@article{eafb37d5bcc341ce9c04193fdf2c94f5,
title = "Gene–environment interactions increase the risk of pediatric-onset multiple sclerosis associated with ozone pollution",
abstract = "Background: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure. Objectives: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86, and HLA-DRB1*15, the strongest genetic variant associated with POMS. 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. County-level-modeled ozone data were acquired from the CDC{\textquoteright}s Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86, and the presence of DRB1*15:01 (DRB1*15) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother{\textquoteright}s education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated. Results: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69–3.59 and 1.95, 95% CI: 1.32–2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15, with a RERI of 2.21 (95% CI: 0.83–3.59) and an AP of 0.56 (95% CI: 0.33–0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14–3.06) and an AP of 0.37 (95% CI: 0.001–0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype. Conclusions: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene–environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.",
keywords = "CD86, DRB1*15, Pediatric onset, gene–environment interaction, multiple sclerosis, ozone pollution",
author = "Amin Ziaei and Lavery, {Amy M.} and Shao, {Xiaorong M.A.} and Cameron Adams and Casper, {T. Charles} and John Rose and Meghan Candee and Bianca Weinstock-Guttman and Greg Aaen and Yolanda Harris and Jennifer Graves and Leslie Benson and Mark Gorman and Mary Rensel and Soe Mar and Tim Lotze and Benjamin Greenberg and Tanuja Chitnis and Janace Hart and Waldman, {Amy T.} and Barcellos, {Lisa F.} and Emmanuelle Waubant",
note = "Funding Information: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for this work include R01NS071463 (PI Waubant), NMSS HC-1509-06233 (PI Casper), and McDonald fellowship award of MSIF (PI Ziaie). Funding Information: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Amin Ziaei, Dr Amy M. Lavery, Ms Xiaorong Ma Shao, Mr Cameron Adams, and Ms Janace Hart report no disclosures relevant to the manuscript. Dr Gregory Aaen has participated in clinical trials funded by Biogen and Roche. Dr Leslie Benson has received funding for research unrelated to this work for a Biogen sponsored clinical trial, and Boston Children{\textquoteright}s Hospital office of faculty development grant. She has also acted as a paid consultant to the National Vaccine Injury Compensation Program. Dr Mark Gorman has participated in clinical trials funded by Roche, Novartis, and Biogen and received research funding from Pfizer. Dr Manu Goyal receives grant support from the NIH, has IBM stock and has received honoraria and trip reimbursement from Capital Medical University, Beijing, Shandong Madic Technologies Co., Ltd, and the Tancheng Talent Office for brain PET conferences in 2019. Dr Jennifer Graves has received grant and clinical trial support from the National MS Society, Race to Erase MS, UCSF CTSI RAP program, Biogen, and Genentech. She has received honoraria from Biogen and Genzyme for non-promotional trainee education events. She has received personal fees from Novartis and Celgene. Dr Yolanda Harris reports no disclosures relevant to the manuscript. Dr Timothy Lotze has served as a consultant/speaker for Biogen. Dr Soe Mar has participated in clinical trials funded by Roche. Dr Jayne Ness has participated in clinical trials funded by Novartis, Chugai, and Roche. Dr Mary Rensel has served as a consultant and/or received research or patient education funds from Serono, Biogen, Medimmune, Novartis, Genentech, NMSS, Improve Consulting, Kijia, and MSAA. Dr John Rose has research support from NMSS, NIH, Guthy Jackson Foundation, PCORI, Friends of MS, Biogen, and VA. Dr Bianca Weinstock-Guttman has served as a consultant/speaker for Biogen, Novartis, Genzyme & Sanofi, Genentech, Abbvie, Bayer, EMD Serono; research support from Biogen, Novartis, Genentech, Genzyme & Sanofi, and EMD Serono. Mr Michael Waltz reports no disclosures relevant to the manuscript. Dr T. Charles Casper has received research support from Roche. Dr Benjamin Greenberg and Dr Meghan Candee report no disclosures relevant to the manuscript. Dr Tanuja Chitnis is an advisory board member for Biogen, Novartis, and Sanofi-Genzyme; has received research support from the National MS Society, Department of Defense, Guthy Jackson Charitable Foundation, Mallinckrodt, Novartis, and Octave; has participated in clinical trials sponsored by Sanofi-Genzyme and Novartis. Dr Amy Waldman reports no disclosures relevant to the manuscript. She has participated in multicenter clinical trials and prospective studies funded by Novartis, Ionis, Genentech, and Travere. She has current grant support from the NIH, NMSS, and Pennsylvania Department of Health. She receives royalties from UpToDate. Dr Lisa F. Barcellos has current funding for research unrelated to this work from the National MS Society and the National Institutes of Health. Dr Emmanuelle Waubant has participated in multicenter clinical trials funded by Genentech, Alexion, and Biogen. She has current support from the NIH, NMSS, PCORI, CMSC, and Race to Erase MS. Publisher Copyright: {\textcopyright} The Author(s), 2022.",
year = "2022",
doi = "10.1177/13524585211069926",
language = "English (US)",
journal = "Multiple Sclerosis",
issn = "1352-4585",
publisher = "SAGE Publications Ltd",
}