Etiology and Risk Factors

Etiology of Multiple Sclerosis (MS)

The exact etiology of multiple sclerosis (MS) is not known, but its development is now known to be influenced by an interplay of background genetic variants and environmental triggers, including both lifestyle factors and exogenous factors – most prominently, Epstein-Barr virus (EBV) infection.

That genetic factors play a role in the development of MS is evidenced by the clinical concordance rate (i.e., the proportion of pairs of individuals that share a disorder) of 25-30% in monozygotic twins, compared to 3-7% of dizygotic twins. This is further underscored by an increased lifetime risk of MS in first degree relatives (~3%) and second-degree relatives (~1%), which is much greater than in the general population (0.1-0.3%). Early candidate gene approaches identified a genetic signal in the human leukocyte antigen (HLA) class II region; HLA genes encode cell-surface proteins that regulate various immune responses. The MS-associated signal was identified as HLA-DRB1*15:01, the only locus now known to confer a moderate increase in MS risk (odds ratio [OR], 3.2). Subsequent efforts were predominantly comprised of genome-wide association studies (GWAS), which identified more than 200 loci associated with MS to date. Of these, approximately 90% are in non-HLA regions, often in intergenic and regulatory (rather than coding) sequences. The OR of these loci is modest, ranging from 1.05 to 1.2. What is known about the genetics of MS development is thus consistent with the common disease/common variant hypothesis, which posits that for common diseases there exist many common genetic variants, each of which contributes only slightly to disease risk.

A number of lifestyle and environmental factors have been linked to increased risk of MS, including EBV infection, smoking (active or passive), adolescent obesity and low sun exposure. Seropositivity to EBV appears to be the strongest and best supported risk factor. A study of 10 million active-duty US military personnel, of whom 955 were diagnosed with MS during their military service, revealed that EBV infection (i.e., conversion from EBV seronegativity to seropositivity), but not infection with any other virus, increases the risk of MS by 32-fold. Furthermore, it has been shown that approximately 20-25% patients with MS produce antibodies to an EBV transcription factor, EBV nuclear antigen 1 (EBNA1); these antibodies are cross-reactive with glial cell adhesion molecule (GlialCAM), a protein expressed in glial cells in the CNS. However, it is still unknown whether EBV infection is a sufficient driver of MS pathogenesis or only triggers the disease in certain cases. Several factors, including cytomegalovirus seropositivity, oral tobacco consumption, alcohol consumption and coffee consumption, have been suggested to decrease the risk of MS, based on non-replicated studies, warranting further study. Environmental and lifestyle factors with established or putative effects on MS risk are presented in Table 1-1.

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As shown in Table 1-1, EBV infection, adolescent obesity and smoking interact with genetic predisposition factors (specifically, polymorphisms in HLA loci) to substantially increase the risk of MS. This suggests a mechanistic convergence of these factors, most likely at the level of adaptive immunity, which promotes an autoimmune response against the central nervous system (CNS).