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Abstract
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.
GLOSSARY
- BMI=
- body mass index;
- chBMI=
- childhood body mass index;
- CI=
- confidence interval;
- CIS=
- clinically isolated syndrome;
- EIMS=
- Epidemiologic Investigation of Risk Factors for MS;
- GEMS=
- Genes and Environment in MS;
- GRS=
- genetic risk score;
- HLA=
- human leukocyte antigen;
- GWAS=
- genome-wide association studies;
- HGDP=
- Human Genome Diversity Project;
- KPNC=
- Kaiser Permanente Northern California;
- MDS=
- multidimensional scaling;
- MS=
- multiple sclerosis;
- OR=
- odds ratio;
- RPGEH=
- Research Program on Genes, Environment, and Health;
- SNP=
- single nucleotide polymorphism;
- UCSF=
- University of California San Francisco;
- vitD GRS=
- genetic instrumental variable for vitamin D;
- wGRS=
- weighted genetic risk score
Footnotes
↵* These authors contributed equally to this work.
Coinvestigators are listed at Neurology.org.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
- Received August 11, 2016.
- Accepted in final form January 20, 2017.
- © 2017 American Academy of Neurology
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