Rare Genetic Variant Linked to MS Risk, Vitamin D Levels


A rare variant of CYP2R1 doubles the risk of low vitamin D and increases MS risk by 40%.

Despoina Manousaki, MS, Multiple Sclerosis

Identifying more of the rare genetic variants of multiple sclerosis (MS), which decrease vitamin D levels dramatically, could help researchers better understand the mechanisms by which vitamin D insufficiency influences susceptibility to MS.

To increase this understanding, an international team recently searched for low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency. Their search identified a synonymous coding genetic variant that has the largest effect on vitamin D levels detected so far in the European population. Results of their analysis also provided further support for the role of vitamin D insufficiency in the development of multiple sclerosis.

“Our findings suggest that almost 1 person in 20 of European descent carries a mutation that confers a twofold risk of having low vitamin D levels,” Despoina Manousaki, MD, FRCPC, (pictured) a pediatric endocrinologist and PhD candidate in the department of human genetics at McGill University in Montreal, Canada, said. “Carrying the same mutation increases the risk of developing multiple sclerosis by 40%.”

The mutation is a synonymous coding variant of CYP2R1, a gene known to play a role in the hydroxylation and metabolism of vitamin D. This gene has a strong association with levels of 25-hydroyvitamin D (25OHD), a widely accepted biomarker for vitamin D status.

To identify this mutation, the team analyzed whole-genome sequencing data from 2 studies that together included nearly 3,000 persons and deep-imputation data from 17 studies that together included nearly 40,000 who had genome-wide genotyping. They restricted their search to single-nucleotide variants (SNVs) with a minor allele frequency of less than 5%.

After identifying the leading SNVs, they tested their effects on vitamin D level by doing a separate, genome-wide study of the association between each SNV and 25OHD level in each of the 19 study cohorts. Meta-analysis of summary statistics from these cohorts showed that one SNV found in CYP2R1 had an effect on 25OHD levels 4 times greater than that of a previously described common variant near CYP2R1. Further analysis of nearly 9,000 persons revealed that carrying one copy of the variant increased the risk of vitamin D insufficiency (odds ratio (OR), 2.2; 95% confidence interval (CI), 1.78—2.78; P < 0.001).

By comparing nearly 6,000 cases with 5,600 controls, the team also found that such carriers had an increased risk of MS (OR, 1.4; 95% CI, 1.19—1.64; P < 0.001).

The key role of CYP2R1 in the conversion of vitamin D to its active form led the team to speculate that carriers of the variant might respond poorly to additional vitamin D. But when they did an interaction analysis to test this hypothesis, they found no clear interaction between the variant and dietary vitamin D intake. However, because of the limitations of their analysis, they concluded that determining whether the variant influences response to vitamin D supplementation requires more study.

“Getting standard oral vitamin D supplements may not restore normal blood vitamin D levels and prevent multiple sclerosis in the affected persons,” Manousaki said. “Specialized forms of vitamin D supplementation may be required.”

The study report appeared in the August 3, 2017 issue of the American Journal of Human Genetics.

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