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.
Environmental Risk Factors
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.
- In one study, 170 people with relapsing-remitting MS (RRMS) seen at Copenhagen University Hospital were studied, each of whom were treated with the MS medication, Tysabri (natalizumab) as well as vitamin D supplements. This study, led by Dr. Julie Hejgaard Laursen, found vitamin D supplementation reduced their overall relapse rate6. While promising, these findings must be replicated, given the small number of participants studied. A study investigating the effect of vitamin D treatment on people with and without vitamin D supplementation may also be worthwhile.
- Dr. Dalia L. Rotstein and colleagues at Massachusetts General Hospital in Boston, MA examined vitamin D levels in combination with treatment of interferon-β (IFN-β), glatiramer acetate (GA), and fingolimod efficacy among 324 individuals with RRMS. In this cohort, higher vitamin D levels were associated with a 30-50% reduced risk of relapses or new inflammatory lesions on MRI in people treated with IFN-β and fingolimod. However, there was no protective effect of higher vitamin D levels in the GA group. This study raises the question of whether the choice of disease-modifying therapy may influence the effect of vitamin D supplementation on MS disease activity7.
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.
- Dr. Kassandra L. Munger at Harvard University led a study in 2009 in two groups of American nurses that showed being obese at 18 years old more than doubled the risk of MS9. This study was confirmed in more recent work by Dr. AK Hedström in Stockholm, Sweden who examined more than 1500 people with RRMS and nearly 3000 non-MS controls to show that BMI during adolescence, rather than childhood, is a critical in dictating MS risk2.
- A variety of lifestyle factors can influence a person’s BMI, including genetics. A study led by Dr. Brent Richards of McGill University examined mutations in genes that correspond to increased susceptibility in BMI, and in turn, if these mutations contribute to increased MS risk using statistical analyses.The study incorporated data from more than 300,000 people who were obese, 14,000 people with MS and 24,000 controls without MS and not obese. The results showed that a higher BMI is closely linked to MS. Particularly, genes known to increase BMI from the overweight to the obese category were associated with a significantly elevated risk of developing MS10.
- Obesity during childhood development, particularly at puberty, has a distinct effect on the risk of pediatric onset MS. A study spearheaded by Dr. Tanuja Chitnis from the Massachusetts Hospital for Children in Boston, MA investigated 254 people with RRMS that were diagnosed with MS under the age of 18 and 420 age-matched individuals. The results demonstrated that both girls and boys with MS had an overweight or obese BMI (54% MS girls, 48% MS boys) compared to healthy subjects (33% girls, 34% boys). The researchers concluded that a higher BMI increased the risk of MS diagnosis – particularly, this effect was pronounced at early adolescence11.
Research efforts have also been invested in exploring the effect of obesity on the effectiveness of currently available MS therapies:
- One study examined over 80 RRMS individuals who were normal, overweight or obese over a two-year span; all individuals received IFN-β treatment within the study’s timeframe. The overweight and obese groups of people receiving IFN-β treatment did not enter periods of remission as readily compared to those of normal BMI receiving the same medication12. More work is being done to identify why IFN-β treatment is less effective in people with elevated BMI. This study, although limited by a small sampling of individuals with MS, reveals that obesity may influence disease progression.
- A meta-analysis of six studies investigating the link between cigarette smoke intake and MS risk was conducted by C.H. Hawkes from Essex, UK. The study distinguished between “ever” and “never smokers” among people with MS and determined how smoking related to the risk of developing MS. They found that MS risk increases among those who smoked prior to disease onset13.
- In a study led by Dr. AK Hedström in Stockholm, Sweden examined whether tobacco smoke and/or Swedish snuff use (a smokeless tobacco powder inhaled or sniffed into the nose) contributed to the risk of MS. They examined data from 902 people with MS and 1855 people without MS using questionnaires. Routine questions regarding demographics and overall health were asked, as well as current and previous smoking habits. Additional questions included: duration of smoking, average number of cigarettes smoked per day, and type of cigarettes smoked. Results showed that current smokers exhibited a higher risk for MS than those that never smoked, and the increased risk for MS among smokers persisted up to five years after quitting4. How cigarette smoke and MS risk are related biologically is not well-understood and is the subject of ongoing research.
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.
- In a study led by Dr. Radu Tanasescu of the University of Nottingham, UK, 1270 people with RRMS answered a series of questions related to their smoking habits, including when they started smoking, the age they stopped smoking (if applicable), and a rough estimate of the number of cigarettes smoked per day. The study showed that each “smoke-free” year was associated with a decreased risk of reaching an Expanded Disability Status Score (EDSS) of 4.0 and 6.0. The researchers offer the following example to explain this finding: an individual with MS who is an ex-smoker and curbed the habit 10 years prior has a 33% lower risk of reaching an EDSS score of 4.0 and 26% reduced risk of reaching EDSS 6.0 compared with an individual with MS who has continued to smoke throughout that 10 year span14.
- Farren Briggs and colleagues from Case Western Research University in Cleveland, Ohio conducted a study of close to 1000 people with MS self-reporting their smoking habits. This randomly selected cohort of people living with MS was drawn from the North American Research Committee on Multiple Sclerosis (NARCOMS) registry that comprises more than 38,000 people with MS. The majority of the study group had RRMS and SPMS. Active smokers experienced diminished health-related quality of life and increased reported disease activity. When their performance on numerous physical and functional scales was assessed, smokers scored worse overall compared to non-smokers15.
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).
- A first of its kind study examining this relationship has been conducted in a group of nearly 400 people with PPMS. This research effort was led by Dr. Marcus Koch and his research team of the University of Calgary, who analyzed data that was previously collected as part of an ongoing study called the Clinical Impact of Multiple Sclerosis (CIMS).However, no significant link between cigarette smoking and disability accumulation could be discerned in this study16.
- A recent study has determined that the presence of EBV can be detected in the blood of nearly 95% of people without MS, and in 99.5% of people with MS. MS risk increases by about 10 times in individuals who had an undiagnosed EBV infection during childhood,and by nearly 20 times in people who developed mononucleosis during adolescence, compared to EBV-negative individuals19. The far-reaching presence of EBV in both individuals with MS and people without MS suggests that the virus alone does not perpetuate the disease. Of note, EBV is the only virus that is implicated in nearly all individuals with adult-onset MS20.
- Michael Pender and colleagues from the University of Queensland in Brisbane, Australia have recently performed work examining T cell response to EBV in people with MS. The study recruited nearly 100 individuals with MS and over 50 people without MS to characterize the immune cells within their blood. The results showed that as compared to individuals without MS, individuals with MS have a reduced amount of CD8+ T cells, the T cell population that kills infected cells, that are specific for EBV. This finding suggests impaired EBV infection control among individuals with MS, which may underlie disease development21.
- David Mock & Margot Mayer-Pröschel from the University of Rochester, NY pioneered work that demonstrated a novel link between HHV-6A-related protein production and demyelination. In an experimental setting, the researchers showed that oligodendrocytes – the cells responsible for producing the myelin that insulates the brain’s axons – are defective in nature once they encounter HHV-6A-related protein22,23.This study suggests that an infectious agent in the CNS of an individual with MS may contribute to the pathogenesis of the disease, but more studies in this area are needed to definitively reach this conclusion.
- Work initiated by LM Villar’s group24 at the University of Alcala in Madrid, Spain detected the presence of HHV-6 antibodies in the cerebrospinal fluid of three out of eight people with PPMS and one out of seven people with RRMS sampled.
Infectious Risk Factors
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 .
Human herpesviruses 6-A
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.
Genetic Risk Factor: HLA DRB1*1501
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.
- In August 2007, the International Multiple Sclerosis Genetics Consortium published a study in the New England Journal of Medicine titled “Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study”. Their investigation of heritable risk factors of MS spanned 931 “family trios”—comprised of an adult with MS and both parents of the individual. Nearly 2500 non-MS controls were recruited for this study as well. When the HLA of the family trios and control subjects were analyzed for sequence variants related to MS risk, the HLA-DRB1*1501 variation was found among 57% of family trios26.
- Performing a separate genome-wide association study on a European cohort of nearly 10,000 people with MS and over 17,000 people without MS, Stephen Sawcer and colleagues from the International Multiple Sclerosis Genetics Consortium confirmed that the HLA-DRB1*1501 variation of the HLA gene is the strongest genetic association linked to MS risk27.
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.
- Sawcer and colleagues’ study27 along with a study spearheaded by Dr. Michaela F. George of the University of California, Berkeley established that having the HLA-DRB1*1501 variant of the HLA allele increases MS risk, but does not contribute to increased MS disease severity25.
- Anneke Van der Walt and colleagues from the Royal Melbourne Hospital in Melbourne, Australia examined the presence of the HLA-DRB1*1501 gene and its influence on MS clinical disease through three indicators: Multiple Sclerosis Severity Score (MSSS), the interval between first and second attack, and brain atrophy, in more than 700 people with RRMS. The researchers demonstrated that the presence of this HLA variation does not influence outcomes, but does contribute to disease risk28.
A Multifactorial Risk Factor: The Gut Microbiome
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.
- One study initiated by Egle Cekanaviciute and Bryan B. Yoo from the University of California and California Institute of Technology, respectively, studied over 140 people—half of whom were diagnosed with MS. Using this cohort, the researchers determined that two bacterial groups, Acinetobacter and Akkermansia, were four times more common in people with MS compared to people without MS. Additional experiments in mice were performed by transferring some of the MS gut bacteria into mice. Within 20 days of this transfer, mice developed severe swelling of the brain. When the gut microbiome of the healthy individuals was transferred to mice with MS-like disease, they experienced milder symptoms29.
- A separate study performed by Kerstin Berer and Lisa Ann Gerdes from Munich, Germany recruited 34 sets of identical twins, where only one twin has MS and examined the bacterial profile of their gut. This study confirmed that the Akkermansia group of bacteria was found in significantly higher levels in the twin with MS. This study then took the gut bacteria of each group of twins and placed them in mice with MS-like disease. Over time, the mice who received intestinal bugs from the twin with MS developed brain swelling three times more often than mice who received bacteria from the non-MS twin. This group of researchers also discovered that gut bacteria from the twin with MS seemed to inhibit the production of molecules that reduce swelling30.
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.
Combinational 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:
- HLA-DRB1*1501 variation and presence of EBV in the blood. P Sundström and colleagues of Umeå University Hospital in Sweden asked whether these longstanding risk factors of MS influence one another, namely if the HLA-DRB1*1501 mutation relates to an increased reactivity of the person’s immune cells to EBV. The results showed that individuals with this specific HLA variation also have immune cells that are highly reactive to EBV infection, compared to individuals without the HLA mutation31.
- AK Hedstrom of the Institute of Environmental Medicine in Stockholm, Sweden investigated in 2011 the dual contributions of smoking and HLA gene variations to MS risk. Overall, the study received responses from more than 1100 people with MS and over 2300 non-MS controls using self-reported questionnaires to assess smoking habits, and blood samples to assess HLA gene variation. Overall, there is a greater than additive effect of HLA-DRB1*1501 variation and smoking in the development of MS32. This interaction between genetics and environment in contributing to MS risk was replicated by a more recent study led by the same researcher in 201733.
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.
1.Handel, A. E., Giovannoni, G., Ebers, G. C. & Ramagopalan, S. V. Environmental factors and their timing in adult-onset multiple sclerosis. Nat. Rev. Neurol. 6, 156–166 (2010).
2.Hedström, A. K., Olsson, T. & Alfredsson, L. Body mass index during adolescence, rather than childhood, is critical in determining MS risk. Mult. Scler. J. 22, 878–883 (2016).
3.Lavery, A. M. et al. The contribution of secondhand tobacco smoke exposure to pediatric multiple sclerosis risk. Mult. Scler. Houndmills Basingstoke Engl. (2018). doi:10.1177/1352458518757089
4.Hedström, A. K., Bäärnhielm, M., Olsson, T. & Alfredsson, L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. Neurology 73, 696–701 (2009).
5.Acheson, E. D., Bachrach, C. A. & Wright, F. M. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatr. Scand. 35, 132–147 (1960).
6.Laursen, J. H., Søndergaard, H. B., Sørensen, P. S., Sellebjerg, F. & Oturai, A. B. Vitamin D supplementation reduces relapse rate in relapsing-remitting multiple sclerosis patients treated with natalizumab. Mult. Scler. Relat. Disord. 10, 169–173 (2016).
7.Rotstein, D. L. et al. Effect of vitamin D on MS activity by disease-modifying therapy class. Neurol. Neuroimmunol. Neuroinflammation 2, (2015).
8.Defining Adult Overweight and Obesity | Overweight & Obesity | CDC. Available at: https://www.cdc.gov/obesity/adult/defining.html. (Accessed: 10th November 2017)
9.Munger, K. L., Chitnis, T. & Ascherio, A. Body size and risk of MS in two cohorts of US women. Neurology 73, 1543–1550 (2009).
10.Mokry, L. E. et al. Obesity and Multiple Sclerosis: A Mendelian Randomization Study. PLOS Med. 13, e1002053 (2016).
11.Chitnis, T. et al. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Ann. Clin. Transl. Neurol. 3, 897–907 (2016).
12.Kvistad, S. S. et al. Body mass index influence interferon-beta treatment response in multiple sclerosis. J. Neuroimmunol. 288, 92–97 (2015).
13.Hawkes, C. H. Smoking is a risk factor for multiple sclerosis: a metanalysis. Mult. Scler. J. 13, 610–615 (2007).
14.Tanasescu, R., Constantinescu, C. S., Tench, C. R. & Manouchehrinia, A. Smoking Cessation and the Reduction of Disability Progression in Multiple Sclerosis: A Cohort Study. Nicotine Tob. Res. doi:10.1093/ntr/ntx084
15.Briggs, F. B., Gunzler, D. D., Ontaneda, D. & Marrie, R. A. Smokers with MS have greater decrements in quality of life and disability than non-smokers. Mult. Scler. J. 1352458516685169 (2017).
16.Javizian, O., Metz, L. M., Deighton, S. & Koch, M. W. Smoking does not influence disability accumulation in primary progressive multiple sclerosis. Eur. J. Neurol. 24, 624–630 (2017).
17.Hjalgrim, H., Friborg, J. & Melbye, M. The epidemiology of EBV and its association with malignant disease. in Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis (eds. Arvin, A. et al.) (Cambridge University Press, 2007).
18.Handel, A. E. et al. An Updated Meta-Analysis of Risk of Multiple Sclerosis following Infectious Mononucleosis. PLOS ONE 5, e12496 (2010).
19.Ascherio, A. & Munger, K. L. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann. Neurol. 61, 288–299 (2007).
20.Pender, M. P. The Essential Role of Epstein-Barr Virus in the Pathogenesis of Multiple Sclerosis. The Neuroscientist 17, 351–367 (2011).
21.Pender, M. P., Csurhes, P. A., Burrows, J. M. & Burrows, S. R. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin. Transl. Immunol. 6, e126 (2017).
22.Ben-Fredj, N. et al. Prevalence of human herpesvirus U94/REP antibodies and DNA in Tunisian multiple sclerosis patients. J. Neurovirol. 19, 42–47 (2013).
23.Campbell, A. et al. Expression of the Human Herpesvirus 6A Latency-Associated Transcript U94A Disrupts Human Oligodendrocyte Progenitor Migration. Sci. Rep. 7, 3978 (2017).
24.Alenda, R. et al. Identification of the major HHV-6 antigen recognized by cerebrospinal fluid IgG in multiple sclerosis. Eur. J. Neurol. 21, 1096–1101 (2014).
25.George, M. F. et al. Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies. Neurol. Genet. 2, e87 (2016).
26.Consortium, I. M. S. G. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007, 851–862 (2007).
27.Sawcer, S. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, nature10251 (2011).
28.Van der Walt, A. et al. Heterogeneity at the HLA-DRB1 allelic variation locus does not influence multiple sclerosis disease severity, brain atrophy or cognition. Mult. Scler. J. 17, 344–352 (2011).
29.Cekanaviciute, E. et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc. Natl. Acad. Sci. 114, 10713–10718 (2017).
30.Berer, K. et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc. Natl. Acad. Sci. 114, 10719–10724 (2017).
31.Sundström, P., Nyström, L., Jidell, E. & Hallmans, G. EBNA-1 reactivity and HLA DRB1*1501 as statistically independent risk factors for multiple sclerosis: a case-control study. Mult. Scler. Houndmills Basingstoke Engl. 14, 1120–1122 (2008).
32.Hedström, A. K. et al. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain 134, 653–664 (2011).
33.Hedström, A. K. et al. The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement. Eur. J. Epidemiol. 1–11 (2017). doi:10.1007/s10654-017-0250-2
34.Bjørnevik, K. et al. Negative interaction between smoking and EBV in the risk of multiple sclerosis: The EnvIMS study. Mult. Scler. Houndmills Basingstoke Engl. 23, 1018–1024 (2017).