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.

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