Pathogenesis of Multiple Sclerosis: Genetic, Environmental, and Random Mechanisms

BACKGROUND MS-pathogenesis requires both genetic factors and environmental events. The question remains, however, whether these factors and events completely describe the MS disease-process. This question was addressed using the Canadian MS-data, which includes 29,478 individuals, representing 65-83% of all Canadian MS-patients. METHODS The “ genetically-susceptible ” subset of the population, ( G ), includes everyone who has any non-zero life-time chance of developing MS, under some environmental-conditions. A “ sufficient ” environmental-exposure, for any “ genetically-susceptible ” individual, includes every set of environmental conditions, each of which is sufficient , by itself, to cause MS in that person. This analysis incorporates several different epidemiologic-parameters , involved in MS-pathogenesis, only some of which are directly-observable, and establishes “ plausible-value-ranges” for each parameter. Those parameter-value combinations (solutions) that fall within these plausible-ranges are then determined. RESULTS Only a fraction of the population can possibly be “ genetically-susceptible ”. Thus, many individuals have no possibility of developing MS under any environmental conditions. Moreover, some “ genetically-susceptible ” individuals, despite their experiencing a “ sufficient ” environmental-exposure, will never develop disease. CONCLUSIONS This analysis explicitly includes all of those genetic factors and environmental events (including interactions), which are necessary for MS-pathogenesis, regardless of whether these are known, suspected, or as yet unrecognized. Nevertheless, in addition, “ true ” randomness seems to play a critical role in disease-pathogenesis. This observation provides empirical evidence that undermines the widely-held deterministic view of nature. Moreover, both sexes seem to have a similar genetic and environmental disease-basis. If so, this indicates that this random element is primarily responsible for the currently-observed differences in disease-expression between susceptible-women and susceptible-men . ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NA ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data is available in the published literature