Genetic risk factors for pediatric-onset multiple sclerosis.
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.
['Gianfrancesco|Milena A|MA|', 'Stridh|Pernilla|P|', 'Shao|Xiaorong|X|', 'Rhead|Brooke|B|', 'Graves|Jennifer S|JS|', 'Chitnis|Tanuja|T|', 'Waldman|Amy|A|', 'Lotze|Timothy|T|', 'Schreiner|Teri|T|', 'Belman|Anita|A|', 'Greenberg|Benjamin|B|', 'Weinstock-Guttman|Bianca|B|', 'Aaen|Gregory|G|', 'Tillema|Jan M|JM|', 'Hart|Janace|J|', 'Caillier|Stacy|S|', 'Ness|Jayne|J|', 'Harris|Yolanda|Y|', 'Rubin|Jennifer|J|', 'Candee|Meghan|M|', 'Krupp|Lauren|L|', 'Gorman|Mark|M|', 'Benson|Leslie|L|', 'Rodriguez|Moses|M|', 'Mar|Soe|S|', 'Kahn|Ilana|I|', 'Rose|John|J|', 'Roalstad|Shelly|S|', 'Casper|T Charles|TC|', 'Shen|Ling|L|', 'Quach|Hong|H|', 'Quach|Diana|D|', 'Hillert|Jan|J|', 'Hedstrom|Anna|A|', 'Olsson|Tomas|T|', 'Kockum|Ingrid|I|', 'Alfredsson|Lars|L|', 'Schaefer|Catherine|C|', 'Barcellos|Lisa F|LF|', 'Waubant|Emmanuelle|E|', '|||']
D005260:Female D020022:Genetic Predisposition to Disease D005820:Genetic Testing D059811:HLA-DRB1 Chains D006801:Humans D016015:Logistic Models D008297:Male D009103:Multiple Sclerosis D020641:Polymorphism, Single Nucleotide D012307:Risk Factors D013548:Sweden
genetics Multiple sclerosis pediatrics epidemiology