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- W4220941798 abstract "Abstract OBJECTIVE To explore the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and to define the limits of this nature based on the statistical uncertainties regarding the various epidemiological observations that have been made. BACKGROUND Certain parameters of MS-epidemiology are directly observable (e.g., the risk of MS-recurrence in siblings and twins of an MS proband, the proportion of women among MS patients, the population-prevalence of MS, and the time-dependent changes in the female-to-male ( F:M ) sex-ratio . By contrast, other parameters can only be inferred from observed parameters (e.g., the proportion of the population that is genetically susceptible, the proportion of women among susceptible individuals, the probability that a susceptible individual will experience an environment sufficient to cause MS given their genotype, and if they do, the probability that they will develop the disease). DESIGN/METHODS The “genetically-susceptible” subset ( G ) of the population ( Z ) is defined to include everyone with any non-zero life-time chance of developing MS under some environmental conditions. For the observed parameters, acceptable ranges are assigned values such that they always include their 95% confidence intervals. By contrast, for the non-observed parameters, the acceptable ranges are assigned such that they cover the entire “plausible” range for each parameter. Using both a Cross-sectional Model and a Longitudinal Model , together with established parameter relationships, we explore, iteratively, trillions of potential parameter combinations and determine those combinations (i.e., solutions) that fall within the acceptable range for the observed and non-observed parameters. RESULTS Both Models and all analyses are consistent and converge to demonstrate that genetic-susceptibitly is limited to 52% or less of the population and to 30% or less of women . Consequently, most individuals (particularly women ) have no chance whatsoever of developing MS, regardless of their environmental exposure. Also, currently, the penetrance of MS in susceptible women is greater than it is in men . Moreover, as expected, the probability that susceptible individuals will develop MS increases with an increased likelihood of these individuals experiencing an environment sufficient to cause MS, given their genotype. Nevertheless, although it is conceivable that these response-curves plateau at 100% for both women and men , this possibility requires extreme conditions and seems remote. Rather, at least men , seem to plateau well below this level and, if so, it is this difference, rather than any differences in the genetic and environmental determinants of disease, that primarily accounts both for the difference in penetrance between women and men and for the increasing proportion of women among of MS patients worldwide. CONCLUSIONS The development of MS (in an individual) requires both that they have an appropriate genotype (which is uncommon in the population) and that they have an environmental exposure sufficient to cause MS given their individual genotype. Nevertheless, even when the necessary genetic and environmental factors, sufficient for MS pathogenesis, co-occur for an individual, this still insufficient for that person to develop MS. Thus, disease pathogenesis, even in this circumstance, seems not to be deterministic but, rather, to involve an important element of chance. Author Summary Certain parameters of MS-epidemiology can be directly observed. These parameters include the risk of MS recurrence in siblings and twins of an MS proband, the proportion of women among MS patients, the population-prevalence of MS, and the time-dependent changes in the female-to-male ( F:M ) sex-ratio . By contrast, there are other parameters of MS-epidemiology, which can’t be observed, but which must be inferred based on the values of the observable parameters. These parameters include the proportion of the general population ( Z ) that is genetically susceptible to MS, the proportion of women among susceptible individuals, the probability that a susceptible individual will experience an environment sufficient to cause MS, and if they do, the likelihood that they will, in fact, develop the MS. We define the subset ( G ) – i.e., the genetically-susceptible subset – to include everyone in ( Z ) who has any non-zero chance of developing MS over their life-time, under some environmental circumstances. For the observed parameters, plausible ranges are assigned acceptable values such that they always include their 95% confidence interval. By contrast, for the non-observed parameters, the acceptable ranges are assigned such that they cover the entire “plausible” range for each parameter. Then, using both a Cross-sectional Model and a Longitudinal Model , together with established parameter relationships, we explore iteratively trillions of potential parameter combinations and determine those combinations (i.e., solutions) that are allowed by the observed and non-observed parameter ranges. The Cross-sectional Model makes two assumptions, commonly made in studies of monozygotic twins, to establish certain relationships between the observed and non-observed parameters. By contrast, the Longitudinal Model makes neither of these assumptions but, rather, this Model utilizes the observed changes in the female-to-male ( F:M ) sex-ratio and the disease prevalence, which have taken place over the past 4–5 decades, to determine the response curves for susceptible individuals, relating their probability of developing MS to their probability of experiencing an environment sufficient to cause MS. Both Models and all analyses are consistent with each other and converge to demonstrate that genetic-susceptibitly is limited to 52% or less of the population and 30% or less of women. Consequently, most individuals have no chance whatsoever of developing MS, regardless of their environmental experiences. Thus, MS is a genetic disease in the sense that, if an individual does not have the correct genetic makeup, they can’t develop the disease. However, the probability that susceptible individuals will develop MS increases with an increased likelihood of these individuals experiencing an environment sufficient to cause MS, given their genotype. Thus, MS is also and environmental disease in the sense that the development of MS (in an individual), in addition to their having an appropriate genotype, requires that they experience an environmental exposure sufficient to cause MS given their individual genotype. Nevertheless, there must be another factor involved in disease pathogenesis because, although it is conceivable that these response-curves plateau at 100% for both women and men , this possibility requires extreme conditions and seems remote. Rather, at least men , seem to plateau well below this and, if so, it is this difference, rather than differences in the genetic and environmental determinants of disease, that primarily accounts both for the difference in penetrance between women and men and for the increasing proportion of women among of MS patients worldwide. Consequently, even when the necessary genetic and environmental factors, sufficient for MS pathogenesis, co-occur for an individual, this still seems to be insufficient for that person to develop MS. Thus, disease pathogenesis, even in this circumstance, seems not to be deterministic but, rather, to involve an important element of chance." @default.
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- W4220941798 date "2022-03-11" @default.
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- W4220941798 title "Multiple Sclerosis: Exploring the Limits of Genetic and Environmental Susceptibility" @default.
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- W4220941798 doi "https://doi.org/10.1101/2022.03.09.22272129" @default.
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