS. What is really very neat is how the investigators' did this study; they used a very cool method called Mendelian Randomization. Yes, Mendelian comes from Gregor Mendel the monk and father of modern genetics. What you need to remember  that vD levels in your blood are not only related to recent sun exposure and diet, there are several genetic variants that also contribute to your blood levels of vD. For example, a variation the function of a vD activating enzyme will affect your vD levels; if you happen to inherit the variant that is less active your vD levels will be lower than someone with a more active enzyme. These genetic variants are inherited and pass from parents to offspring according to the laws of Mendelian genetics. Mendelian randomization is simply the method of using the genetic variants as a proxy for the biological process under study; it allows you examine the causal effect of a modifiable exposure on disease in a non-experimental way."


"What this study showed that four genetic variants in the genome were significantly associated with vD levels, specifically the 25-hydroxy, or 25OHD, form of vD. Using a Canadian population from an osteoporosis study they found that the number of vD decreasing variants was strongly associated with lower vD levels. Using this information they were able to impute genetically low vD levels based on the number of genetic variants. In short, for each genetically determined one-standard-deviation decrease in vD level (log-transformed) conferred a 2.0-fold increase in the odds of getting MS. In summary genetic causes of low vD levels increase your risk of getting MS. This confirms other evidence linking low vD levels to MS risk."

"How important is this study? Very! It also suggests that is specifically low vD levels, and not lack of sunlight exposure, that is the risk factor for getting MS. What should we do about? We should start an International MS Prevention Study, or possibly two, ASAP. A great disappoint was the output, or more correctly lack of output, of the NMSS vD Prevention Task Force meeting I attended in April 2011 (see programme below). All the MS vD Experts were invited to attend the taskforce meeting with the hope of designing an International Trial vD prevention trial. Unfortunately, there was no consensus and the output of the meeting never saw the light of day; tragically no trial was ever started."

"The next generation of MSers will almost certainly look back at us and say: 'You knew about the link between low vD levels and MS risk and you did nothing about it. Why? I now have MS because of your inactivity'. I will respond: 'guilty as accused!'."




“The best time to plant a tree is twenty years ago. The second best time is now. We really have no excuse not to do an International vD MS Prevention Trial.” 


Mokry et al. Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study. PLoS Med. 2015; 12:e1001866.

BACKGROUND: Observational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.


METHODS AND FINDINGS: We identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple SclerosisGenetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.

CONCLUSIONS: A genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.

50 comments:

  1. To begin with GP's could advise those who have had glandular fever to take vitamin D tablets.
    Seven months after I experienced my first MS relapse/symptoms I was tested for vitamin D for the first time and it was low at 23 nmol/L. I requested blood tests and i'm glad I did. It would of been interesting to know what my vit D level was at the time of my first relapse.

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  2. How does this account for the latitudinal gradient in MS epidemiology? What does this say regarding low vitD levels as a consequence or cause?

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    1. As these are people with a genetic propensity to have lower vitamin D (from birth) it would indicate that low vitamin D is a cause of MS but just one of many. The risk factor is doubled in this group. It would back up the latitudinal gradient for MS, where the further from the equator, the less sunlight intensity therefore the less ability to make vitaminD from sunlight and a higher incidence of MS.

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    2. I would argue it is not the sun intensity, as such, but the length of the time when you cannot make vitamin d from sun light. It is how many months in a year the UV index stays below 3.

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    3. That's what I meant to say. we certainly don't make much vitamin D from sunlight in the UK for much of the year.

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    4. As Prof G states : "It also suggests that is specifically low vD levels, and not lack of sunlight exposure, that is the risk factor for getting MS" Since everywhere on the planet receives the same amount of sunlight throughout the year it would seem that genetic variances in the way vitD is stored and/or metabolized have a determining factor in MS. Populations in the far North and South latitudes receive the most sun exposure in the long summer months and produce large amounts of the vitamin. I would argue that these people have evolved to store vitD and subsequently release it during the short winter days. Maybe MSers with decreasing allele frequency and less genetic variances for 25OHD were unable to store and release vitD properly and were predisposed to developing MS.

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    5. Vitamin d is produced specifically by UVB in the sunlight not sunlight itself. UVB is absorbed by the atmosphere and so only when the sun is high in the sky can you make vitamin d. So the long daylight hours in the summer at high latitudes do not help as the sun is mainly low in the sky. Secondly the UVB in sunlight both creates and destroys the precursor to vitamin d in the skin and so after a short time equilibrium is reached and you can make no more.So production each day is limited, so long days in summer are not an advantage. Thirdly the half life of 25(OH)D in the human body appears to be about 20 to 30 days and the vitamin d winter 6 months long (UK) so those at 30 days may have a slight advantage but it is not that great. The great evolutionary advantage in Europeans was sunburn. In spring, when vitamin d was needed the most, the little UVB present in sunlight forms some precursor in the skin and the heating of the skin makes the conversion to vitamin d more efficient. A second mechanism the body may use to conserve vitamin d when levels are low is to turn off certain uses. So to conserve vitamin d for blood calcium control the immune system uses may stop. Whatever the effect of vitamin d in MS it is only one risk factor, but it is the one that is very easy to fix and at little cost.

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  3. Prevention is great, finding a cure could be better ;) Is there a study (or multiple) testing the regular take of vD as a treatment?

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    1. The PrevANZ Vit D3 trial is being run in Australian and New Zealand
      https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363026
      "To determine the relative efficacy of oral, daily, Vitamin D3 (1,000IU or 5000IU or 10,000IU) compared with placebo, in reducing the risk of recurrent disease activity (clinical demyelinating event or MRI activity) in the 12 months following onset of a first demyelinating event."

      However, I believe that at the bottom end of the doses being used there will be little or no evidence of benefit - especially as many people with MS take 5,000 units or more daily already. Some alternative approaches are heavily into mega-dosing with amounts of up to 150,000 units if your levels are low - recommending maintenance of a minimum level of 150 n/mol and up to 250n/mol be maintained (this translates to 60ng/ml to 100ng/ml).

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    2. This is getting near similar to the Vitamin D Council though they state between 100nmol/L to 200nmol/L (40ng/ml to 80ng/ml) is sufficient. They suggest 125nmol/L (50ng/ml) is the ideal level to aim for.
      http://www.vitamindcouncil.org/about-vitamin-d/testing-for-vitamin-d/

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  4. I would argue that the trial of vitamin d as a way of avoiding MS is already under way. It started when countries started giving children vitamin d supplements in a concerted manner.

    All we need now is to get the RDA to a sensible value.

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  5. First relapse in january 2014, then in may, then in june, then in february 2015 and nobody: nor GP, nor neuro, nor MS neuro, nor MS nurse, told me nothing about vitamin D. In UK.

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    1. Anon at 4.22pm - that is really appalling that all of your treating clinicians were so ignorant.

      However, as Prof G has noted above "The best time to plant a tree is twenty years ago. The second best time is now." - so go for it with the VitD3 now. First priority (if you have not already done so) is to get your levels checked, and inform yourself about what a suitable level for PwMS is. Do not just get fobbed off by your doctor telling you that your levels are fine - insist on being told the actual results - you are entitled to this information.
      (depending on where you are the results may be in ng/ml or n/mol - the conversion factor is 2.5 i.e. 50ng/ml is the same as 125n/mol).

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    2. Thanks. I'm taking 10.000 ui vitD3/day for my own way after read all Prof G posts about. I feel better.

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  6. Prof G, I keep reading that vitamin K could be benefitial to take and as important as taking vitamin D. Vitamin K for brain health and bones. Vitamin K1 found in green leafy vegetables and bacteria produce K2 in the gut.
    I was thinking that if MSers may have problems in the gut. Terry Whals diet includes lots of vegetables (including green leafy) to help symptoms.
    Vitamin K for MS might be an interesting area for research?

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  7. My big question about Vitamin D3 is: after the disease began as D3 should be taken? And if this replacement really make a difference in the evolution of the disease ... It has a neurologist "crazy" here in Brazil who claims to have created a protocol to base the daily replacement of the D3, but are even high doses, more than 40,000 iu per day. I know some of his patients, only deal with these high doses of D3 and make a free diet full of calcium, no DMT, some are good, they report doing such a protocol for over 05 years, but others continue to relapse and or progression disease ... So my question is, D3 would be a factor to prevent or actually after the established disease resetting it may or may not change the setting of MS?

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    1. 40,000IU a day of vitamin d is about the level you will see toxicity in some people after a number of months. Toxicity from vitamin d occurs when the 25(OH)D levels in the blood become so high they disrupt the ability of the parathyroid and active vitamin d [ 1,25(OH)D ] hormone to control the blood calcium levels. The 'crazy' here is using calcium restrictions to reduce the risk of toxicity.

      If we assume that vitamin d can affect MS after it is started and that evidence is limited,then those with genetic defects in producing vitamin d would be helped, but those with genetic defects in using vitamin d would see no effect. We cannot check for genetic defects in using vitamin d in controlling MS as we have no idea how it would work.

      Cinara: 10,000IU a day has never been observed to cause toxicity and 79nmol/L is actually still quite low. Toxicity set in around 750nmol/L.

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    2. The Vitamin D Council state that toxic levels are over 375nmol/L (150ng/ml).

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    3. The Vitamin D Council put in a safety margin, which is sensible as there are lawyers about. 750nmol/L is from Am J Clin Nutr. 2008 Aug;88(2):582S-586S. Pharmacokinetics of vitamin D toxicity. Jones G.

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    4. We all could debate about this for a long time (debating is good). The paper from 2008 is quite old and I wonder if research has moved on since then. Vitamin D toxicity is dangerous as can cause irregular heat beat and eventially can weaken bones. Other consequences of vitamin D toxicity is a buildup of calcium in your blood (hypercalcemia), which can cause poor appetite, nausea and vomiting. Weakness, frequent urination and kidney problems also may occur.

      Perhaps a doc from Team G could comment? thanks

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    5. The subject of vitamin D in Brazil causes a lot of debate and controversy, and I think the theme CCSVI causes in other countries ... What I can say is I know patients who are doing well such a protocol with very high doses of VD without DMT, as I know patients who remain tend disease progression. Those who advocate such treatment do not publish one article about it. So for more until it can be sure "foundation" in theory it should be brought to the test of serious study, to be published and put on analysis of the scientific community ... I think it's the RV another factor preventing IN that right is even achieve it sufficiency in the body ... Here in Brazil at least is considered within the normal VD rates between 50-100 nmol / L of blood ... So for now I will continue with the 10,000 daily and ui looking for parathyroid hormone levels, under the gaze of my neuro, which for now for the parameters here are good ... If consensus about change there then I "change" next ...

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    6. AnonymousSunday, August 30, 2015 8:32:00 a.m. All the symptoms of vitamin d toxicity are those of high blood calcium (hypercalcemia), there are no other known toxic effects. The symptoms in your list have one cause and if the blood calcium is not high there is no toxicity. By the way, you can get high blood calcium levels from very low 25(OH)D as well.

      If anything the world is now less worried. "Vitamin D Is Not as Toxic as Was Once Thought: A Historical and an Up-to-Date Perspective MF Holick - Mayo Clinic Proceedings, 2015 - mayoclinicproceedings.org"

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    7. It is sensible for anyone starting vitamin d to watch for toxicity symptoms even at low doses , because the effects of diseases such as granulomatous disorders (sarcoidosis), William syndrome, some lymphomas, and genetic disorders (absence of the 25-hydroxyvitamin D-24 hydroxylase.) are masked by very low vitamin d intake. Given even small amounts of vitamin d they cause high blood calcium levels because the conversion of 25(OH)D to 1,25(OH)D is not regulated. Sarcoidosis and 1,25(OH)D generating lymphomas is how it was realised that vitamin d played a part in the immune system.

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    8. Can I recommend the following article on vitamin d for those wanting a modern view on toxicity: "Changing Incidence of Serum 25-Hydroxyvitamin D Values Above 50 ng/mL: A 10-Year Population-Based Study" May 2015 Volume 90, Issue 5, Pages 577–586, Mayo Clinic Proceedings. It is open access.

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    9. A good debate is so educational to get a wide range of views. Good Stuff!

      I've not thought about watching out for toxicity symptoms but I will now.

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    10. Another view on high vitamin D levels is this study from 2015.
      Scientists from the University of Copenhagen have now shown a connection between high levels of vitamin D and increased risk of cardiovascular deaths.
      http://healthsciences.ku.dk/news/news2015/high-levels-of-vitamin-d-is-suspected-of-increasing-mortality-rates/

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    11. I've personally seen in front of me some MS patients who took high vitamin D (> 40K IU/d) as a sole therapy and after some months/years had a remarkable improvement in both the symptoms and RMI (the lesions actually shrank and some disappeared). The trick is not to be concerned in the 25OHD levels when adjusting the vit. D dosage, but in the PTH levels, which should be close to the normal lower range. I am convinced it is far better at modifying the disease than IFN. Despite it working with almost zero side effects, if blood calcium levels are monitored, and a low-calcium diet is prescribed, there are ethical issues and liabilities that may arise from using doses higher than the UL.

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    12. This can be regression to the mean as MS becomes less active with time

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  8. I think you've answered your own question there "but others continue to relapse and or progression disease". Your body requires micronutrients for a variety of reasons and vitamin D is the same. Deficiency might be the key and increased amounts above a certain threshold may not make any difference. In cases like vitamin A, you can become toxic from it - ergo the advice that you don't try and make up your deficit by taking more multivitamins.

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    1. Thanks Neuro Doc Gananapagvan. No, I did not mean, nor plan to do the protocol to why I still see no reason to be so. I already thought that it would not do much "take-liter" Vitamin D after the start of the disease. I do the daily replacement but with the D3 at a dose of 10,000 UI, under the guidance of my neuro. And I'm realizing the control of serum levels of VD every 6 months at the beginning of the disease was about 22 noml/L, I am currently with 79 nmol/L and blood calcium levels are controlled, it is good, or not ? I think yes, maybe...

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    2. Brazilian neuro says only 5% patients don't respond to treatment high doses vitD. I think he is necessarily "crazy" for change the future of DMT

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  9. I hate to wright this again it was brushed off be for, res more women with ms I had read where experiments with monkeys 40 years under stress and we all know women stress over nothing they found the vt d was not getting to the parts of the brain it was so post to when they did an autopsy. am not saying men to and how can it be explaned in kids ,maybe stress to .

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    1. Dear Anon
      We get lots of posts of comments on stress and we are well aware of the importance of stress. If you read comments someone mentions stress every couple of weeks, (it may be the same person) and there is no point replying yes stress does appear to be important but as stress is such a difficult thing to quantify and means different things to different people.

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    2. Yup MD - it is often the same person - you can always tell when it is because they don't know the difference between affect and effect when they write their comment i.e. "stress effects MS...."

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    3. Anon at 2.27pm I think you must be mistaken. If we do a search on this blog stress and MS goes back some years.
      Take for example
      http://multiple-sclerosis-research.blogspot.com/2012/08/survey-results-stress.html
      83% on this survey replied yes stress exacerbates MS on the 20th Aug 2012. I had my first MS symptom many months after this. I didn't really know what MS was until my doctor said I might have it.....

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    4. You can always tell.....i'll keep an eye out.

      Anon 5:54 I think you you need to search the comments compared to the posts

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    5. Anon at 12:37 I would suggest you could read different MS forums such as the MS Society, this topic often comes up which is sad to see, do a search of comments and threads.

      MD do you read these forums? they are good to get an idea of what were going through.

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    6. Every one of the MS Organisation websites in various countries (The UK's MS Trust is one of the best sites) which I looked at when I was first diagnosed mentions stress - the information is out there about managing stress and its negative effects on MS. These days, with almost every clinician being overworked and time-poor it is almost "mandatory" for patients to do some research on their own behalf, and be pro-active in learning about their health condition/s, and that includes what is good or bad for whatever it is they are diagnosed with. These days it is essential that patients share the driving and not just be a passenger on their health journey.

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    7. Anon at 2:27 are you pharma rep, troll or just generally not a nice person?

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    8. Anon at 9.17 pm on Sept 2
      This is Anon at 2.27pm
      I am none of those which you list - just a person with MS whose future is no longer what it used to be a few years ago thanks to the disabilities caused by MS. The person with stress issues posted many many comments on this blog about stress (all identifiable by the confusion between affect and effect), and others (including me) responded with supportive and practical comments about how to deal with stress, the risks of clinging on to stress as a cause of everything to do with MS, and how to move on from blaming all in the medical profession for what had happened.

      It was clear from the comments posted in an effort to support and help the original poster that many other people had had similar extremely difficult journeys on the road to diagnosis, have suffered from seeing clinicians who should have known better or more, but we had all moved on with a recognition that clinging to the wrongs of the past was not good for us or for our MS. It was a bit sad really, but has become apparent over time (from their posts) that this person has made progress and started to take control of their own life - which we all have to do at some point, even though this b.... disease can be so unpredictable.

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    9. Your comments are not supportive I am sorry to tell you, not one bit and it seems any comment with a spelling mistake you think is written by the same person.
      You do not know what I went through, you have no idea. I have moved on and I would not begin to judge your MS journey, I do not know your MS history in fine detail.
      This blog is not a friendly forum I get that. You comments put me off reading this blog.

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    10. Soory you feel this way.....to answer anon. Sorry i dont read the forums because thos will take up more of my day but i guess you can try unrelated comments to address burning issues

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    11. MD the person that made comment August 29, 12:37pm is not the same person as Anon September 03, 8.41pm. You can tell by looking at the comments.

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  10. I don't get it. "...if you happen to inherit the variant that is less active your vD levels will be lower than someone with a more active enzyme." If the evolutionary drive for efficiency of vD production led to lighter skin tones in areas of the planet receiving less UVB, why has there not been the same evolutionary drive towards elimination of genetic variants which scupper vD production? I mean, there's not much point in me being pale as Dracula if I have crap genes which don't allow my body to make use of that? Unless pale skin arose for biological reasons largely unrelated to vD production.

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    1. Heading off on a tangent, but this may supply part of the answer I was looking for: https://www.ucsf.edu/news/2014/06/115741/human-evolution-changes-skin%E2%80%99s-barrier-set-northern-europeans-apart

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    2. I would argue that white skin is not to increase overall vitamin d production but to reduce the length of the winter. As vitamin d has a half life in the body of 20 to 30 days and the vitamin d winter in Northern Europe is 6 months long people are always going to be deficient by spring no matter how much they started with in the summer. Our ancestors with white skin would have much more sun exposure than modern Europeans as they spent a lot of time out doors and therefore would show some tanning in the summer/autumn. In the early spring sun burn would heat the skin improving the vitamin d production rate from the limited UVB. The driving force behind this evolutionary change is likely related to calcium (rickets) and child birth rather than MS, and trades a short term advantage at breeding age for a long term disadvantage afterwards.

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  11. For vitamin D to work well other vitamins and minerals are needed, these include vitamin K, vitamin A, boron, zinc and magnesium. These can all come from a good healthy diet and for me it really show's the importance of eating enough different fruit and vegetables, nuts and seeds and whole grain. I also eat some fish and chicken.

    This is a reason why diet and MS needs research.
    Zinc suppliments are not advised for those taking immunossuppressants (including prednisone) without speaking to a doctor first.

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  12. One of the greatest problems with vitamin d research, if I may put it politely, is that it is under powered. So the paper that generated headlines like "Vitamin D may be harmful for obese teenagers" and "Obese Teens May Not Reap Vitamin D Benefits: When Supplements Hurt More Than Help" (at least 100 that I counted) was an open label trial of 19 obese adolescents using 100,000 IU/month for 3 months. The drop in parathyroid hormone was significant but ignored in the press release, while the effect on triglycerides or cholesterol was small. I stuns me this got past the reviewers.

    There was a double blind trial of vitamin d that used 400IU/day, which when you looked carefully, let both arms of the trial take up to 1000IU a day if they wished. and no record was kept.

    There is a paper which shows a U shaped curve of vitamin d against a heart risk factor, but when you look the graph only has 3 points (the centre of 3 ranges) and they have basically joined the dots. And the U shape only appear after you have adjusted for things like BMI.

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  13. I am thinking along the lines of trying to future proof from MS. Would it be the case that if you were a mother with MS and you had four daughters, one of whom already has an immune disorder and another has had glandular fever and they have not yet reached adulthood - if it was feasible assuming that the cost was bearable to have mother and daughters tested and the results indicated that the daughter having had glandular fever an additive risk factor and another daughter had the same variant - would it be prudent to commence Vitamin D supplementation now? Of course the answer will be that RCT would need to be sort out the many factors involved in this question not the least being the longitudinal nature of follow up. Vitamin D is a cheap and effective multipurpose supplement - would it do harm to the daughters if a blood test indicated low Vitamin D levels? I realise the question of dose is moot at the moment.

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    1. My mother had MS and I have MS, we talked to our pediatrician about our daughters aged 3 and 5 - the recommendation was to supplement with Vitamin D. I think that you should speak with your doctor before starting any supplements.

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