Genetic risk factors for pediatric-onset multiple sclerosis

for the Network of Pediatric Multiple Sclerosis Centers

doi:10.1177/1352458517733551

Genetic risk factors for pediatric-onset multiple sclerosis

for the Network of Pediatric Multiple Sclerosis Centers

Pediatrics

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)_meta = 2.95, p < 2.0 × 10⁻¹⁶). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (OR_avg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR_meta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10⁻¹⁶) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

Original language	English (US)
Pages (from-to)	1825-1834
Number of pages	10
Journal	Multiple Sclerosis Journal
Volume	24
Issue number	14
DOIs	https://doi.org/10.1177/1352458517733551
State	Published - Dec 1 2018

Funding

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Drs Gianfrancesco, Stridh, Graves, Chitnis, Waldman, Lotze, Schreiner, Belman, Weinstock–Guttman, Aeen, Tillema, Ness, Rubin, Candee, Krupp, Gorman, Benson, Rodriguez, Mar, Kahn, Casper, Shen, Hillert, Hedstrom, Olsson, Kockum, and Schaefer report no disclosures. Ms Rhead, Shao, Hart, Caillier, Harris, Roalstad, D. Quach and H. Quach report no disclosures. Dr Waldman has research support from the NIH, NINDS K23NS069806 (PI: Waldman). Dr Greenberg The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by the NIH NINDS: 1R01NS071463 (PI: Waubant), R01NS049510 (PI: Barcellos), NIH NIEHS: R01ES017080 (PI: Barcellos), NIH NIAID: R01AI076544 (PI: Barcellos), NIH RC2AG036607 (PI: Schaefer), the National MS Society HC 0165 (PI: Casper), the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, and the Ellison Medical Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Keywords

Multiple sclerosis
epidemiology
genetics
pediatrics

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1177/1352458517733551

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@article{3679a644fe5b4780b8f5753fb78679bd,

title = "Genetic risk factors for pediatric-onset multiple sclerosis",

abstract = "Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10−16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10−16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.",

keywords = "Multiple sclerosis, epidemiology, genetics, pediatrics",

author = "{for the Network of Pediatric Multiple Sclerosis Centers} and Gianfrancesco, {Milena A.} and Pernilla Stridh and Xiaorong Shao and Brooke Rhead 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 Tillema, {Jan M.} 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 Anna Hedstrom and Tomas Olsson and Ingrid Kockum and Lars Alfredsson and Catherine Schaefer and Barcellos, {Lisa F.} and Emmanuelle Waubant",

note = "Publisher Copyright: {\textcopyright} The Author(s), 2017.",

year = "2018",

month = dec,

day = "1",

doi = "10.1177/1352458517733551",

language = "English (US)",

volume = "24",

pages = "1825--1834",

journal = "Multiple Sclerosis Journal",

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TY - JOUR

T1 - Genetic risk factors for pediatric-onset multiple sclerosis

AU - for the Network of Pediatric Multiple Sclerosis Centers

AU - Gianfrancesco, Milena A.

AU - Stridh, Pernilla

AU - Shao, Xiaorong

AU - Rhead, Brooke

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 M.

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 - Hedstrom, Anna

AU - Olsson, Tomas

AU - Kockum, Ingrid

AU - Alfredsson, Lars

AU - Schaefer, Catherine

AU - Barcellos, Lisa F.

AU - Waubant, Emmanuelle

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10−16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10−16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

AB - Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. Methods: Cases with onset <18 years (n = 569) and controls (n = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n = 7588). Results: HLA–DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta = 2.95, p < 2.0 × 10−16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 2.77, 95% confidence interval: 2.33, 3.32, p < 2.0 × 10−16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA–DRB1*15:01 and HLA–A*02. Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA–DRB1*15:01 and HLA–A*02 are also associated with POMS.

KW - Multiple sclerosis

KW - epidemiology

KW - genetics

KW - pediatrics

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U2 - 10.1177/1352458517733551

DO - 10.1177/1352458517733551

M3 - Article

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SN - 1352-4585

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SP - 1825

EP - 1834

JO - Multiple Sclerosis Journal

JF - Multiple Sclerosis Journal

IS - 14

ER -

Genetic risk factors for pediatric-onset multiple sclerosis

Abstract

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Keywords

ASJC Scopus subject areas

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