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Gene–environment interactions increase the risk of paediatric-onset multiple sclerosis associated with household chemical exposures
  1. Zahra Nasr1,
  2. Vinicius Andreoli Schoeps1,
  3. Amin Ziaei1,
  4. Akash Virupakshaiah1,
  5. Cameron Adams2,
  6. T Charles Casper3,
  7. Michael Waltz3,
  8. John Rose3,
  9. Moses Rodriguez4,
  10. Jan-Mendelt Tillema4,
  11. Tanuja Chitnis5,
  12. Jennifer S Graves6,
  13. Leslie Benson7,
  14. Mary Rensel8,
  15. Lauren Krupp9,
  16. Amy T Waldman10,
  17. Bianca Weinstock-Guttman11,
  18. Tim Lotze12,
  19. Benjamin Greenberg13,
  20. Gregory Aaen14,
  21. Soe Mar15,
  22. Teri Schreiner16,
  23. Janace Hart1,
  24. Steve Simpson-Yap17,18,19,
  25. Clementina Mesaros20,
  26. Lisa F Barcellos2,21,
  27. Emmanuelle Waubant1
  1. 1UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, California, USA
  2. 2Genetic Epidemiology and Genomics Laboratory, Divisions of Epidemiology and Biostatistics, School of Public Health, University of California Berkeley, Berkeley, California, USA
  3. 3University of Utah Health, Salt Lake City, Utah, USA
  4. 4Mayo Clinic, Rochester, Minnesota, USA
  5. 5Brigham and Women's Hospital, Harvard Medical school, Boston, Massachusetts, USA
  6. 6University of California San Diego, San Diego, California, USA
  7. 7Childrens Hospital Boston, Boston, Massachusetts, USA
  8. 8Cleveland Clinic, Cleveland, Ohio, USA
  9. 9New York University Medical Center, New York City, New York, USA
  10. 10Division of Child Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  11. 11Jacobs School of Medicine and Biomedical Sciences University of Buffalo, Buffalo, New York, USA
  12. 12Texas Children's Hospital, Houston, Texas, USA
  13. 13University of Texas Southwestern Medical Center, Dallas, Texas, USA
  14. 14Loma Linda University Children's Hospital, Loma Linda, California, USA
  15. 15Washington University in St. Louis, St Louis, Missouri, USA
  16. 16Denver Children's Hospital, Denver, Colorado, USA
  17. 17Neuroepidemiology Unit, The University of Melbourne School of Population and Global Health, Melbourne, Carlton, Australia
  18. 18Clinical Outcomes Research Unit (CORe), Royal Melbourne Hospital, The University of Melbourne, Melbourne, Parkville, Australia
  19. 19Multiple Sclerosis Flagship, Menzies Institute for Medical Research, University of Tasmania, Tasmania, Hobart, Australia
  20. 20Department of Systems Pharmacology and Translational Therapeutics (SPATT), University of Pennsylvania, Philadelphia, Pennsylvania, USA
  21. 21Department of Integrative Biology, University of California Berkeley, Berkeley, California, USA
  1. Correspondence to Dr Emmanuelle Waubant, University of California San Francisco, San Francisco, CA 94117, USA; emmanuelle.waubant{at}


Background We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis.

Methods Using a case–control paediatric multiple sclerosis study, gene–environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.

Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence of DRB1*15 and the absence of A*02, and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, including IL-6 (rs2069852), BCL-2 (rs2187163) and NFKB1 (rs7665090).

Results 490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products and NFKB1 SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence of HLA-A*02 (AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products and NFKB1 SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found with IL-6 and BCL-2 SNP GG genotypes.

Conclusions The presence of gene–environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.

  • multiple sclerosis
  • genetics
  • paediatric neurology

Data availability statement

Data may be obtained from a third party and are not publicly available.

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Data availability statement

Data may be obtained from a third party and are not publicly available.

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  • Contributors ZN, AZ, CA, CM, LFB and EW contributed to the conception and design of the study; ZN, VS, AZ, CA, TCC, MW, SS-Y, LFB and EW contributed to the acquisition and analysis of data; ZN, VS, AZ, AV, CA, TCC, MW, JR, MR, J-MT, TC, JG, LB, MR, LK, AW, BW-G, TL, BG, GA, SM, TS, JH, SS-Y, CM, LFB and EW contributed to draft the text and preparing the figures. EW is responsible for the overall content as the guarantor.

  • Funding Funding for this work includes R01NS071463 (PI Waubant), NMSS HC-1509-06233 (PI Casper) and MSIF (PI Nasr).

  • Competing interests EW has current support from the NIH, NMSS, PCORI, CMSC and Race to Erase MS.

  • Provenance and peer review Not commissioned; externally peer reviewed.