Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS

Gianfrancesco, M. A.; Stridh, P.; Rhead, B.; Shao, X.; Xu, E.; Graves, J. S.; Chitnis, T.; Waldman, A.; Lotze, T.; Schreiner, T.; Belman, A.; Greenberg, B.; Weinstock-Guttman, B.; Aaen, G.; Tillema, J. M.; Hart, J.; Caillier, S.; Ness, J.; Harris, Y.; Rubin, J.; Candee, M.; Krupp, L.; Gorman, M.; Benson, L.; Rodriguez, M.; Mar, S.; Kahn, I.; Rose, J.; Roalstad, S.; Casper, T. C.; Shen, L.; Quach, H.; Quach, D.; Hillert, J.; Baarnhielm, M.; Hedstrom, A.; Olsson, T.; Kockum, I.; Alfredsson, L.; Metayer, C.; Schaefer, C.; Barcellos, L. F.; Waubant, E.

Neurology. 2017 Mar 31; 88(17):1623-1629


OBJECTIVE: To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS). METHODS: We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820). RESULTS: Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01, and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model. CONCLUSIONS: We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.

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