Author Topic: (Abst.) Vitamin D and MS risk: A Mendelian randomization study  (Read 202 times)

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Offline agate

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From PubMed, August 26, 2015:

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PLoS Med. 2015 Aug 25;12(8):e1001866. doi: 10.1371/journal.pmed.1001866. eCollection 2015.

Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study

Mokry LE1, Ross S1, Ahmad OS2, Forgetta V2, Smith GD3, Leong A4, Greenwood CM5, Thanassoulis G6, Richards JB7.

Author information


1Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

2Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.

3MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.

4Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.

5Department of Oncology, McGill University, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.

6Department of Medicine, McGill University, Montreal, Quebec, Canada; Preventive and Genomic Cardiology, McGill University Health Center, Montreal, QC.

7Centre for Clinical Epidemiology, Department of Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Department of Twin Research and Genetic Epidemiology, King's College London, United Kingdom.

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 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.

PMID: 26305103

The abstract can be seen here.
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Offline agate

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PLoS One contains an Editors' Summary of the article abstracted above. Extracts:

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Why Was This Study Done?

Why the immune system attacks myelin to cause MS is unclear but probably involves both genetic and environmental risk factors. One potential environmental risk factor is reduced levels of vitamin D. Circulating levels of 25-hydroxyvitamin D (25OHD; the clinical determinant of vitamin D status) are determined in part by exposure to sunlight, and MS is more common at higher latitudes, where exposure to sunlight is decreased. Other epidemiological studies (investigations that examine disease patterns in populations) also suggest an association between lower vitamin D level and an increased risk of MS but cannot prove that a decreased vitamin D level actually causes MS. Individuals who develop MS might share another unknown characteristic that increases their risk of MS (confounding), or individuals who have MS might spend less time outdoors and, as a result, have lower circulating vitamin D levels (reverse causation). It is important to know whether a decreased vitamin D level increases the risk of MS because vitamin D insufficiency is becoming increasingly common. Here, the researchers undertake a Mendelian randomization study to determine whether circulating vitamin D level has a causal effect on MS susceptibility. Because gene variants are inherited randomly, they are not prone to confounding. Reverse causation is also prevented since MS does not change genetic variants. So, if vitamin D level actually affects MS risk, genetic variants that affect vitamin D level should be associated with altered susceptibility to MS.

What Did the Researchers Do and Find?

The researchers first ascertained the effect on 25OHD level among participants in the Canadian Multicentre Osteoporosis Study of four single nucleotide polymorphisms (SNPs, a type of genetic variant) that were associated with 25OHD level in a genome-wide association study (SUNLIGHT). Each of the SNPs explained an important proportion of the population-level variance in 25OHD level in the Canadian Multicentre Osteoporosis Study. The researchers then used the SNPs to examine whether there was an association between genetically reduced 25OHD level and susceptibility to MS among participants in the International Multiple Sclerosis Genetics Consortium study, a genome-wide association study involving up to 14,498 people with MS and 24,091 healthy controls. They found that a genetic decrease in the natural-log-transformed 25OHD level by one standard deviation was associated with a 2-fold increased risk of MS. In practical terms, this finding means that increasing an individual’s circulating 25OHD level by approximately 1.5-fold decreases their odds of developing MS by 50%.

What Do These Findings Mean?

These findings show that, among the participants of the International Multiple Sclerosis Genetics Consortium study, all of whom were of European ancestry, genetically lowered 25OHD level was strongly associated with increased susceptibility to MS. 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. Moreover, although these findings support a role for vitamin D in MS susceptibility, they provide no information about whether vitamin D modulates the course of MS after its onset, and they may not apply to people of non-European ancestry. Nevertheless, these findings provide a strong rationale for undertaking randomized controlled trials to investigate whether vitamin D supplementation can prevent the onset and/or progression of MS.
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Offline agate

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Multiple Sclerosis News Today contains an article about this study, excerpted below (August 27, 2015):

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Study Shows Correlation between Risk of Multiple Sclerosis and Low Vitamin D Levels

By Patricia Silva, Ph.D.

An international team led by researchers at McGill University in Canada recently published in the journal PLOS Medicine data supporting a link between low vitamin D levels and the risk of multiple sclerosis (MS). The study is entitled “Vitamin D and Risk of Multiple Sclerosis: A Mendelian Randomization Study.”

...

Reduced levels of vitamin D [measured through 25-hydroxyvitamin D (25OHD), the clinical determinant of vitamin D status] have been suggested to contribute to the risk of developing multiple sclerosis; however, it is not clear if this connection is causal. It is important for researchers to better understand this possible connection, as vitamin D insufficiency is becoming increasingly common.

In the study, researchers investigated whether genetically reduced vitamin D levels could indeed contribute to the risk of MS. The team analyzed individuals for particular mutations associated with the 25OHD gene and found four mutations that resulted in lower vitamin D levels. To investigate the possible link between the effects of genetically lowered 25OHD on the odds of MS, participants in the International Multiple Sclerosis Genetics Consortium study, which includes 14,498 multiple sclerosis patients and 24,091 healthy individuals, were assessed for their vitamin D levels and susceptibility for MS.

Researchers found that a decrease in vitamin D levels was strongly linked to a two-fold increased risk of MS. According to a news release, the findings led the authors to conclude that “genetically lowered vitamin D levels are strongly associated with increased susceptibility to multiple sclerosis. Whether vitamin D sufficiency can delay, or prevent, multiple sclerosis onset merits further investigation in long-term randomized controlled trials.”

In order to further investigate the issue, clinical trials are already being developed with this purpose: “Ongoing randomized controlled trials are currently assessing vitamin D supplementation for the treatment and prevention of multiple sclerosis … and may therefore provide needed insights into the role of vitamin D supplementation,” concluded the research team.

Vitamin D is among the most popular supplements taken by MS patents, based on preliminary research revealing that the vitamin is indeed beneficial in helping to manage the disease. These further studies could put the use of Vitamin D in treating MS into better focus for researchers and physicians.
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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From MedPage Today, August 29, 2015:

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What to Make of Vitamin D, MS, & Mendelian Randomization

It depends who you ask, study author found

by Kristina Fiore
Staff Writer, MedPage Today


A Mendelian randomization study suggested that low vitamin D levels may play a causal role in the development of multiple sclerosis.

In an analysis of data from large cohort studies, each genetically determined standard deviation drop in log-transformed 25-hydroxyvitamin D (25OHD) levels conferred a two-fold increase in the odds of having MS, Brent Richards, MD, of McGill University, and colleagues reported online in PLOS Medicine.

The point of Mendelian randomization is to avoid the confounding that typically occurs with observational data. It is supposed to be a way to help discern whether some environmental factor -- like vitamin D levels -- is causally linked to an outcome.

So instead of looking at the relationship between MS and measured vitamin D levels -- an environmental factor that can be influenced by confounding -- this strategy looks at gene variants that aren't impacted by those limitations to get a sense of the direct relationship between the risk factor and outcome.

"It's called 'nature's randomized controlled trial' because whether someone gets a certain variant is a random event," Richards said, adding that his group is "not claiming causality here. Rather, we're providing evidence that supports causality."

But how accurate is Mendelian randomization for discerning causality?
"It depends on who you ask," Richards told MedPage Today. "I believe it can produce evidence supporting or contradicting causality."

He thinks it's especially useful in cases where it's unlikely that a randomized controlled trial of necessary length and scope would ever be accomplished -- as would be the case with vitamin D, he said.

For their study, Richards and colleagues looked at data from the largest genome-wide association study (GWAS) to date on vitamin D -- the SUNLIGHT study of nearly 34,000 people.

That study revealed four major single nucleotide polymorphisms (SNPs) that were linked with decreased 25OHD levels.

They then validated those four SNPs using data on 2,347 participants in population-based cohort study, the Canadian Multicenter Osteoporosis Study -- and confirmed that the count of low vitamin D alleles was strongly associated with lower levels of 25OHD.

Finally they conducted the Mendelian randomization analysis using data from the International Multiple Sclerosis Genetics Consortium study, the largest GWAS to date for MS -- totaling nearly 14,500 cases and 24,000 healthy controls.

They found that each genetically determined standard deviation drop in log-transformed 25OHD levels conferred a two-fold increase in the odds of MS (95% CI 1.7 to 2.5, P=7.72 x 10-12).

That relationship persisted in sensitivity analyses that excluded SNPs possibly influenced by population stratification or pleiotropy and included only SNPs involved in 25OHD synthesis or metabolism.

They said the findings are consistent with observational evidence that low vitamin D levels influence the risk of MS -- including epidemiological studies that show a higher prevalence of MS in higher-latitude regions with diminished exposure to sunlight.

The next step, Richards said, would be to do a clinical trial to investigate whether vitamin D supplementation might prevent or delay the onset of MS in patients who are already at elevated risk, such as those having family members with the condition.

"We think these findings strongly suggest people at risk for MS should ensure they have normal vitamin D levels," Richards said.

When you ask experts in epidemiology and biostatistics who have worked extensively with Mendelian randomization, they say the study was well executed.

Nicholas Timpson, PhD, an epidemiologist at the University of Bristol, said that Mendelian randomization studies "should not be taken as gold standard as there are a series of caveats which, as for most studies, may influence interpretation" -- but he called the findings "compelling evidence."
"It is well undertaken and the use of Mendelian randomization in this case is a genuine contribution to the potential for a causal relationship between exposure and disease," Timpson told MedPage Today.

Stephen Burgess, PhD, a biostatistician at the University of Cambridge, noted that one strength of the current study is that it doesn't depend on a single genetic variant, but looks at four individual variants that contribute to vitamin D status, making for "strong support of the claim of causation."
But a limitation is that the study is "only able to make the general conclusion that increasing vitamin D levels should lower MS risk," Burgess told MedPage Today. It gives no indication of what levels of vitamin D are likely to be beneficial or optimal, nor does it suggest which patients vitamin D supplementation would be most beneficial for, he said.

While these questions need to be answered in an RCT, Burgess said there are aspects of Mendelian randomization design that RCTs wouldn't be able to take into account -- and life-long vitamin D exposure is one of them.
"At the end of the day, the proof of the pudding is in the eating," Burgess said. "What will convince clinicians is this: do results from Mendelian randomization correspond favorably with results from RCTs? At the moment the answer is a resounding yes -- statins, PSCK9 inhibitors (positive), and CETP-inhibitors (null) for CHD risk, folic acid for stroke risk (null in Western populations, positive in East Asians) -- [are] now supported by trial evidence."

But what happens when you ask a clinician? Perry Wilson, MD, of Yale, who is a MedPage Today physician reviewer, said the main study outcome -- the standard deviation changes in log-transformed 25OHD levels -- is "statistically clean, but clinically meaningless."

"The big finding is that, yes, people with MS were more likely to carry at least one of those low vitamin D genes," Wilson said. "But beyond saying that, the effect size is very hard to relate, since they were predicated on a standard deviation increase in log-transformed vitamin D."

Richards disclosed no financial relationships with industry.

The article can be seen here.
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.

Offline agate

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MedPage Today has provided a short video clip criticizing this type of study and its outcomes (September 1, 2015):

http://www.medpagetoday.com/Neurology/MultipleSclerosis/53336?xid=nl_mpt_DHE_2015-09-01&eun=g345846d0r
MS Speaks--online for 17 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010. Glatopa (glatiramer acetate 40mg 3 times/week) since 12/16/20.