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The nature of genetic susceptibility to multiple sclerosis: constraining the possibilities

BACKGROUND: Epidemiological observations regarding certain population-wide parameters (e.g., disease-prevalence, recurrence-risk in relatives, gender predilections, and the distribution of common genetic-variants) place important constraints on the possibilities for the genetic-basis underlying susc...

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Autor principal: Goodin, Douglas S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847201/
https://www.ncbi.nlm.nih.gov/pubmed/27117889
http://dx.doi.org/10.1186/s12883-016-0575-6
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author_facet Goodin, Douglas S.
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description BACKGROUND: Epidemiological observations regarding certain population-wide parameters (e.g., disease-prevalence, recurrence-risk in relatives, gender predilections, and the distribution of common genetic-variants) place important constraints on the possibilities for the genetic-basis underlying susceptibility to multiple sclerosis (MS). METHODS: Using very broad range-estimates for the different population-wide epidemiological parameters, a mathematical model can help elucidate the nature and the magnitude of these constraints. RESULTS: For MS no more than 8.5 % of the population can possibly be in the “genetically-susceptible” subset (defined as having a life-time MS-probability at least as high as the overall population average). Indeed, the expected MS-probability for this subset is more than 12 times that for every other person of the population who is not in this subset. Moreover, provided that those genetically susceptible persons (genotypes), who carry the well-established MS susceptibility allele (DRB1*1501), are equally or more likely to get MS than those susceptible persons, who don’t carry this allele, then at least 84 % of MS-cases must come from this “genetically susceptible” subset. Finally, because men, compared to women, are at least as likely (and possibly more likely) to be susceptible, it can be demonstrated that women are more responsive to the environmental factors that are involved in MS-pathogenesis (whatever these are) and, thus, susceptible women are more likely actually to develop MS than susceptible men. Finally, in contrast to genetic susceptibility, more than 70 % of men (and likely also women) must have an environmental experience (including all of the necessary factors), which is sufficient to produce MS in a susceptible individual. CONCLUSIONS: As a result, because of these constraints, it is possible to distinguish two classes of persons, indicating either that MS can be caused by two fundamentally different pathophysiological mechanisms or that the large majority of the population is at no risk of the developing this disease regardless of their environmental experience. Moreover, although environmental-factors would play a critical role in both mechanisms (if both exist), there is no reason to expect that these factors are the same (or even similar) between the two. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12883-016-0575-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-48472012016-04-28 The nature of genetic susceptibility to multiple sclerosis: constraining the possibilities Goodin, Douglas S. BMC Neurol Research Article BACKGROUND: Epidemiological observations regarding certain population-wide parameters (e.g., disease-prevalence, recurrence-risk in relatives, gender predilections, and the distribution of common genetic-variants) place important constraints on the possibilities for the genetic-basis underlying susceptibility to multiple sclerosis (MS). METHODS: Using very broad range-estimates for the different population-wide epidemiological parameters, a mathematical model can help elucidate the nature and the magnitude of these constraints. RESULTS: For MS no more than 8.5 % of the population can possibly be in the “genetically-susceptible” subset (defined as having a life-time MS-probability at least as high as the overall population average). Indeed, the expected MS-probability for this subset is more than 12 times that for every other person of the population who is not in this subset. Moreover, provided that those genetically susceptible persons (genotypes), who carry the well-established MS susceptibility allele (DRB1*1501), are equally or more likely to get MS than those susceptible persons, who don’t carry this allele, then at least 84 % of MS-cases must come from this “genetically susceptible” subset. Finally, because men, compared to women, are at least as likely (and possibly more likely) to be susceptible, it can be demonstrated that women are more responsive to the environmental factors that are involved in MS-pathogenesis (whatever these are) and, thus, susceptible women are more likely actually to develop MS than susceptible men. Finally, in contrast to genetic susceptibility, more than 70 % of men (and likely also women) must have an environmental experience (including all of the necessary factors), which is sufficient to produce MS in a susceptible individual. CONCLUSIONS: As a result, because of these constraints, it is possible to distinguish two classes of persons, indicating either that MS can be caused by two fundamentally different pathophysiological mechanisms or that the large majority of the population is at no risk of the developing this disease regardless of their environmental experience. Moreover, although environmental-factors would play a critical role in both mechanisms (if both exist), there is no reason to expect that these factors are the same (or even similar) between the two. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12883-016-0575-6) contains supplementary material, which is available to authorized users. BioMed Central 2016-04-27 /pmc/articles/PMC4847201/ /pubmed/27117889 http://dx.doi.org/10.1186/s12883-016-0575-6 Text en © Goodin. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Goodin, Douglas S.
The nature of genetic susceptibility to multiple sclerosis: constraining the possibilities
title The nature of genetic susceptibility to multiple sclerosis: constraining the possibilities
title_full The nature of genetic susceptibility to multiple sclerosis: constraining the possibilities
title_fullStr The nature of genetic susceptibility to multiple sclerosis: constraining the possibilities
title_full_unstemmed The nature of genetic susceptibility to multiple sclerosis: constraining the possibilities
title_short The nature of genetic susceptibility to multiple sclerosis: constraining the possibilities
title_sort nature of genetic susceptibility to multiple sclerosis: constraining the possibilities
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847201/
https://www.ncbi.nlm.nih.gov/pubmed/27117889
http://dx.doi.org/10.1186/s12883-016-0575-6
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