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

Abstract

AbstractBACKGROUNDMS-pathogenesis requires both genetic factors and environmental events. The question remains, however, whether these factors and eventscompletelydescribe 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.METHODSThe “genetically-susceptible” subset of the population, (G), includeseveryonewho hasany non-zerolife-time chance of developing MS, undersomeenvironmental-conditions. A “sufficient” environmental-exposure, forany“genetically-susceptible” individual, includeseveryset of environmental conditions, each of which issufficient, by itself, tocauseMS in that person. This analysis incorporates several differentepidemiologic-parameters, involved in MS-pathogenesis, only some of which are directly-observable, and establishes “plausible-value-ranges”for each parameter. Thoseparameter-valuecombinations (solutions) that fall within theseplausible-rangesare then determined.RESULTSOnly a fraction of the population can possibly be “genetically-susceptible”. Thus, many individuals haveno possibilityof developing MS underanyenvironmental conditions. Moreover,some“genetically-susceptible” individuals, despite their experiencing a “sufficient” environmental-exposure,will neverdevelop disease.CONCLUSIONSThis analysisexplicitly includesall 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 betweensusceptible-womenandsusceptible-men.