Nancy A. Melville

October 25, 2016

BALTIMORE — A genetic risk score identifying the risk for low vitamin D levels may help predict the risk for relapse in pediatric patients with multiple sclerosis (MS) and also offers evidence, albeit not proof, supporting the theory of vitamin D as having a causative role in the disease, according to new research.

"We have identified a genetic score that is associated not only with vitamin D levels but also of relapse in pediatric patients," said senior author Jennifer Graves, MD, PhD, an assistant professor at the University of California, San Francisco, School of Medicine.

The study, presented here at the American Neurological Association (ANA) 2016 Annual Meeting, involved patients enrolled from two pediatric MS centers who met criteria for pediatric MS or had clinically isolated syndrome with a high risk for MS.

During follow-up and assessment for relapses, the patients' DNA samples were genotyped for 29 functional single-nucleotide polymorphisms (SNPs) in vitamin D pathway genes that have been identified as being associated with 25-OH vitamin D levels in humans.

Using linear regression models, the researchers found that 6 of the 29 polymorphisms were strongly associated with vitamin D levels in the pediatric patients with MS after correction for multiple comparisons.

In the initial discovery set of 182 children, a high-risk score with carriers of all 6 risk alleles was associated with vitamin D levels that were an average of 15 ng/mL lower.

"The difference was of high statistical significance, and the risk score explained 13% of the variance in vitamin D level," Dr Graves said.

In a replication set of 110 patients, a nearly identical effect size of 15-ng/mL vitamin D levels was seen (P = .002), explaining an 8.7% variance in vitamin D level.

A 6-unit higher vitamin D risk score was furthermore associated with as much as a 94% higher hazard for relapse (hazard ratio, 1.94; 95% confidence interval, 1.19 - 3.15; P = .007).

Dr Graves noted that in addition to its relevance to the risk for MS relapse, the genetic risk score could have implications extending beyond MS.

"These results support a causal association of vitamin D with relapse activity in MS, and the score may have some utility in other disease states where vitamin D may be contributing to disease course," she said.

With low vitamin D levels known to be associated with the risk for MS relapse, neurologists prescribe supplementation to most patients and monitor their vitamin D levels.

The study importantly addresses the challenges of relapse in pediatric patients with MS, commented Gregory Wu, MD, an assistant professor of neurology at Washington University School of Medicine, St. Louis, Missouri.

"This study was performed in a pediatric cohort, which makes it unique," Dr Wu told Medscape Medical News. "In children with MS, relapsing disease is far more common than in the adult population."

"The fact that this is a modifiable environmental influence on MS is such an important aspect of the study," he noted. "Now with this information there is an even stronger rationale to make efforts to make an intervention to vitamin D."

The causative nature of vitamin D still remains in question, Dr Wu noted.

"I would certainly agree that this is more data to support the hypothesis that lower vitamin D levels are causative toward MS relapse," he said. "[However], it strengthens the argument by going into more direct genetic pathway analysis in a mechanistic fashion."

Craig M. Powell, MD, PhD, agreed that the study does not prove a causative role but nevertheless offers important additional evidence on the issue.

"These data do not prove that low vitamin D levels cause MS relapse, nor do they prove that genetic risk for low vitamin D causes MS relapse," Dr Powell, director of preclinical research in neurology and of the developmental brain disorders section in neurology at the University of Texas Southwestern Medical Center, in Dallas, told Medscape Medical News.

"These data do not prove that low vitamin D levels cause MS relapse, nor do they prove that genetic risk for low vitamin D causes MS relapse," he told Medscape Medical News.

"These data do, however, add to the evidence demonstrating correlations between low vitamin D and MS relapse."

Important missing pieces of the puzzle include gaps in evidence on which specific factors result in relapse.

"What the study does not address is whether the genetic risk score affects risk of relapse or the vitamin D level affects risk of relapse or some separate but correlated factor affects risk of relapse," Dr Powell said.

Meanwhile, the prediction of relapse in MS continues to be a frequent clinical challenge.

"Risk prediction in MS is a tricky business," Dr Powell said. "Knowing the factors associated with increased risk in a population is difficult to apply to a given individual."

The new findings nevertheless contribute to evidence on the importance of vitamin D, he noted.

"I do not think these additional new findings will be directly used clinically just yet, but they provide additional support for measuring vitamin D levels in MS patients and for recommending vitamin D supplements in MS patients."

"Medically appropriate levels of vitamin D supplementation are very low risk for MS patients."

Dr Graves is supported by grants from Race to Erase MS, the National Multiple Sclerosis Society, Biogen, and Genentech. Dr Wu has disclosed no revant financial relationships. Dr Powell had no disclosures relating to the study, but he has received research support from Novartis.

American Neurological Association (ANA) 2016 Annual Meeting. Abstract S109. Presented October 16, 2016.

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