{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T04:50:33Z","timestamp":1791435033940,"version":"4.3.3"},"reference-count":39,"publisher":"SAGE Publications","issue":"3","license":[{"start":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T00:00:00Z","timestamp":1707436800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Mult Scler"],"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Objective:<\/jats:title>\n                    <jats:p>Prior Epstein\u2013Barr 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>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\u2019s education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>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\u2009&lt;\u20090.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI\u2009=\u200910.25, 95% confidence interval (CI)\u2009=\u20093.78 to 16.72; AP\u2009=\u20090.61, 95% CI\u2009=\u20090.47 to 0.75). There was evidence for multiplicative interaction ( p\u2009&lt;\u20090.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR)\u2009=\u20093.43, 95% CI\u2009=\u20091.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction ( p\u2009=\u20090.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP\u2009=\u20090.30, 95% CI\u2009=\u20090.03 to 0.58).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13524585231224685","type":"journal-article","created":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T03:41:06Z","timestamp":1707450066000},"page":"308-315","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":11,"title":["Gene\u2013environment interactions: Epstein\u2013Barr virus infection and risk of pediatric-onset multiple sclerosis"],"prefix":"10.1177","volume":"30","author":[{"given":"Amin","family":"Ziaei","sequence":"first","affiliation":[{"name":"University of California San Francisco, San Francisco, CA, USA\/Department of Pathology & Laboratory Medicine, University of California, Irvine Medical Center (UCIMC), Orange, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Solomon","sequence":"additional","affiliation":[{"name":"Division of Epidemiology and Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T Charles","family":"Casper","sequence":"additional","affiliation":[{"name":"The University of Utah, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Waltz","sequence":"additional","affiliation":[{"name":"The University of Utah, Salt Lake City, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6732-151X","authenticated-orcid":false,"given":"Bianca","family":"Weinstock-Guttman","sequence":"additional","affiliation":[{"name":"Buffalo General Hospital, State University of New York at Buffalo, Buffalo, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Aaen","sequence":"additional","affiliation":[{"name":"Loma Linda University Children\u2019s Hospital, Loma Linda, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Wheeler","sequence":"additional","affiliation":[{"name":"The University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Graves","sequence":"additional","affiliation":[{"name":"University of California San Diego, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie","family":"Benson","sequence":"additional","affiliation":[{"name":"Pediatric Multiple Sclerosis and Related Disorders Program, Boston Children\u2019s Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Gorman","sequence":"additional","affiliation":[{"name":"Pediatric Multiple Sclerosis and Related Disorders Program, Boston Children\u2019s Hospital, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9613-8394","authenticated-orcid":false,"given":"Mary","family":"Rensel","sequence":"additional","affiliation":[{"name":"Cleveland Clinic, Cleveland, OH, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soe","family":"Mar","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis, St. Louis, MO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Lotze","sequence":"additional","affiliation":[{"name":"Texas Children\u2019s Hospital, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2091-8201","authenticated-orcid":false,"given":"Benjamin","family":"Greenberg","sequence":"additional","affiliation":[{"name":"The University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9897-4422","authenticated-orcid":false,"given":"Tanuja","family":"Chitnis","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy T","family":"Waldman","sequence":"additional","affiliation":[{"name":"Division of Child Neurology, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7003-807X","authenticated-orcid":false,"given":"Lauren","family":"Krupp","sequence":"additional","affiliation":[{"name":"New York University Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith A","family":"James","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janace","family":"Hart","sequence":"additional","affiliation":[{"name":"University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa F","family":"Barcellos","sequence":"additional","affiliation":[{"name":"Division of Epidemiology and Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Waubant","sequence":"additional","affiliation":[{"name":"University of California San Francisco, San Francisco, CA, 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