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Genetic and Environmental Susceptibility to Multiple Sclerosis

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.