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Relationships with MS not unique to relapsing-onset phenotypes
  1. Steve Simpson-Yap1,2
  1. 1 Neuroepidemiology Unit, The University of Melbourne School of Population and Global Health, Melbourne, Victoria, Australia
  2. 2 MS Research Flagship, Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  1. Correspondence to Dr Steve Simpson-Yap, Neuroepidemiology Unit, The University of Melbourne School of Population and Global Health, Melbourne, Victoria, Australia; steve.simpsonyap{at}unimelb.edu.au

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Here, Hedstrom and colleagues show that lifestyle/environmental/genetic relationships seen for relapsing-onset multiple sclerosis (MS) are also seen for progressive-onset MS

The aetiology of multiple sclerosis (MS) reflects a complicated interrelationship of environmental, lifestyle and genetic risk factors, each comprising a unique causal pie to realise disease in each patient. Of these factors, there is variable evidence in support of each, though some of the strongest and most consistent have been tobacco smoke,1 Epstein-Barr virus (EBV) exposure2 and the major histocompatibility locus, particularly the HLA-DRB1*15:01 allele,3 while less consistent evidence exists for factors including sun exposure/vitamin D,4 5 alcohol intake6 and BMI.7 In addition to exploring direct effects of these risk factors, the interaction between them, particularly gene–environment interaction, is of great interest as well as highly biologically plausible. A seminal publication by van der Mei et al explored the interaction between early childhood infant sibling exposure, a measure of early pathogen exposure and HLA-DRB1 genotype, finding those with less infant sibling exposure had a greater risk of MS, but this relationship was fourfold higher among those of HLA-DRB1 risk variant genotype, though this did not differ by anti-EBV-EBNA IgG titre.8 This study, like many like it, was not able to differentiate between participants of relapsing-onset versus progressive-onset MS types, due to the infrequency of progressive-onset ases. While Professor van der Mei has since undertaken the Primary Progressive Case–Control Study, which aims to recruit a sufficient population of progressive-onset cases to evaluate the relationships of lifestyle, environment and genetic factors with disease risk in this patient subgroup, this study is yet ongoing.

Hedstrom and colleagues leveraged the wealth of the medical information retained within the Swedish central medical register to explore the relationships of these factors with MS risk among relapsing and progressive-onset MS cases and whether these relationships differed between the patient subgroups.9 Using two large case–control studies, one established MS (Genes and Environment in MS) and one newly diagnosed MS (Epidemiological Investigation of MS), comprising 7520 relapsing-onset MS, 540 progressive-onset MS and 11 386 controls, the authors were able to explore the direct effects of a range of environmental and lifestyle factors’ associations with MS risk between the two MS patient subgroups as well as their additive interaction with HLA-DRB1 genotype. Among relapsing-onset and progressive-onset MS cases, the authors found that ever tobacco smoking was associated with 50% and 90% higher MS risk, obese adolescent BMI with 70% and 80% higher MS risk, and high anti-EBNA-1 IgG titre with 300% and 200% higher MS risk, respectively. Lower sun exposure was also associated with 30% higher MS risk among both MS phenotypes, while higher alcohol intake (>89 g/week among women >114 g/week among men) was associated with 30% and 50% lower MS risk and snuff use with 30% and 40% lower MS risk among relapsing and progressive-onset MS, respectively. Of especial interest, however, was assessing additive interaction of these with HLA-DRB1 genotype, those with the HLA-DRB1*1501 risk variant showed 6 and 4.6-fold enhancement of the adolescent obesity association and 3.4 and 4.4-fold enhancement of the low sun exposure association among relapsing and progressive-onset cases, respectively, and roughly 3.0-fold and 3.5-fold enhancement of the smoking and anti-EBV-EBNA (Epstein-Barr Nuclear Antigen) associations between both MS phenotypes.

These results are of interest, not merely in their substantiation of these risk factors’ relationships with MS risk, but particularly showing that the concern heretofore that due to the infrequency of progressive-onset cases in most previous epidemiological studies, associations seen might only have reflected relationships among the relapsing-onset cases. While obviously the pathophysiology of progressive-onset MS is distinct from that of relapsing-onset, the results of this study indicate that the deleterious associations of smoking, EBV exposure, obesity, and low sun exposure are not restricted to the relapsing-onset MS cases. Moreover, that both the measures of association of their direct effects, as well as the degree of enhancement among those with the HLA-DRB1 risk variant, are so similar suggests their modes of action may be comparable across MS phenotypes. This is encouraging in the utilisation of these risk factors as diagnostic elements for predicting MS risk. In addition, interventions targeting these aspects of environment and lifestyle might have benefits for progressive as well as relapsing-onset MS, this a potentially valuable adjunct to established methods of care in MS.

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Footnotes

  • Correction notice This article has been corrected since ti appeared Online First. Title has been abbreviated.

  • Contributors SS-Y authored the editorial.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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