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We aimed to investigate whether smoking acts synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case\u2013control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p\u2009&lt;\u20090.0001). There was an additive interaction between current smoking and high EBNA-1 antibody levels (AP 0.3, 95% CI 0.2\u20130.4), but not between past smoking and high EBNA-1 antibody levels (AP 0.01, 95% CI \u2212\u00a00.1 to 0.1), with regard to MS risk. An interaction also occurred between current smoking and IM history (AP 0.2, 95% CI 0.004\u20130.4), but not between past smoking and IM history (AP \u2212\u00a00.06, 95% CI \u2212\u00a00.4 to 0.3). Current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved.<\/jats:p>","DOI":"10.1038\/s41598-020-67883-w","type":"journal-article","created":{"date-parts":[[2020,7,3]],"date-time":"2020-07-03T10:02:47Z","timestamp":1593770567000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Smoking and Epstein\u2013Barr virus infection in multiple sclerosis development"],"prefix":"10.1038","volume":"10","author":[{"given":"Anna Karin","family":"Hedstr\u00f6m","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Brenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Butt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Hillert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Waterboer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Kockum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Olsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Alfredsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,3]]},"reference":[{"key":"67883_CR1","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1007\/s10654-013-9853-4","volume":"28","author":"AK Hedstr\u00f6m","year":"2013","unstructured":"Hedstr\u00f6m, A. 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Kockum received speaker's fees from Merck-Serono, and is involved in a project sponsored by Biogen. Hillert received honoraria for serving on advisory boards for Biogen and Novartis and speaker\u2019s fees from Biogen, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis. He has served as principal investigator for projects sponsored by, or received unrestricted research support from, Biogen, Merck-Serono, TEVA, Novartis and Bayer-Schering. TO served on scientific advisory boards and received speaker honoraria Novartis, Merck-Serono, Biogen Idec, TEVA and Genzyme; served as Co-editor of Current Opinion in Immunology; received from Novartis and Biogen; and receives research support from Novartis, Genzyme, Biogen Idec, the Swedish Research Council (07488), EU fp7 Neurinox, and CombiMS, and the Swedish Brain Foundation. Alfredsson received research support from the Swedish Medical Research Council (Dnr 2016-02349), the Swedish Council for Health, Working Life and Welfare (Dnr 2015-00195) and the Swedish Brain Foundation; has\u00a0received speaker\u00a0honoraria from\u00a0Biogen Idec and TEVA.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10960"}}