1. Epidemiology & Genetics of Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the myelinated axons of the central nervous system; for those with MS, myelin sheaths are destroyed by one’s immune system, leading to a deficiency in the communication between one’s body and brain. There are four different types of MS including primary progressive MS, progressive relapsing MS, relapsing-remitting MS and secondary progressive MS. The epidemiology of MS covers sex ratios and the age statistics of MS, as well as prevalence rates, incidence rates and geographical differences. For example, prevalence of MS increases the farther you move away from the equator, suggesting links to sunlight exposure[1]. Tying into epidemiology is the investigation of the role of genetics in MS development. Those with two or more close relatives (parents or siblings) with MS are 40 times more likely to develop MS than someone without affected relatives[1]. Also, a few genetic factors have been linked to MS, most notably the role of the Human Leukocyte Antigen (HLA). Certain HLA types have been hypothesized to play a role in the malfunctioning of the immune system which leads to the destruction of myelin proteins by one’s own T-Cells[1].

1.1. Epidemiology

1.1.1 Geography

Multiple studies have shown that Multiple Sclerosis (MS) prevalence is higher when nations are farther away from the equator. In northern parts of Europe and North America, particularly Canada, prevalence rates are as high as 100-200 for a population of 100,000, while incidence rates are 5-6 per 100,000 people per year[2]. The amount of ultraviolet B (UVB) radiation decreases the further you are from the equator in terms of latitude, and for most people, sunlight is an important factor in sustaining healthy levels of Vitamin D, something which is not commonly found in the diet of many people[2]. In figure 1, zone 1 has sufficient UVB radiation while zones 2 and 3 indicate regions with insufficient UVB radiation, with the colour change from red to yellow to orange to green to dark green indicating decreasing UVB radiation[2]. When compared with Figure 2, there is a relationship between the prevalence of MS and the insufficient UVB radiation exposure; nations which are farther away from the equator in terms of latitude have higher prevalence rates of MS and lower UVB radiation. The increasing prevalence does not continue on forever. A comprehensive meta-analysis dating back to 2011 showed that prevalence rates reached a peak at 55°, and then moving in an inverse manner once latitude of 60° was reached[3].

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Figure 2. Distribution of MS prevalence. Brown indicates very low levels (<10 per 100,000),
yellow indicates medium-low levels of 10-30 per 100,000, red indicates medium levels ranging from
30-90 per 100,000 and blue is the highest with >100 per 100,000 (2014)

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Figure 1. Distribution of sufficient UVB radiation divided into zones.
Zone 1 has sufficient UVB radiation year round, Zone 2 insufficient for at least one
month of the year and Zone 3 insufficient year round; increasing insufficiency seen
in colour change from red all the way to dark green (2014)

Despite UVB radiation’s correlation with MS prevalence, there are some anomalies. The southern Mediterranean island Sardinia has fairly high prevalence rates, with 157 of every 100,000 people being afflicted with MS, despite its relatively close proximity to the equator compared to northern parts of North America and Europe[4]. Also, the Inuit people in Northern Canada have relatively low MS prevalence rates, most likely due to their high consumption of oily fish, which are a very good source of Vitamin D[2].

Within countries, there has been conflicting evidence about the role of latitude in MS prevalence. One study found that MS prevalence increased as latitude increased within Sweden[5]. However, a study done in Norway, Sweden’s Scandinavian neighbour, showed that prevalence did not increase as latitude increased; in fact, the middle portion of Norway had the highest prevalence rates of MS (249 per 100,000 people), while Northern areas of Norway only had a prevalence rate of 191 per 100,000 people[6].

1.1.2 Ethnicity

Northern Europeans or people with Northern European ancestry have a much higher risk of developing MS compared to other ethnicities, including ethnicities found in similar latitude regions[7]. MS susceptibility is very low in people who are Chinese, Japanese and Mongolian, even if they live outside of their respective countries[4]. For example, Japanese in Japan and Japanese Americans both have MS prevalence rates of 5 per 100,000 people[7]. African Americans have a MS prevalence rate roughly half that of Americans of Northern European backgrounds[7]. A number of factors may cause these prevalence rates amongst races including genetic, environmental and lifestyle factors.

However, various studies have shown that it may not be genetic susceptibility that causes the variations in MS rates amongst races, but mainly environmental factors. MS prevalence rates in West Africans are fairly low in comparison to places of high prevalence and incidence, such as Northern Ireland[4]. However, the children of West African immigrants in the UK have MS prevalence and incidence rates similar to those of Northern Ireland[4]. Another study showed that British immigrants in South America who came to South America as adults had an MS prevalence rate of 60 per 100,000 people, while British immigrants who came to South America as children had a prevalence rate of only 15 per 100,000 people, and local populations had a rate of less than 5 per 100,000 people[4]. This study showed that ethnicity is a factor, but age differences also play an important role in prevalence, as well as the effect of environmental factors before and after adolescence[4].

1.1.3 Sex Ratios

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Figure 3. Sex ratios of MS in Canada between 1935-1980. Female to Male sex ratio plotted along
the y-axis; an increase in the ratio can be seen throughout the years, with a slight drop in the early 1970s (2006)

Globally, women are afflicted with MS roughly twice to thrice as much as men are, with rates varying between nations[2]. For at least 50 years now, the MS incidence rate of Canadian women has been increasing[8]. Between the years 1931-1980, the sex ratio between women and men increased from 1.9:1 to 3.2:1, and there has been no evidence suggesting a decrease in the incidence rates of men during this time frame[9]. In Canada, there is a significant increase in the sex ratio when comparing birth years; as birth years progress between 1931-1980, there is an accompanying increase in the sex ratio, with a brief decrease occurring in those born in the early 1970s (Figure 3)[8]. This increase in sex ratios encompasses those afflicted with all variations of MS; however the largest increase has been seen in relapse remitting MS, and the sex ratio is higher in relapse-remitting MS as opposed to primary-progressive MS[9]. Similar findings have been found in other areas of the world, including Denmark, where there has been a steady increase from about 1.5:1 to over 2:1 since the 1950s[10].

Although it is not known exactly why there is a higher MS incidence ratio within females compared to males, differences in environmental factors, genetics and hormones may play a role in this increased female incidence. During puberty, there is an elevated risk of developing MS in females, possibly due to the increase in estrogen in the body[11]. While at low levels, estrogens may promote inflammation and neurodegeneration, high levels of estrogens play an opposite effect and in fact decrease inflammation[11]. During pregnancy, the mother`s levels of estradiol, an estrogen, is increased, and so is progesterone, a steroid hormone. In mothers with MS, there is a substantial decrease in relapse risk during the third trimester, while there is an increase in relapse risk in the first few months after birth, suggesting a role in the levels of the aforementioned hormones in MS[11]. Furthermore, childless females and females who delay childbirth have increased risk levels of MS[11].

1.1.4 Age Statistics

The onset of MS can occur at any age, but is most common between the ages of 15 and 45 years of age[2]. However, it is quite possible that the onset could have occurred earlier in life compared to the age of onset[2].There has been evidence of the processes of MS occurring in a much earlier age than when the first MS symptoms are recorded, and these vary greatly from person to person, with genetic and environmental factors playing a role in the variability[12]. In some cases, the patient dies without ever knowing that they had MS, only to be discovered during a post-mortem examination; these rates can be as high as 0.1%[2].

MS is fairly uncommon in children and teenagers, with prevalence rates approximately in the range of 2.2-5% for those under the age of 16, and MS prevalence rates of pre-pubescent children are as low as 0.1-0.7%[12].

Furthermore, genetic heritability also seems to play a role in the age of onset of MS. Some sibling pairs show a similar age of onset of MS, often occurring within the same year; the strongest such relation occurs in monozygotic twins[13].

1.1.5 Heritability

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Figure 4. Monozygotic twins. Monozygotic twins have a larger risk of
developing MS if their twin has MS compared to any other familial occurrence.

It has been known since the late 1800s that there is a familial occurrence for MS[7]. Studies have shown that the risk of developing MS increases if an individual is related to someone that is afflicted with MS[14]. Also, the closer related one is to the affected individual, the larger the risk. Furthermore, the more affected individuals one is related to, the greater the risk of developing MS[7].

Concerning the general population, there is only a 0.1% chance of developing MS in the Northern Hemisphere[7]. The risk increases to approximately 1% if someone has a first cousin afflicted with MS[14]. These numbers continue to rise, with an estimated 1-2% risk for those with an uncle or aunt with MS; those with a sibling, child or parent with MS have a roughly 2-5% chance of developing MS[14]. If both parents have MS, then the risk jumps up to roughly 6-10%[14]. The worst case scenario is that of monozygotic twins, with an approximate 25-30% risk of one twin developing MS if the other is affected by MS[7][14]. Overall, roughly 1.9-4.7% of MS patients have a relative who is also affected by MS[15].

1.2. Genetics

1.2.1 Human Leukocyte Antigen

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Figure 6. Chromosome 6 indicating HLA-DRB1 position.
The HLA-DRB1 locus has been strongly associated with
MS development, specifically in northern populations
of Europe and North America (2014)

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Figure 5. Chromosome 6. Short arm of Chromosome 6 is
where the HLA region is found, an area integral to MS susceptibility.

While much is still not known on the specific genetic nature of MS, the first breakthrough has come through identification of a link between the Human Leukocyte Antigen (HLA) gene and MS prevalence[1]. Genes associated with HLA are crucial to the immune system, and deficiencies in these genes can cause abnormal immune system functioning, leading to the autoimmune response found in MS[15]. HLA gene is found on the short arm of chrosome 6; the DRB1 locus, most importantly the DRB1*1501 allele, has been identified as having the most substantial genetic association in those affected with MS that are from northern populations of Europe and North America[16]. Numerous studies have also showed that the DRB1*1501 allele causes the age of onset to occur earlier in life, and the more of the allele that is expressed, the earlier the age of onset[6].

However, just carrying this allele does not guarantee that one will get MS; in fact, a very small number of people with this allele develop MS. Moreover, since MS involves complex traits and not Mendelian traits (found in Huntington’s disease for example), the likelihood that a certain genotype will result in the development of MS is fairly slim[7]. None of the HLA alleles cause MS when acting alone; in fact, most of these alleles are found in the MS-free population[7].The likelihood of MS development is caused by having susceptibility alleles associated with this locus, which are found in various places throughout the genome. Estimates place the total number of susceptibility alleles usually related to MS development at 50-200[2].

1.2.2 Interleukin Receptors

Through a genome wide association study (GWAS), it was further confirmed that the HLA gene was definitely related to MS susceptibility but also found two other loci not associated with the HLA gene which were also involved in MS susceptibility. These loci are two different interleukin receptors, interleukin-2 (IL2Rα) receptor and interleukin-7 receptor (IL7Rα); interleukin receptors are also involved in the proper functioning of the immune system. However, this finding did not help much in finding genetic variants associated with MS. For example, the IL2Rα variant was found in 88% of MS patients compared to 85% in the healthy population; similar results are found in the IL7Rα variant, with the percentages being 78% and 75% respectively. These findings suggest that since these variants are very common, there doesn’t seem to be a loss of function or abnormal functionality associated with these variants. Also, the slightly larger occurrence of the variants in MS populations in comparison to healthy populations means that the likelihood that these variants will affect the risk of developing MS is very small[7].

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