Vitamin D genes influence MS relapses in children

Jennifer S Graves¹, Lisa F Barcellos², Lauren Krupp³, Anita Belman⁴, Xiaorong Shao², Hong Quach², Janace Hart¹, Tanuja Chitnis⁵, Bianca Weinstock-Guttman⁶, Gregory Aaen⁷, Leslie Benson⁸, Mark Gorman⁸, Benjamin Greenberg⁹, Timothy Lotze¹⁰, Mar Soe¹¹, Jayne Ness¹², Moses Rodriguez¹³, John Rose¹⁴, Teri Schreiner¹⁵, Jan-Mendelt Tillema¹³, Amy Waldman¹⁶, T Charles Casper¹⁷, Emmanuelle Waubant¹

Affiliations

¹ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
² School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
³ Pediatric Multiple Sclerosis Center, New York University Langone Medical Center, New York, NY, USA.
⁴ Stony Brook University, Stony Brook, NY, USA.
⁵ Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, USA.
⁶ Jacobs Pediatric Multiple Sclerosis Center, SUNY University at Buffalo, Buffalo, NY, USA.
⁷ Pediatric Multiple Sclerosis Center, Loma Linda University Children's Hospital, San Bernardino, CA, USA.
⁸ Pediatric Multiple Sclerosis and Related Disorders Program, Boston Children's Hospital, Boston, MA, USA.
⁹ University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁰ The Blue Bird Circle Clinic for Multiple Sclerosis, Texas Children's Hospital, Houston, TX, USA.
¹¹ Pediatric MS & Demyelinating Disease Center, Washington University, St. Louis, MI, USA.
¹² Center for Pediatric-Onset Demyelinating Disease, Children's of Alabama, Birmingham, AL, USA.
¹³ Pediatric Multiple Sclerosis Center, Mayo Clinic, Rochester, MA, USA.
¹⁴ Department of Neurology, The University of Utah, Salt Lake City, UT, USA.
¹⁵ Rocky Mountain MS Center, University of Colorado, Denver, Denver, CO, USA.
¹⁶ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁷ Department of Pediatrics, The University of Utah, Salt Lake City, UT, USA.

PMID: 31081484
PMCID: PMC6851448
DOI: 10.1177/1352458519845842

Vitamin D genes influence MS relapses in children

Jennifer S Graves et al. Mult Scler. 2020 Jul.

. 2020 Jul;26(8):894-901.

doi: 10.1177/1352458519845842. Epub 2019 May 13.

Authors

Affiliations

¹ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
² School of Public Health, University of California, Berkeley, Berkeley, CA, USA.
³ Pediatric Multiple Sclerosis Center, New York University Langone Medical Center, New York, NY, USA.
⁴ Stony Brook University, Stony Brook, NY, USA.
⁵ Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, USA.
⁶ Jacobs Pediatric Multiple Sclerosis Center, SUNY University at Buffalo, Buffalo, NY, USA.
⁷ Pediatric Multiple Sclerosis Center, Loma Linda University Children's Hospital, San Bernardino, CA, USA.
⁸ Pediatric Multiple Sclerosis and Related Disorders Program, Boston Children's Hospital, Boston, MA, USA.
⁹ University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁰ The Blue Bird Circle Clinic for Multiple Sclerosis, Texas Children's Hospital, Houston, TX, USA.
¹¹ Pediatric MS & Demyelinating Disease Center, Washington University, St. Louis, MI, USA.
¹² Center for Pediatric-Onset Demyelinating Disease, Children's of Alabama, Birmingham, AL, USA.
¹³ Pediatric Multiple Sclerosis Center, Mayo Clinic, Rochester, MA, USA.
¹⁴ Department of Neurology, The University of Utah, Salt Lake City, UT, USA.
¹⁵ Rocky Mountain MS Center, University of Colorado, Denver, Denver, CO, USA.
¹⁶ Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁷ Department of Pediatrics, The University of Utah, Salt Lake City, UT, USA.

PMID: 31081484
PMCID: PMC6851448
DOI: 10.1177/1352458519845842

Abstract

Objective: The aim of this study was to determine whether a vitamin D genetic risk score (vitDGRS) is associated with 25-hydroxyvitamin D (25(OH)D) level and multiple sclerosis (MS) relapses in children.

Methods: DNA samples were typed for single nucleotide polymorphisms (SNPs) from four genes previously identified to be associated with 25(OH)D levels. SNPs with strong associations with 25(OH)D after multiple comparison correction were used to create a genetic risk score (vitDGRS). Cox regression models tested associations of vitDGRS with relapse hazard.

Results: Two independent SNPs within or near GC and NADSYN1/DHCR7 genes were strongly associated with 25(OH)D levels in the discovery cohort (n = 182) after Bonferroni correction. The vitDGRS of these SNPs explained 4.5% of the variance of 25(OH)D level after adjustment for genetic ancestry. Having the highest versus lowest vitDGRS was associated with 11 ng/mL lower 25(OH)D level (95% confidence interval (CI) = -17.5, -4.5, p = 0.001) in the discovery cohort. Adjusting for ancestry, sex, disease-modifying therapy (DMT), and HLA-DRB1*15 carrier status, the highest versus lowest vitDGRS was associated with 2.6-fold (95% CI = 1.37, 5.03, p = 0.004) and 2.0-fold (95% CI = 0.75, 5.20, p = 0.16) higher relapse hazard in the discovery and replication cohorts, respectively.

Conclusion: The vitDGRS identifies children at greater risk of relapse. These findings support a causal role for vitamin D in MS course.

Keywords: Genetics; epidemiology; pediatric multiple sclerosis; vitamin D.

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Figures

**Figure 1:. Association of SNPs related to genes *GC, CYP2R1, NADSYN1, and DHCR7*, and 25-OH vitamin D level in children with MS**
Manhattan plot of the p-value (y-axis) of the association between vitamin D pathway SNPs (x-axis) and 25-OH vitamin D level. Three final SNPs selected from independent linkage disequilibrium blocks are indicated by the blue lines (rs7041_a (GC), and -rs12807827 (*NADSYN1*).

See this image and copyright information in PMC

References

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Vitamin D genes influence MS relapses in children

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Vitamin D genes influence MS relapses in children

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