Genetic and Environmental Susceptibility to Multiple Sclerosis
Main Article Content
Abstract
OBJECTIVE: To explore the nature and basis of environmental and genetic susceptibility to multiple sclerosis (MS).
BACKGROUND Susceptibility to multiple sclerosis (MS) is complex but clearly involves both environmental events and genetic factors. Certain epidemiological observations regarding MS (e.g., proportion of women among MS patients, population-prevalence of MS, impact of birth-month and migration patterns on the likelihood of MS, recurrence-risks for MS in siblings and twins, and time-dependent changes in MS-prevalence and the female to male sex-ratio) are well-established.
DESIGN/METHODS: We define the “genetically-susceptible” subset (G) to include everyone with any non-zero life-time chance of developing MS. Individuals who have no chance of developing MS, regardless of their environmental experiences, belong to the mutually exclusive “non-susceptible” subset (G–). We consider the implications that these well-established epidemiological observations have regarding the genetic and environmental basis of susceptibility to MS. In addition, we use the change in the female to male sex ratio, observed over a 35-year interval in Canada, to construct the response curves relating an increasing likelihood of MS to an increasing probability of a susceptible individual experiencing an environmental exposure sufficient to cause MS.
RESULTS: Environmental susceptibility to MS requires at least three different events – one occurring during the intrauterine or early post-natal period, another during childhood or adolescence, and a third (or more) many years later. Vitamin D deficiency and Epstein-Barr viral infections are likely involved. Moreover, we demonstrate that only a very small fraction of the general populations throughout Europe and North America is susceptible to MS. The vast majority of individuals in these populations has no chance whatsoever of developing MS, regardless of their environmental experiences. Even among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, only a small minority can possibly be members the (G) subset. Also, despite the preponderance of women among MS patients, compared to men, women are less likely to be susceptible and have a higher environmental threshold for developing MS. Nevertheless, the penetrance of MS in susceptible women is substantially greater than it is in men. Moreover, MS-probability in susceptible individuals increases with an increasing likelihood of a sufficient environmental exposure, especially among women. However, these response-curves plateau at under 50% for women and at a significantly lower level for men.
CONCLUSIONS: The pathogenesis of MS requires both a genetic predisposition and a suitable environmental exposure. Nevertheless, genetic-susceptibility is rare in the population and requires specific combinations of non-additive genetic risk-factors. By contrast, a sufficient environmental exposure (however many events are involved, whenever these events need to act, and whatever these events might be) is common, currently occurring in, at least, 76% of susceptible individuals. In addition, the environmental response-curves (especially in men) plateau well below 50%, which indicates that disease pathogenesis is partially stochastic.
Article Details
How to Cite
GOODIN, Douglas S..
Genetic and Environmental Susceptibility to Multiple Sclerosis.
Medical Research Archives, [S.l.], v. 9, n. 6, june 2021.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2413>. Date accessed: 24 nov. 2024.
doi: https://doi.org/10.18103/mra.v9i6.2413.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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9. Goodin DS. The Genetic and Environmental Bases of Complex Human-Disease: Extending the Utility of Twin-Studies. PLoS One. 2012;7(12): e47875.
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16. Dyment DA, Herrera BM, Cader Z, et al. Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance. Hum Mol Genet 2005;14:2019-2026.
17. Ramagopalan, SV, Anderson, C, Sadovnick, AD, Ebers, GC. Genomewide study of multiple sclerosis. N. Engl. J. Med. 2007;357, 2199–2200.
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22. Sadovnick AD, Ebers GC, Dyment DA, et al., and the Canadian Collaborative Study Group. Evidence for genetic basis of multiple sclerosis. Lancet 1996;347:1728-1730.
23. Ebers GC, Yee IML, Sandovnick AD, Duquette P, and the Canadian Collaborative Study Group. Conjugal multiple sclerosis: Population-based prevalence and recurrence risks in offspring. Ann Neurol. 2000;48:927-931.
24. Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC, the Canadian Collaborative Study Group. Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A. 2003;100:12877–82.
25. Dyment DA, Yee IML, Ebers GC, SadovnickAD, and the Canadian Collaborative Study Group. Multiple sclerosis in stepsiblings: Recurrence risk and ascertainment. J Neurol Neurosurg Psychiatry. 2006;77:258–259.
26. Orton SM, Herrera BM, Yee IM, et al., and the Canadian Collaborative Study Group. Sex ratio of multiple sclerosis in Canada: A longitudinal study. Lancet Neurol. 2006;5:932–6.
27. Sadovnick AD, Yee IML, Ebers GC, and the Canadian Collaborative Study Group. Multiple sclerosis and birth order: A longitudinal cohort study. Lancet Neurol. 2005;4:611–617.
28. Ebers GC, Sadovnick AD, Dyment DA, et al. Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet. 2004;363: 1773–1774.
29. Bager P, Nielsen NM, Bihrmann K, et al. Sibship characteristics and risk of multiple sclerosis: A nationwide cohort study in Denmark. Am J Epidemiol. 2006;163:1112–1117.
30. Kantarci OH, Barcellos LF, Atkinson EJ, et al. Men transmit MS more often to their children vs women: The Carter effect Neurology. 2006;67:305–310
31. Herrera BM, Ramagopalan SV, Orton S, et al. Parental transmission of MS in a population-based Canadian cohort. Neurology. 2007;69:1208–1212.
32. Islam T, Gauderman WJ, Cozen W, et al. Differential twin concordance for multiple sclerosis by latitude of birthplace Ann Neurol. 2006;60:56–64.
33. Robertson NP, Fraser M, Deans J, et al. Age-adjusted recurrence risks for relatives of patients with multiple sclerosis. Brain. 1996;119, 449-455.
34. Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359:1221-31.
35. Willer CJ, Dyment DA, Sadovnick AD, et al. Timing of birth and risk of multiple sclerosis: population based study. Br Med J. 2005;330:120-124.
36. Templer DI, Trent NH, Spencer DA, et al. Season of birth in multiple sclerosis. Acta Neurol Scand. 1992;85:107-109.
37. Staples J, Ponsonby AL, Lim L. Low maternal exposure to ultraviolet radiation in pregnancy, month of birth and risk of multiple sclerosis in offspring: a longitudinal analysis. Br Med J. 2010;340:c1640.
38. Torkildsen Ø, Aarseth J, Benjaminsen E, et al. Month of birth and risk of multiple sclerosis: confounding and adjustments. Ann Clin Transl Neurol. 2014;1:141–144.
39. Pantavou KG, Bagos PG. Season of birth and multiple sclerosis: a systematic review and multivariate meta‑analysis J Neurol. 2020;267:2815–2822.
40. Fiddes B, Wason J, Kemppinen A, et al. Confounding underlies the apparent month of birth effect in multiple sclerosis. Ann Neurol. 2013;73:714-270.
41. Fiddes B, Wason J, Sawcer S. Confounding in association studies: month of birth and multiple sclerosis J Neurol. 2014;261:1851-1856.
42. Dean G, Kurtzke JF. On the risk of multiple sclerosis according to age at immigration to South Africa. Br Med J. 1971;3:725-729.
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