@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 = "Funding Information: 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 Funding Information: has research support from the NIH, Guthy Jackson Charitable Foundation, Medimmune, Chugai, Acorda, Genentech, and PCORI and consulting from Novartis and Alexion. Dr Rose has research support from VA, NMSS, Guthy Jackson Charitable Foundation, Arrien Pharmaceuticals, Teva Neuroscience, and Biogen. He is a member of the Medical Advisory Board for the DECIDE trial, which is funded by Biogen and AbbVie. Dr Alfredsson received research support from the Swedish Medical Research Council (K2013– 69X–14973–10–4), the Swedish Council for Health, Working Life and Welfare (Dnr 2012–0325), and the Swedish Brain Foundation and has received speaker honoraria from Biogen Idec and TEVA. Dr Barcellos is funded by the NIH, the National MS Society, and the Race to Erase MS. Dr Waubant is funded by the NIH, the NMSS, and the Race to Erase MS. She volunteers on an advisory board for a Novartis trial. She has received honorarium or travel support from ACTRIMS, ECTRIMS, and AAN. Funding Information: 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. Funding Information: L.F.B. and E.W. contributed equally to the manuscript. Authors and their institutions as part of the Network of Pediatric Multiple Sclerosis Centers are listed in the supplemental material (Supplementary Appendix 2). 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. 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",
issn = "1352-4585",
publisher = "SAGE Publications Ltd",
number = "14",
}