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/. doi:10.1371/journal.pmed.1001866.g002
Genetic findings support observational evidence that lower vitamin D levels are associated with increased risk of multiple sclerosis. Using Mendelian randomization to reduce the possibility of confounding the authors examined whether there was an association between genetically reduced vitamin D levels (measured by the level of 25-hydroxyvitamin D, the clinical determinant of vitamin D status) and susceptibility to multiple sclerosis among participants in the International Multiple Sclerosis Genetics Consortium study, which involves 14,498 people with multiple sclerosis and 24,091 healthy controls. They found a genetic decrease in the natural-log-transformed vitamin D level by 1 standard deviation was associated with a 2X increased risk of multiple sclerosis.
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). doi:10.1371/journal.pmed.1001866.g001
While the Mendelian randomization approach used by the authors 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. Nevertheless the authors conclude, “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.”
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. doi:10.1371/journal.pmed.1001866.g003
“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.” http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001866
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