Hope Center Member Publications: February 25, 2024

Gene–environment interactions: Epstein–Barr virus infection and risk of pediatric-onset multiple sclerosis” (2024) Multiple Sclerosis Journal

Gene–environment interactions: Epstein–Barr virus infection and risk of pediatric-onset multiple sclerosis
(2024) Multiple Sclerosis Journal, . 

Ziaei, A.a q , Solomon, O.b , Casper, T.C.c , Waltz, M.c , Weinstock-Guttman, B.d , Aaen, G.e , Wheeler, Y.f , Graves, J.g , Benson, L.h , Gorman, M.h , Rensel, M.i , Mar, S.j , Lotze, T.k , Greenberg, B.l , Chitnis, T.m , Waldman, A.T.n , Krupp, L.o , James, J.A.p , Hart, J.a , Barcellos, L.F.b , Waubant, E.a

a University of California San Francisco, San Francisco, CA, United States
b Division of Epidemiology and Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, CA, United States
c The University of Utah, Salt Lake City, UT, United States
d Buffalo General Hospital, State University of New York at Buffalo, Buffalo, NY, United States
e Loma Linda University Children’s Hospital, Loma Linda, CA, United States
f The University of Alabama at Birmingham, Birmingham, AL, United States
g University of California San Diego, San Diego, CA, United States
h Pediatric Multiple Sclerosis and Related Disorders Program, Boston Children’s Hospital, Boston, MA, United States
i Cleveland Clinic, Cleveland, OH, United States
j Washington University in St. Louis, St. Louis, MO, United States
k Texas Children’s Hospital, Houston, TX, United States
l The University of Texas Southwestern Medical Center, Dallas, TX, United States
m Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
n Division of Child Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
o New York University Medical Center, New York, NY, United States
p Oklahoma Medical Research Foundation, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
q Department of Pathology & Laboratory Medicine, University of California, Irvine Medical Center (UCIMC), Orange, CA, United States

Background and Objective: Prior Epstein–Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother’s education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). Results: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). Conclusion: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk. © The Author(s), 2024.

Author Keywords
CD68;  DRB1*15;  Epstein–Barr virus;  gene–environment interaction;  multiple sclerosis;  Pediatric onset

Funding details
National Multiple Sclerosis SocietyNMSSHC-1509-06233, UM1AI144292
Multiple Sclerosis International FederationMSIF

Document Type: Article
Publication Stage: Article in Press
Source: Scopus