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 language | English (US) |
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Pages (from-to) | 1825-1834 |
Number of pages | 10 |
Journal | Multiple Sclerosis Journal |
Volume | 24 |
Issue number | 14 |
DOIs | |
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