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. 2021 Jul;92(7):717-722.
doi: 10.1136/jnnp-2020-325676. Epub 2021 Mar 9.

DRB1-environment interactions in multiple sclerosis etiology: results from two Swedish case-control studies

Anna Karin Hedström  1 , Jan Hillert  2 , Nicole Brenner  3 , Julia Butt  3 , Tim Waterboer  3 , Pernilla Strid  2 , Ingrid Kockum  2 , Tomas Olsson #  2 , Lars Alfredsson #  4
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DRB1-environment interactions in multiple sclerosis etiology: results from two Swedish case-control studies

Anna Karin Hedström et al. J Neurol Neurosurg Psychiatry. 2021 Jul.

Abstract

Objective: We aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for HLA-DRB1*15:01.

Methods: Using population-based case-control studies (6985 cases, 6569 controls), subjects with different genotypes and smoking, EBNA-1 status and adolescent Body Mass status, were compared regarding MS risk, by calculating OR with 95% CI employing logistic regression. The interaction between different genotypes and each environmental factor was evaluated on the additive scale.

Results: The effect of each DRB1*15:01 allele on MS risk was additive on the log-odds scale for each additional allele. Interaction between DRB1*15:01 and each assessed environmental factor was of similar magnitude regardless of the number of DRB1*15:01 alleles, although ORs were affected. When any of the environmental factors were present in DRB1*15:01 carriers without the protective A*02:01 allele, a three-way interaction occurred and rendered high ORs, especially among DRB1*15:01 homozygotes (OR 20.0, 95% CI 13.1 to 30.5 among smokers, OR 21.9, 95% CI 15.0 to 31.8 among those with elevated EBNA-1 antibody levels, and OR 44.3, 95% CI 13.5 to 145 among those who reported adolescent overweight/obesity).

Conclusions: The strikingly increased MS risk among DRB*15:01 homozygotes exposed to any of the environmental factors is a further argument in favour of these factors acting on immune-related mechanisms. The data further reinforce the importance of preventive measures, in particular for those with a genetic susceptibility to MS.

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Conflict of interest statement

Competing interests: Hedström has nothing to disclose. Hillert received honoraria for serving on advisory boards for Biogen and Novartis and speaker’s 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. Waterboer, Brenner, Butt and Strid have nothing to disclose. Olsson received honoraria for advisory boards an unrestricted MS research grants from Biogen, Novartis, Sanofi, Roche and Merck. Alfredsson reports grants from Swedish Research Council, grants from Swedish Research Council for Health Working Life and Welfare, grants from Swedish Brain Foundation, during the conduct of the study; personal fees from Teva, personal fees from Biogene Idec, outside the submitted work.

Figures

Figure 1
Figure 1
OR of developing MS for subjects with different combinations of DRB1*15:01, A*02:01 and environmental exposures (smoking, EBNA-1 status and adolescent BMI, respectively), compared with unexposed subjects without the genetic risk factors. Based on data from online supplemental eTables 5–7. BMI, body mass index; MS, multiple sclerosis.
See this image and copyright information in PMC

References

    1. Moutsianas L, Jostins L, Beecham AH, et al. . Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat Genet 2015;47:1107–13. 10.1038/ng.3395 - DOI - PMC - PubMed
    1. , Sawcer S, et al. , International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2 . Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011;476:214–9. 10.1038/nature10251 - DOI - PMC - PubMed
    1. Patsopoulos NA, Barcellos LF, Hintzen RQ, et al. . Fine-Mapping the genetic association of the major histocompatibility complex in multiple sclerosis: HLA and non-HLA effects. PLoS Genet 2013;9:e1003926. 10.1371/journal.pgen.1003926 - DOI - PMC - PubMed
    1. International Multiple Sclerosis Genetics Consortium . Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 2019;365. 10.1126/science.aav7188. [Epub ahead of print: 27 09 2019]. - DOI - PMC - PubMed
    1. Hedström AK, Katsoulis M, Hössjer O, et al. . The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement. Eur J Epidemiol 2017;32:909–19. 10.1007/s10654-017-0250-2 - DOI - PMC - PubMed

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