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

Milena A. Gianfrancesco, Pernilla Stridh, Brooke Rhead, Xiaorong Shao, Edison Xu, Jennifer S. Graves, Tanuja Chitnis, Amy Waldman, Timothy Lotze, Teri Schreiner, Anita Belman, Benjamin Greenberg, Bianca Weinstock-Guttman, Gregory Aaen, Jan-Mendelt Tillema, Janace Hart, Stacy Caillier, Jayne Ness, Yolanda Harris, Jennifer RubinMeghan Candee, Lauren Krupp, Mark Gorman, Leslie Benson, Moses Rodriguez, Soe Mar, Ilana Kahn, John Rose, Shelly Roalstad, T. Charles Casper, Ling Shen, Hong Quach, Diana Quach, Jan Hillert, Maria Bäärnhielm, Anna Hedstrom, Tomas Olsson, Ingrid Kockum, Lars Alfredsson, Catherine Metayer, Catherine Schaefer, Lisa F. Barcellos, Emmanuelle Waubant

Research output: Contribution to journalArticle

41 Citations (Scopus)

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 5 394 cases, 10,875 controls) and Sweden (n 5 175 cases, 5,376 controls; total n 5 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 5 0.02) after controlling for sex, genetic ancestry, HLADRB1∗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 5 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.

Original languageEnglish (US)
Pages (from-to)1623-1629
Number of pages7
JournalNeurology
Volume88
Issue number17
DOIs
StatePublished - Apr 25 2017

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Vitamin D
Multiple Sclerosis
Body Mass Index
Pediatrics
Serum
Odds Ratio
Confidence Intervals
Random Allocation
HLA Antigens
Sweden
Meta-Analysis

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Gianfrancesco, M. A., Stridh, P., Rhead, B., Shao, X., Xu, E., Graves, J. S., ... Waubant, E. (2017). Evidence for a causal relationship between low Vitamin D, high BMI, and pediatric-onset MS. Neurology, 88(17), 1623-1629. https://doi.org/10.1212/WNL.0000000000003849

Evidence for a causal relationship between low Vitamin D, high BMI, and pediatric-onset MS. / Gianfrancesco, Milena A.; Stridh, Pernilla; Rhead, Brooke; Shao, Xiaorong; Xu, Edison; Graves, Jennifer S.; Chitnis, Tanuja; Waldman, Amy; Lotze, Timothy; Schreiner, Teri; Belman, Anita; Greenberg, Benjamin; Weinstock-Guttman, Bianca; Aaen, Gregory; Tillema, Jan-Mendelt; Hart, Janace; Caillier, Stacy; Ness, Jayne; Harris, Yolanda; Rubin, Jennifer; Candee, Meghan; Krupp, Lauren; Gorman, Mark; Benson, Leslie; Rodriguez, Moses; Mar, Soe; Kahn, Ilana; Rose, John; Roalstad, Shelly; Casper, T. Charles; Shen, Ling; Quach, Hong; Quach, Diana; Hillert, Jan; Bäärnhielm, Maria; Hedstrom, Anna; Olsson, Tomas; Kockum, Ingrid; Alfredsson, Lars; Metayer, Catherine; Schaefer, Catherine; Barcellos, Lisa F.; Waubant, Emmanuelle.

In: Neurology, Vol. 88, No. 17, 25.04.2017, p. 1623-1629.

Research output: Contribution to journalArticle

Gianfrancesco, MA, Stridh, P, Rhead, B, Shao, X, Xu, E, Graves, JS, 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, TC, Shen, L, Quach, H, Quach, D, Hillert, J, Bäärnhielm, M, Hedstrom, A, Olsson, T, Kockum, I, Alfredsson, L, Metayer, C, Schaefer, C, Barcellos, LF & Waubant, E 2017, 'Evidence for a causal relationship between low Vitamin D, high BMI, and pediatric-onset MS', Neurology, vol. 88, no. 17, pp. 1623-1629. https://doi.org/10.1212/WNL.0000000000003849
Gianfrancesco MA, Stridh P, Rhead B, Shao X, Xu E, Graves JS et al. Evidence for a causal relationship between low Vitamin D, high BMI, and pediatric-onset MS. Neurology. 2017 Apr 25;88(17):1623-1629. https://doi.org/10.1212/WNL.0000000000003849
Gianfrancesco, Milena A. ; Stridh, Pernilla ; Rhead, Brooke ; Shao, Xiaorong ; Xu, Edison ; Graves, Jennifer S. ; Chitnis, Tanuja ; Waldman, Amy ; Lotze, Timothy ; Schreiner, Teri ; Belman, Anita ; Greenberg, Benjamin ; Weinstock-Guttman, Bianca ; Aaen, Gregory ; Tillema, Jan-Mendelt ; Hart, Janace ; Caillier, Stacy ; Ness, Jayne ; Harris, Yolanda ; Rubin, Jennifer ; Candee, Meghan ; Krupp, Lauren ; Gorman, Mark ; Benson, Leslie ; Rodriguez, Moses ; Mar, Soe ; Kahn, Ilana ; Rose, John ; Roalstad, Shelly ; Casper, T. Charles ; Shen, Ling ; Quach, Hong ; Quach, Diana ; Hillert, Jan ; Bäärnhielm, Maria ; Hedstrom, Anna ; Olsson, Tomas ; Kockum, Ingrid ; Alfredsson, Lars ; Metayer, Catherine ; Schaefer, Catherine ; Barcellos, Lisa F. ; Waubant, Emmanuelle. / Evidence for a causal relationship between low Vitamin D, high BMI, and pediatric-onset MS. In: Neurology. 2017 ; Vol. 88, No. 17. pp. 1623-1629.
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title = "Evidence for a causal relationship between low Vitamin D, high BMI, and pediatric-onset MS",
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 5 394 cases, 10,875 controls) and Sweden (n 5 175 cases, 5,376 controls; total n 5 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 5 0.02) after controlling for sex, genetic ancestry, HLADRB1∗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 5 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.",
author = "Gianfrancesco, {Milena A.} and Pernilla Stridh and Brooke Rhead and Xiaorong Shao and Edison Xu and Graves, {Jennifer S.} and Tanuja Chitnis and Amy Waldman and Timothy Lotze and Teri Schreiner and Anita Belman and Benjamin Greenberg and Bianca Weinstock-Guttman and Gregory Aaen and Jan-Mendelt Tillema and Janace Hart and Stacy Caillier and Jayne Ness and Yolanda Harris and Jennifer Rubin and Meghan Candee and Lauren Krupp and Mark Gorman and Leslie Benson and Moses Rodriguez and Soe Mar and Ilana Kahn and John Rose and Shelly Roalstad and Casper, {T. Charles} and Ling Shen and Hong Quach and Diana Quach and Jan Hillert and Maria B{\"a}{\"a}rnhielm and Anna Hedstrom and Tomas Olsson and Ingrid Kockum and Lars Alfredsson and Catherine Metayer and Catherine Schaefer and Barcellos, {Lisa F.} and Emmanuelle Waubant",
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T1 - Evidence for a causal relationship between low Vitamin D, high BMI, and pediatric-onset MS

AU - Gianfrancesco, Milena A.

AU - Stridh, Pernilla

AU - Rhead, Brooke

AU - Shao, Xiaorong

AU - Xu, Edison

AU - Graves, Jennifer S.

AU - Chitnis, Tanuja

AU - Waldman, Amy

AU - Lotze, Timothy

AU - Schreiner, Teri

AU - Belman, Anita

AU - Greenberg, Benjamin

AU - Weinstock-Guttman, Bianca

AU - Aaen, Gregory

AU - Tillema, Jan-Mendelt

AU - Hart, Janace

AU - Caillier, Stacy

AU - Ness, Jayne

AU - Harris, Yolanda

AU - Rubin, Jennifer

AU - Candee, Meghan

AU - Krupp, Lauren

AU - Gorman, Mark

AU - Benson, Leslie

AU - Rodriguez, Moses

AU - Mar, Soe

AU - Kahn, Ilana

AU - Rose, John

AU - Roalstad, Shelly

AU - Casper, T. Charles

AU - Shen, Ling

AU - Quach, Hong

AU - Quach, Diana

AU - Hillert, Jan

AU - Bäärnhielm, Maria

AU - Hedstrom, Anna

AU - Olsson, Tomas

AU - Kockum, Ingrid

AU - Alfredsson, Lars

AU - Metayer, Catherine

AU - Schaefer, Catherine

AU - Barcellos, Lisa F.

AU - Waubant, Emmanuelle

PY - 2017/4/25

Y1 - 2017/4/25

N2 - 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 5 394 cases, 10,875 controls) and Sweden (n 5 175 cases, 5,376 controls; total n 5 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 5 0.02) after controlling for sex, genetic ancestry, HLADRB1∗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 5 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.

AB - 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 5 394 cases, 10,875 controls) and Sweden (n 5 175 cases, 5,376 controls; total n 5 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 5 0.02) after controlling for sex, genetic ancestry, HLADRB1∗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 5 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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