ARTICLE IN BRIEF
An analysis of several genome-wide association studies offers additional evidence to support the association between low circulating levels of vitamin D and an increased risk of multiple sclerosis.
A new genetics study strengthens evidence from earlier observational studies that vitamin D deficiency is associated with an elevated risk of multiple sclerosis (MS).
Vitamin D is strongly suspected of being one of multiple risk factors for MS based on epidemiological studies, but it has been difficult to prove that the correlation is causal. This latest study focused on four genetic variants associated with vitamin D synthesis or metabolism to make a case that vitamin D insufficiency is likely directly linked to an increased risk for MS.
“The identification of vitamin D as a causal susceptibility factor for MS may have important public health implications since vitamin D insufficiency is common and vitamin D supplementation is both relatively safe and cost-effective,” the researchers wrote in the Aug. 25 online edition of PLoS Medicine. “These findings provide rationale for further investigating the potential therapeutic benefits of vitamin D supplementation in preventing the onset and progression of MS.”
Brent Richards, MD, an associate professor of medicine at McGill University and senior author of the paper, told Neurology Today that the findings “only speak to prevention. They cannot speak to treatment.
“What we can say is that individuals at risk for multiple sclerosis, such as those with a family history, should be sure they have adequate vitamin D levels,” he said.
Figure. SNPS found t…
The new study used a research method called Mendelian randomization, which uses genetic associations to test the effects of biomarkers on the risk of disease, to evaluate whether genetically lowered vitamin D levels influenced MS risk. The multi-step study focused on four single nucleotide polymorphisms (SNPs) that had been previously associated with 25-hydroxyvitamin D (25OHD) levels in the so-called SUNLIGHT study (Study of Underlying Genetic Determinants of Vitamin D and Highly Related Trials), a genome-wide association study comprising nearly 34,000 participants. All four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing vitamin D levels, the study authors noted.
Using another database, the Canadian Multicentre Osteoporosis Study, the researchers calculated the degree to which each of the four genetic variants affected vitamin D levels. They then used those calculations to determine whether there was an association between genetically reduced vitamin D levels and susceptibility to MS among participants in the International Multiple Sclerosis Genetics Consortium study, a genome-wide association study involving about 14,500 people with MS and 24,000 healthy controls.
“Using summary data for MS and 25OHD levels from large European populations, our study demonstrates that a genetic decrease in natural-log transformed 25OHD by 1 SD [standard deviation] was associated with a two-fold increase in risk of MS, providing strong evidence in support of a causal role of vitamin D in MS susceptibility,” the researchers concluded.
An editorial summary by the PLoS Medicine editors noted that, in practical terms, the findings suggest that increasing an individual’s circulating 25OHD level by approximately 1.5-fold decreases the odds of developing MS by 50 percent.
But the editors also noted that because the study involved only people of European descent, it is not clear whether the findings apply to other ethnicities. They also pointed out the difficulty in separating out vitamin D as a risk factor for MS.
Circulating levels of vitamin D are determined “in part by exposure to sunlight, and MS is more common at higher latitudes, where exposure to sunlight is decreased,” they wrote. People who get MS might share an unknown risk factor (confounding), or they may have lower vitamin D levels because they spend more time indoors (reverse causation), the editors noted.
“Although the Mendelian randomization approach used here largely avoids the possibility of confounding or reverse causation, the reliability of these findings may be limited by some of the assumptions made by the researchers during their analysis,” they wrote.
MS experts who were not involved with the current study told Neurology Today that that it would be difficult to conduct a randomized controlled trial of vitamin D for MS prevention because it would have to involve a very large number of people over many years to get results that would be statistically meaningful. Right now the focus is primarily on determining if supplementation with the vitamin can help slow disease progression or lengthen the time between relapses, they said.
But they agreed that the genetic study provided important new information on the association between vitamin D insufficiency and MS.
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Alberto Ascherio, MD, PhD, a professor of nutrition and epidemiology at the Harvard T.H. Chan School of Public Health and a professor of medicine at Harvard Medical School, said the new study “is an important complement to the work that we and others have done over the past 10 years.
“It provides strong evidence in favor of causality,” said Dr. Ascherio, who led the research team that in 2006 published a seminal study in the Journal of the American Medical Association (JAMA) that showed an association between higher vitamin D levels and decreased risk of MS. The study, which involved blood samples from healthy young adult US military personnel, found that men and women with the highest levels of vitamin D had a 60 percent lower risk of developing MS than their counterparts with the lowest levels.
Dr. Ascherio and colleagues published another study in 2014 in JAMA Neurology that showed that among patients with MS who were treated with interferon beta-1b, a lower level of vitamin D early in disease was a predictor for worse MS activity and disease progression.
Ellen M. Mowry, MD, FAAN, an associate professor of neurology and epidemiology at Johns Hopkins University, agreed with others that the findings of the genetic study provided good insights, but added that the final word is not in. “I think we should be cautious in the way we advise people about taking vitamin D. While observational data is encouraging, just like with any medication it deserves more study,” she said.
Dr. Mowry said it is possible that an acceptable vitamin D level for one person may not be high enough for another person, and that a one-size-fits all approach to supplementation may not be ideal. She recently published a small study in the journal Multiple Sclerosis that found that when the same dose of vitamin D was given for 90 days to a group of MS patients with vitamin D deficiency, as well as healthy controls with a deficiency, the MS group ended up having lower circulating levels of the vitamin.
She is now leading a multicenter study, funded by the National MS Society, that aims to randomize 172 MS patients to the standard adult dose of 600 international units (IU) or 5,000 IU of vitamin D daily. Over the two years of the study, researchers will measure clinical changes and quality of life factors and conduct MRI brain scans to look at number of lesions, gray matter volume, and cortical thickness.
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“If we do confirm that supplementing with vitamin D is helpful, we’ll also have to determine the best target range.”
David A. Hafler, MD, FAAN, the William S. and Lois Stiles Edgerly professor of neurology and immunobiology and chair of neurology at Yale School of Medicine, also praised the work of the study authors, adding: “I think the data on vitamin D is becoming more and more compelling.”
Dr. Hafler, who studies autoimmunity and inflammatory factors related to MS, said that genome mapping and a growing number of MS-related genetic studies have helped provide “a fuller picture of MS.” He said there are 250 known genetic variants associated with MS, including ones related to vitamin D metabolism. His Yale research lab has found, among other things, that high dietary intake of salt appears to be another risk factor for MS. Other environmental risk factors include smoking, obesity, and infection with Epstein-Barr virus.
“It’s not bad genes or bad environmental factors necessarily that put a person at risk for MS. It’s the combination of the genes and environment,” Dr. Hafler said. “To fully understand that interplay, there’s still more work that needs to be done.”
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