PMID- 38332747 OWN - NLM STAT- MEDLINE DCOM- 20240314 LR - 20240314 IS - 1477-0970 (Electronic) IS - 1352-4585 (Linking) VI - 30 IP - 3 DP - 2024 Mar TI - Gene-environment interactions: Epstein-Barr virus infection and risk of pediatric-onset multiple sclerosis. PG - 308-315 LID - 10.1177/13524585231224685 [doi] AB - 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. FAU - Ziaei, Amin AU - Ziaei A AD - University of California San Francisco, San Francisco, CA, USA/Department of Pathology & Laboratory Medicine, University of California, Irvine Medical Center (UCIMC), Orange, CA, USA. FAU - Solomon, Olivia AU - Solomon O AD - Division of Epidemiology and Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, CA, USA. FAU - Casper, T Charles AU - Casper TC AD - The University of Utah, Salt Lake City, UT, USA. FAU - Waltz, Michael AU - Waltz M AD - The University of Utah, Salt Lake City, UT, USA. FAU - Weinstock-Guttman, Bianca AU - Weinstock-Guttman B AUID- ORCID: 0000-0001-6732-151X AD - Buffalo General Hospital, State University of New York at Buffalo, Buffalo, NY, USA. FAU - Aaen, Greg AU - Aaen G AD - Loma Linda University Children's Hospital, Loma Linda, CA, USA. FAU - Wheeler, Yolanda AU - Wheeler Y AD - The University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Graves, Jennifer AU - Graves J AD - University of California San Diego, San Diego, CA, USA. FAU - Benson, Leslie AU - Benson L AD - Pediatric Multiple Sclerosis and Related Disorders Program, Boston Children's Hospital, Boston, MA, USA. FAU - Gorman, Mark AU - Gorman M AD - Pediatric Multiple Sclerosis and Related Disorders Program, Boston Children's Hospital, Boston, MA, USA. FAU - Rensel, Mary AU - Rensel M AUID- ORCID: 0000-0001-9613-8394 AD - Cleveland Clinic, Cleveland, OH, USA. FAU - Mar, Soe AU - Mar S AD - Washington University in St. Louis, St. Louis, MO, USA. FAU - Lotze, Tim AU - Lotze T AD - Texas Children's Hospital, Houston, TX, USA. FAU - Greenberg, Benjamin AU - Greenberg B AUID- ORCID: 0000-0002-2091-8201 AD - The University of Texas Southwestern Medical Center, Dallas, TX, USA. FAU - Chitnis, Tanuja AU - Chitnis T AUID- ORCID: 0000-0002-9897-4422 AD - Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Waldman, Amy T AU - Waldman AT AD - Division of Child Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. FAU - Krupp, Lauren AU - Krupp L AUID- ORCID: 0000-0001-7003-807X AD - New York University Medical Center, New York, NY, USA. FAU - James, Judith A AU - James JA AD - Oklahoma Medical Research Foundation, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. FAU - Hart, Janace AU - Hart J AD - University of California San Francisco, San Francisco, CA, USA. FAU - Barcellos, Lisa F AU - Barcellos LF AD - Division of Epidemiology and Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, CA, USA. FAU - Waubant, Emmanuelle AU - Waubant E AD - University of California San Francisco, San Francisco, CA, USA. LA - eng PT - Journal Article DEP - 20240209 PL - England TA - Mult Scler JT - Multiple sclerosis (Houndmills, Basingstoke, England) JID - 9509185 RN - 0 (HLA-DRB1 Chains) RN - 0 (Antibodies) SB - IM MH - Adult MH - Child MH - Humans MH - *Epstein-Barr Virus Infections/complications MH - Herpesvirus 4, Human MH - *Multiple Sclerosis MH - Risk Factors MH - HLA-DRB1 Chains/genetics MH - Antibodies OTO - NOTNLM OT - CD68 OT - DRB1*15 OT - Epstein-Barr virus OT - Pediatric onset OT - gene-environment interaction OT - multiple sclerosis COIS- Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. EDAT- 2024/02/09 06:42 MHDA- 2024/03/14 06:47 CRDT- 2024/02/09 03:43 PHST- 2024/03/14 06:47 [medline] PHST- 2024/02/09 06:42 [pubmed] PHST- 2024/02/09 03:43 [entrez] AID - 10.1177/13524585231224685 [doi] PST - ppublish SO - Mult Scler. 2024 Mar;30(3):308-315. doi: 10.1177/13524585231224685. Epub 2024 Feb 9.