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Onderaan abstract + link naar volledig artikel in Plos Medicine
Persbericht McGill universiteit Canada
Association between low vitamin D and MS
Having low levels of vitamin D doubles the risk of developing multiple sclerosis, an association that researchers conclude supports a causal relationship
Low levels of vitamin D significantly increase the risk of developing multiple sclerosis (MS), according to a study led by Dr. Brent Richards of the Lady Davis Institute at the Jewish General Hospital, and published in PLOS Medicine.
This finding, the result of a sophisticated Mendelian randomization analysis, confirms a long-standing hypothesis that low vitamin D is strongly associated with an increased susceptibility to MS. This connection is independent of other factors associated with low vitamin D levels, such as obesity.
“Our finding is important from a public health perspective because vitamin D insufficiency is common, especially in northern countries like Canada where exposure to sunlight – a common natural source of vitamin D – is decreased through the long winter and where we see disproportionately high rates of MS,” asserts Dr. Richards, who is also an Associate Professor of Medicine and Human Genetics and William Dawson Scholar at McGill University. “We would recommend that individuals, particularly those with a family history of MS, should ensure that they maintain adequate vitamin D levels. This is a common sense precaution, given that vitamin D supplementation is generally safe and inexpensive.”
Adequate intake of vitamin D is defined by the United States’ Institute of Medicine as 600 international units per day for both males and females under the age of 70. Many people, especially in northern climates, may require supplements in order to maintain this level.
The most common permanent neurological disorder affecting young adults
MS, a progressively degenerative disease, is the most common permanent neurological disorder affecting young adults. It is a debilitating autoimmune condition that most often strikes people in their twenties or early thirties. The prospect that vitamin D may serve as a protective measure to prevent its onset is a very exciting development.
The link between vitamin D insufficiency or deficiency and risk of developing MS has been an important area of investigation in the MS research community,” says Dr. Karen Lee, Vice President of Research at the MS Society of Canada. “This research brings us a step closer to understanding whether low vitamin D is a trigger of MS and not just a result of the disease itself. I’m encouraged by the data and hope that it will prompt further research into whether supplementing with vitamin D could reduce the risk or slow the progression of MS.”
By taking the precaution of maintaining a normal level of vitamin D, a person at risk could decrease their risk of acquiring MS by an important degree. “While low vitamin D is by no means the only risk factor, we have identified one risk that can be removed from the equation, which could have a significant impact towards preventing this terrible disease,” concludes Lauren Mokry, who is the first author on the paper and a graduate student at McGill University.
Publicatie – zie link volledig artikel:
“Vitamin D and risk of Multiple Sclerosis: a Mendelian Randomization Study,” by Lauren E Mokry, Stephanie Ross, Omar S. Ahmad, Vincenzo Forgetta, George Davey-Smith, Aaron Leong, Celia MT Greenwood, George Thanassoulis, J. Brent Richards. PLOS Medicine
HTTPS://WWW.MCGILL.CA/NEWSROOM/CHANNELS ... -MS-254752
Volledig artikel
OPEN ACCESS PEER-REVIEWED
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Copyright: © 2015 Mokry et al. This is an open access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are credited.
RESEARCH ARTICLE
Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study
Lauren E. Mokry1, Stephanie Ross1, Omar S. Ahmad1,2, Vincenzo Forgetta1,2, George
Davey Smith3, Aaron Leong4,5, Celia M. T. Greenwood6,7,8,9, George Thanassoulis2,10, J.
Brent Richards1,2,7,8,11*
1 Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research,
Jewish General Hospital, McGill University, Montreal, Quebec, Canada, 2 Department of Medicine, McGill
University, Montreal, Quebec, Canada, 3 MRC Integrative Epidemiology Unit, School of Social and
Community Medicine, University of Bristol, Bristol, United Kingdom, 4 Division of General Internal Medicine,
Massachusetts General Hospital, Boston, Massachusetts, United States of America, 5 Department of
Medicine, Harvard Medical School, Boston, Massachusetts, United States of America, 6 Department of
Oncology, McGill University, Montreal, Quebec, Canada, 7 Department of Epidemiology, Biostatistics and
Occupational Health, McGill University, Montreal, Quebec, Canada, 8 Department of Human Genetics,
McGill University, Montreal, Quebec, Canada, 9 Lady Davis Institute, Jewish General Hospital, Montreal,
Quebec, Canada, 10 Preventive and Genomic Cardiology, McGill University Health Center, Montreal, QC,
11 Department of Twin Research and Genetic Epidemiology, King’s College London, United Kingdom
Abstract
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 Sclerosis Genetics 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 logtransformed
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.
Association of SUNLIGHT SNPs with 25OHD Level
Table 1 displays the four SNPs that achieved genome-wide significance for 25OHD level in SUNLIGHT
and describes their association with 25OHD [19]. Each of these SNPs explained an important
proportion of the population-level variance in 25OHD level, as reflected by the F-statistic.
Association of SUNLIGHT SNPs with Multiple Sclerosis Susceptibility
Table 1. Characteristics of SNPs used as instrumental variables
Table 2. Mendelian randomization estimate of the association of decreased 25OHD with the risk of
multiple sclerosis
Table 3. Mendelian randomization estimate of the association of decreased 25OHD with the risk of
multiple sclerosis excluding the DHCR7 locus.
Table 4. Mendelian randomization estimate of the association of decreased 25OHD with the risk of
multiple sclerosis stratified by SNPs near genes involved in 25OHD synthesis versus metabolism
using a fixed-effects model.
Table 5. Clinical equivalence of a 1-SD natural-log increase in 25OHD for various vitamin D
thresholds.
Clinically Relevant 25OHD Threshold 25OHD Level Required to Decrease Odds of MS by 50%a
Vitamin D deficient (25 nmol/l) 36.86 nmol/l
Vitamin D insufficient (50 nmol/l) 73.72 nmol/l
Vitamin D sufficient (75 nmol/l) 110.6 nmol/l
Fig 1. Schematic representation of Mendelian randomization analysis. The leftmost box lists SNPs that
were genome-wide significant for 25OHD level in SUNLIGHT (n = 33,996). The blue arrow represents the
effect of SNPs on multiply adjusted natural-log-transformed 25OHD level using data from CaMos (n = 2,347).
The green arrow represents the causal association of decreased 25OHD level with the risk of MS using data
from the largest genetic association study to date for MS (the IMSGC Immunochip study, up to 14,498 cases
and 24,091 healthy controls).
Fig 2. Vitamin D pathway. In blue are the genes containing, or in proximity to, SNPs that were genome-wide
significant for 25OHD level in SUNLIGHT (n = 33,996). The p-values for the association with 25OHD level
were 1.9 × 10−109 for GC, 2.1 × 10−27 for DHCR7, 3.3 × 10−20 for CYP2R1, and 6.0 × 10−10 for CYP24A1. Note
that each gene plays an independent role in modulating the level of 25OHD. Kidney and liver images credit:
https://openclipart.org/.
Fig 3. 25OHD level by number of 25OHD-decreasing alleles in the CaMos cohort. Here we show the
box-plot of natural-log-transformed 25OHD by the count of 25OHD-decreasing alleles in the CaMos
population. A count of zero represents individuals with no 25OHD-decreasing alleles (or homozygous at each
loci for the 25OHD-increasing allele), and a count of six represents an individual with six 25OHD-decreasing
alleles. No individuals with a count of seven or more 25OHD-decreasing alleles were observed in this cohort.
The center line and error bars represent the mean level of natural-log-transformed 25OHD and its 95% CI for
each respective allele count. Note a negative trend between allele count and mean natural-log-transformed
25OHD.
Fig 4. Mendelian randomization estimate of the association of 25OHD level with risk of multiple sclerosis.
Estimates obtained using a fixed-effects model.
Fig 5. Mendelian randomization estimate of the association of 25OHD level with risk of multiple sclerosis excluding
the DHCR7 locus. Estimates obtained using a fixed-effects model.
Acknowledgments
We wish to kindly thank the SUNLIGHT Consortium, IMSGC, and the IMSGC/WTCCC2
study for access to their data.
PLOS Medicine | DOI:10.1371/journal.pmed.1001866 August 25, 2015
http://www.plosmedicine.org/article/fet ... tation=PDF
Reader Comments (3)
Vitamin D May Exert Positive Effects by Increasing Dehydroepiandrosterone (DHEA)
Posted by jamesmhoward on 26 Aug 2015 at 17:36 GMT
I suggest the connection of vitamin D and multiple sclerosis, and other diseases positively affected by vitamin D, is increased dehydroepiandrosterone (DHEA).
It is my hypothesis that low DHEA exposes negative effects of malfunctioning genes involved in MS. (“Multiple Sclerosis: A Theory,” at:
http://anthropogeny.com/M... )
It is known that vitamin D receptors are involved in the synthesis of DHEA; it has been found to be involved in bone metabolism: “The study shows that the VDR gene predicts synthesis and/or metabolism of sexual steroid precursor DHEA in parallel with bone mineral density (BMD).” (Horm Metab Res. 2002 Mar;34(3):127-31) I think this relationship will exist in other tissues. Therefore, I suggest low vitamin D levels may be involved in low levels of DHEA.
No competing interests declared.
Vitamin D Pathway
Posted by SteveMeaney on 26 Aug 2015 at 11:15 GMT
Just to note that there is an error in the vitamin D pathway - the product of the "italic"DHCR7"italic" gene, 7-dehydrocholesterol reductase, acts to convert 7-dehydrocholesterol to cholesterol, not the other way around as it depicted in the image.
No competing interests declared.
How much vitamin D should I take?
Posted by jjcannell on 25 Aug 2015 at 19:59 GMT
Mokry et al, in a way, answered a question that short term randomized controlled trials (RCT) cannot answer. The authors answered the question, "What happens if I have low vitamin D levels all your life?" The answer is that you double your risk of multiple sclerosis.
Given that fact, how much vitamin D or sunshine should I get to prevent MS? No one knows. The only way to answer that question would be to give pregnant women, their children and then the subsequent adults different physiological doses of vitamin D all their lives and see who gets MS. For obvious reasons, such a study will never be done. In that way, Mendelian randomization studies are more conclusive proof that RCT.
The Vitamin D Council has a simple answer. You should get enough sunshine and/or take enough supplements to have "natural" vitamin D levels. "Natural" vitamin D levels are the levels lifeguards or free-living hunter gatherers in modern day Tanzania have, which are about 50 ng/ml, right in the middle of the reference range for vitamin D, which is 20 - 100 ng/ml.
To obtain such levels from the sun, you have to sunbathe for 10 - 30 minutes/day, not just expose your face and arms. When you can't sunbathe you need to take around 5,000 IU/day of vitamin D3/day. In fact a recent study found that to get 97.5% of all Americans above 20 ng/ml would require 8,000 Iu/day, so 5,000 IU/day is conservative. The Institute of Medicine found that 10,000 IU/day was the No Observed Adverse Effects Level or NOAEL. This means no study has ever found 10,000 IU/day is dangerous.
MS is ot the only Mendelian randomization study to find a link between disease and vitamin D. Total mortality and cancer are also linked to vitamin D deficiency. There are many reasons to have "natural" vitamin D levels.
Competing interests declared: I am the founder and executive director of the non-profit Vitamin D Council and I get a royalty when Purity Products sells a vitamin D formula with my name on it.
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