Abstract
Prevention of multiple sclerosis requires intervention on modifiable causes of the condition making it necessary to establish what those causes are. MS is often stated to be a polygenic disease, with causal contributions from environmental factors and gene-environment interactions, implying an additive and independent relationship of these factors. Mechanistically there are no independent contributions of genes or environmental factors to traits. This model is unrealistic but still useful and underlies the concept of heritability, a foundational parameter in population genetics. However, it perpetuates a debate on an irreconcilable dichotomy about whether MS is primarily genetic or environmental. In particular, epidemiological evidence now exists for a causal, possibly even necessary, role for Epstein Barr Virus in MS. The additive model makes it unintuitive to reconcile MS as a genetic disease but also independently a viral illness. In this perspective it is argued that starting from a realistic interaction only model, based on broadly accepted biological premises, and working forward to explain why the classical additive model gives useful results, there is actually no paradox. An integrated approach using population genetic studies, immunology and molecular virology offers a particularly promising route to establish the elusive role of EBV in MS pathology, as EBV is a large and complex virus and its latency, dysregulated in most EBV-related pathologies, is hard to study in vivo. This approach may offer a route to prevention of MS altogether.
Highlights
Prevention of multiple sclerosis (MS) occurring altogether, rather than prevention of MS disability by early diagnosis and effective treatment, would require intervening on the modifiable causes of MS, making it critical to establish what those are
MS: Complex Trait Viral Illness disease incidence over a small number of generations [8, 9], marked geographical variation in disease risk between and within countries coupled with findings of migration studies [10, 11], and serological [Epstein Barr Virus (EBV)] and robust lifestyle associations indicate the importance of environmental factors even decades prior to diagnosis [12]
In the case of EBV infection, which is the only consistent, strong, and temporal association that has far been suggested to be necessary for MS [13,14,15,16,17,18,19,20,21,22,23,24,25], the evidence for a causal relationship in at least most cases of MS is unusually strong as specific viruses are rarely necessary for clinical syndromes, so the apparent necessity of EBV in MS is strikingly unusual [26]
Summary
Prevention of multiple sclerosis (MS) occurring altogether, rather than prevention of MS disability by early diagnosis and effective treatment, would require intervening on the modifiable causes of MS, making it critical to establish what those are. Acknowledging the epidemiological data, MS is often described as a complex genetic disease, with important causal contributions coming from environmental factors and gene-environment interactions [30,31,32,33,34,35,36,37]. This statement and paraphrases of it sound etiological but describe the classic additive model of population genetics which is primarily concerned with a related but different concept: partitioning the variation of a trait observed in a given population into the sources of that variation (Equation 1) [38, 39]. Thereafter, it is argued that by focussing the tools of population genetics, immunology, and molecular epidemiology on the difficult problem of latent EBV, an elusive epigenetic master manipulator of memory B cells, and by investigating MS as both a complex genetic disease and probably a viral pathology simultaneously, exciting opportunities for attempting MS prevention may arise
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
