Sunday, 25 September 2016

Demystifying vitamin D: new study links variants in vitamin D genes to risk of MS

Abstract
Objective: We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.

Methods: We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18–20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.

Results: Findings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p 5 0.04, 95% confidence interval (CI): 0.64–0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p 5 0.03, 95% CI: 0.76–0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p 5 0.003, 95% CI: 0.76–0.94). No association was observed for age at onset or disease severity.

Conclusions: These results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors.

The interpretation
The association between low levels of vitamin D and the risk of multiple sclerosis (MS) has been demonstrated in several big studies. There is clearly a correlation between vitamin D status and MS risk, but this does not imply causation. It is difficult to tell from big observational studies whether vitamin D deficiency causes MS or whether there is something else going on. This graphic depicts three possible explanations for the observed association:


Potential explanations for the observed association between vitamin D status and MS risk


This question is important because if we had unequivocal evidence that low vitamin D increased peoples’ risk of developing MS, we would have a stronger case for prescribing vitamin D as a preventative measure for selected patients.

Why is it so tricky to prove a causal relationship between vitamin D status and MS risk? In big population studies of MS, investigators do their best to measure all kinds of variables – factors that could influence risk - and they try to control for these when they analyse the data to look for causal relationships.
However, these studies cannot ever fully overcome the problem of reverse causation - the possibility that MS causes low vitamin D levels - and the problem of confounding – the possibility that other factors, such as ethnicity, sunshine exposure, or obesity predispose to MS independently of their effect on vitamin D status.

So, how can we ever work out if low vitamin D causes MS in big population studies?

Lisa Barcellos and friends have come up with a clever answer to this problem. They used a technique called Mendelian Randomisation to get around the problems of reverse causation and confounding. The approach is called Mendelian Randomisation because it relies on one of Mendel’s laws of inheritance – this states that which alleles (versions) of a gene are inherited is independent of the inheritance of other genes. Everyone in the population will therefore have a random selection of alleles affecting vitamin D status. So if you know how these alleles relate to vitamin D status, you can use the genotype (i.e. the set of alleles someone has) as a surrogate marker of vitamin D status. This obviates the problems of reverse causation and confounding.

Barcellos et al found 3 single nucleotide polymorphisms (SNPs) from published work that are closely associated with vitamin D levels. They then tried to see if these SNP alleles were associated with MS risk, age of onset, and disease severity.

This approach is neat because SNPs are encoded in the genome for life - they are not affected by lifestyle factors, environmental factors, or by MS itself. So if these SNPs provide an accurate surrogate marker of vitamin D status, they provide a simple way of determining whether low vitamin D levels actually cause MS, rather than just being correlated with it. This approach to studying associations can be thought of as a natural randomised controlled trial, whereby MS risk can be compared in people with SNPs predisposing to low vitamin D vs. those with SNPs predisposing to normal vitamin D.

This study collected data from 2 separate massive cohorts, totalling a whopping >7000 people with MS and >14000 healthy controls. The pooled odds ratio for developing MS was 0.85, meaning that the odds of developing MS are significantly reduced by having genes that predispose to normal vitamin D. There was no association between these SNPs and either age of onset or severity.


The Mendelian Randomisation method for studying the relationship between vitamin D status and MS risk


While population data is never going to be as convincing as a randomised controlled trial, this study provides quite strong evidence that vitamin D status has a causal role in determining risk of MS. These findings only apply to Caucasian people, as non-Caucasian people were excluded from the study. A key assumption of this study is that the SNPs assessed only influence MS risk via their effects on vitamin D status – while we have no evidence that this assumption is wrong, we do not know what the exact function of these SNPs is, and so it is possible that they have as yet unknown effects which influence MS risk.

We now have another important piece of evidence that low vitamin D causes a slight increase in MS risk. But it is a separate question whether supplementing vitamin D reduces the risk of developing MS. Unfortunately this can only be answered through a well-designed randomised controlled trial.







10 comments:

  1. I wonder how one could design proper controlled *prevention* study
    especially given relative rare occurrence of MS in population

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    Replies
    1. Hi vasy,

      You're right - with great difficulty. That's why we probably won't get better evidence than this in my opinion. Once we understand more about who is at risk of Ms is May be easier to do a prevention trial in carefully selected 'at risk' people

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    2. What about trialling the children of PwMS?

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    3. "What about trialling children of pwms?"

      I am RRMS, my dad's brother also had it. My 15 year old daughter's vit D level was under 25. She is seeing a paediatrician (it took 7 GP appointments to persuade them to refer her) for painful loose joints, frequent unexplained bouts of dizziness which are always worse when she has a virus and can last a few days (Ehlers Danlos so far ruled out)with lethargy. She has moments of confusion/going blank, bouts of anxiety and has felt a tapping sensation on her head.
      I worry and do try not to over think these things, but it is difficult.
      I have wondered whether it would be useful for someone to monitor her progress, though I wouldn't want to scare her, I wonder if it could be done from a distance. If she were to develop ms in the future it could be useful to someone to have seen how things went at an early stage.
      She is prescribed D3 1000iu daily.

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    4. I find the RDA for vitamin d truly weird. The RDA for a new born baby is 400IU a day (a new born weighs on average 3.5kg). The RDA for a fully grown adult (say 100kg) is 400IU a day. Vitamin d is stored in the blood as 25(OH)D and is measured as weight of 25(OH)D per unit volume. Assuming that weight approximates to volume, the adult has 28 times the volume, so why is the RDA not 28 times higher? I most obviously should not be the same.

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  2. It is Dr.BenJ, this theme of Vitamin D and MS is very controversial. Here in Brazil has a neurologist who applies a "proper treatment protocol" with extremely high daily doses of vitamin D3 and a fully restricted diet of calcium, accompanied by drinking plenty of water. Has even commented here that when I say high doses are high even: up to 20,000 IU / day of D3. So I know people who follow this protocol and are for years without relapses or progression of MS, and also know who made the D3 protocol and had worsening of disease. According to some, this neuro must have a base of 5,000 patients being treated with this protocol, only he does not publish a study about.

    But anyway, what could be behind this answer or without Vitamin D3?
    Vitamin D3 was actually controlling the immune system and/or intestinal bacteria?

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  3. The other confounding factor in all of this, that is constantly ignored, is that there are two ways to have a higher 25(OH)D. One is to be more efficient at harvesting it (from sun, food or supplements) and the other is to not use it. People who are good at conserving vitamin d may do so by turning off the very mechanism that protects against MS. The answer will only come from long term study using doses of about 10,000IU a day taken every day. But as as a rule of thumb everyone is deficient so take a supplement.

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  4. Moreover it is a question that I have, and I think that science also has: if there is this causal link between vitamin D deficiency and MS, for the simple replacement it can not stop, stop the disease in those who have disease highly active or progressive, for example?

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  5. I've been reading that some drugs cause the body to absorb less vitamin D. These include laxatives, steroids, and anti-seizure medicines. So would it be important then for those taking anti-seizure medicines such as Gabapentin, Phenytoin, Pregabalin have their vitamin D monitored, such as once a year or every six months?

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  6. I have MS and I get my adult children to take 10,000 iu of vitamin D. Since my daughter has been doing that she does not suffer from migraines any more. I have read you would need much more than that per day for it yo become toxic

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