Genetic risk factors for pediatric-onset multiple sclerosis

for the Network of Pediatric Multiple Sclerosis Centers

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
JournalMultiple Sclerosis Journal
DOIs
StateAccepted/In press - Oct 1 2017

Fingerprint

Multiple Sclerosis
Pediatrics
Major Histocompatibility Complex
Biological Phenomena
Sweden
Meta-Analysis
Logistic Models
Odds Ratio
Regression Analysis
Confidence Intervals

Keywords

  • epidemiology
  • genetics
  • Multiple sclerosis
  • pediatrics

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Genetic risk factors for pediatric-onset multiple sclerosis. / for the Network of Pediatric Multiple Sclerosis Centers.

In: Multiple Sclerosis Journal, 01.10.2017.

Research output: Contribution to journalArticle

for the Network of Pediatric Multiple Sclerosis Centers. / Genetic risk factors for pediatric-onset multiple sclerosis. In: Multiple Sclerosis Journal. 2017.
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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 = "epidemiology, genetics, Multiple sclerosis, 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",
year = "2017",
month = "10",
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language = "English (US)",
journal = "Multiple Sclerosis",
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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 - 2017/10/1

Y1 - 2017/10/1

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.

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KW - genetics

KW - Multiple sclerosis

KW - pediatrics

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