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Canada has one of the highest rates of Multiple Sclerosis (MS),
yet the cause of MS is incompletely understood. Researchers are
invested in identifying the underlying cause of MS and have found
that multiple factors are involved. These risk factors, or
exposures that increase the chance of developing MS, fall under
different categories; the environment, infectious agents, and
genetics and in combination, are thought to play a role in the
onset of MS. More recently, researchers have found that the
bacteria that line a person’s intestines (gut) has the capacity
to influence the development of the disease. Understanding how
each of these risk factors give rise to MS could lead to targeted
treatments of MS and ultimately, a cure.
Certain surroundings and lifestyle choices can increase MS risk. Among the most studied environmental risk factors for MS are vitamin D levels, childhood obesity, and smoking. Vitamin D deficiency can influence MS risk early in life1 and obesity has been found to be critical in dictating MS risk during adolescence2. The association between smoking and MS, however, is more complex, with evidence showing that secondhand smoke exposure may be related to the risk of pediatric MS3, while active smoking is later acting and highly apparent in adulthood4.
Formative studies conducted in the early 1960s examined the association between latitude and MS prevalence. The findings from these early studies revealed that regions further from the equator had larger populations of people with MS, and diagnosis was more common in the winter months5. These convincing findings encouraged further research examining the relationship between sun exposure, vitamin D and MS risk. This relationship has now been well-documented, and more information on vitamin D and MS can be found here.
Recent research has examined the relationship between vitamin D supplementation and disease-modifying therapies.
Body mass index (BMI) serves as the standard tool to quantify overweight or obesity. A BMI greater than 30 kg/m2 is considered obese, while the threshold for being overweight is a BMI greater than 25 kg/m2 and less than 308. The link between obesity and MS, and implications on MS risk, is a recent area of investigation.
Research efforts have also been invested in exploring the effect of obesity on the effectiveness of currently available MS therapies:
Smoking is another modifiable risk factor for MS.
While a relationship between cigarette smoke and MS risk before disease onset has been established, the effect of quitting smoking and disability progression in people diagnosed with MS has been less studied.
Given the demonstrated link between smoking cessation and reduction of disease burden in people with RRMS, it is important to consider how smoking could influence the disease course and disability accumulation in people with primary progressive MS (PPMS).
Many infectious agents have been investigated as potential risk factors for MS. The infection for which the best evidence exists is Epstein-Barr Virus (EBV). EBV is the most common cause of infectious mononucleosis, an illness highly prevalent among adolescents. Primary EBV infection during adolescence leads to infectious mononucleosis in more than half of affected individuals17 and people with clinically diagnosed infectious mononucleosis have a more than a two-fold increased chance of getting MS18 .
The human central nervous system (CNS) is rife with latent viruses, the majority of which belong to the human herpesvirus family. Particularly, infection with human herpesviruses 6-A (HHV-6A) tends to result in viral latency, meaning the virus is in a state where it is not fully infectious. Infectious or not, latent HHV-6A can still be detected in the blood of all those infected via the production of HHV-6A-related proteins. Previous studies have shown that people with MS have increased production of HHV-6A related proteins in their blood compared to people without MS21,22.
Variations in multiple genes are thought to contribute to MS risk. The best studied involve changes to the HLA-DRB1 gene. This gene belongs to the human leukocyte antigen (HLA) complex family. The HLA complex allows the immune system to discriminate between the body’s own proteins and proteins made by foreign invaders (like viruses or bacteria). HLA genes come in different variations, which makes the immune system apt to respond to foreign invaders. Changes in many HLA genes have been linked to increased MS risk, with the HLA-DRB1*1501 variation the strongest associated genetic change related to MS development25,26.
While HLA-DRB1*1501 variation may be a risk factor for MS development, it is not considered as a genetic factor related to the clinical course or severity of MS.
The trillions of bacteria that call the intestines home are collectively termed the gut microbiome. Changes in the gut microbiome are a newly identified potential risk factor for MS. Initial studies have uncovered the strains of bacteria that are elevated in individuals with MS compared to healthy controls. Research has built on this by looking at how these increased families of bacteria act on the immune system and contribute to MS risk.
It is important to note that both of these exciting studies have looked at small populations of individuals with MS, but research is ongoing in this field. The gut microbiome and its changes in composition between people with MS and people without MS may serve as a promising therapeutic avenue to explore. For now, however, more research needs to be done on how intestinal bugs may trigger MS, and how gut bacteria may interact with other risk factors for MS.
Recent studies involving gene-environmental interactions and MS risk have examined the roles of various known MS risk factors and how they may act together to influence MS risk:
On the other hand, some research has shown no interaction of certain risk factors associated with the development of MS. Kjetil Bjørnevik from the University of Bergen, in Norway and colleagues, retrieved data from 1904 people with MS and 3694 people without MS from Norway, Italy, and Sweden, all of whom had prior reports on smoking and infectious mononucleosis status. Both of these environmental risk factors alone increased MS risk in each of the studied populations. However, examining these risk factors in combination with one another demonstrated no increased risk association for MS. The findings suggest that smoking and infectious mononucleosis contribute to MS risk, but do so independently of one another. Their respective contributions to MS biology may involve similar pathways, however, more studies are required to parse this out more conclusively34.
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