International Journal of Medical and Health Research

Online ISSN: 2349-4182 Print ISSN: 2349-5979, Impact Factor: (RJIF 5.54)
www.medicalsjournals.com
Volume 2; Issue 3; March 2016; Page No. 55-57

Multiple sclerosis: Genetic factors, risk and prevalence

1
Hira Mubeen, 2 Saima Jabeen, 3 Sadaf Shoaib, 4 Muhammad Waseem Shoaib, 5 Shahid Raza
1, 5
University of South Asia, Lahore, Pakistan
2, 3, 4
District Head Quarter (DHQ) Hospital, Faisalabad, Pakistan

Abstract
Multiple sclerosis (MS) is a neurodegenerative disabling disease of the central nervous system commonly affecting young adults.
MS is characterized mostly with autoimmune response. MS is more often transmitted to the next generation by mothers than
fathers suggesting an epigenetic influence. Many gene expression studies have been undertaken to look at the specific patterns of
gene transcript levels in MS. One of the possible reasons of this parent-of origin effect might be the human leukocyte antigen
(HLA). Major environmental risk factors for MS, vitamin D deficiency, smoking and Ebstein–Barr virus are all known to exert
epigenetic changes. Further research is needed to establish mechanisms of early diagnosis, treatment and prevention in humans and
to explore preventative strategies. This review highlight, the genetic factors, challenges, risks, and ways of prevention for better
understanding of MS disease.

Keywords: HLA, gene transcript, Ebstein Barr virus

1. Introduction immune mediators, including T cells, B cells, macrophages

Multiple sclerosis (MS) is a chronic inflammatory disorder of and microglia, as well as cytokines, chemokines, complement
the central nervous system. The CNS consists of the brain and and other toxic agents. Demyelinated axons are exposed to the
spinal cord. This disorder damages the protective layer inflammatory mediators leading to axonal damage and
“myelin” surrounding the nerves “axons” and nerves within neuronal loss in the pathoanatomical substrate of irreversible
the CNS. As a result, messages from the brain and spinal cord functional impairment and disability [3, 4]. Normal appearing
may short circuit, causing reduced body function. Many white and gray matter are also different in MS compared with
studies over the last two to three decades have indicated that healthy controls.
MS is a T cell-mediated autoimmune disease [1]. MS is
genetically complex and there may be no single genes of Genetics of MS
major attributable risk. Instead, MS may result from the Various studies about genetics of MS suggested the
contribution of several genes exhibiting low or moderate involvement of multiple genes located on human leukocyte
effect [2]. The most dangerous complication is usually antigen. One of the first major susceptibility gene which is
infection, which may occur when patient is suffering from MS located in the short arm of chromosome 6. HLA locus contains
for a long time and is not as strong as an normal individual. many genes that have pivotal functions in the immune system.
Infection may often be successfully treated if recognized early. Although there are some changes depending on the genetic
The effects and symptoms of MS vary within each individual. background, association studies indicate an HLA class II
Some people experience symptoms for a short period of time haplotype (DRB1*15:01– DQA1*01:02–DQB1*06:02)
and afterward may remain symptom-free for years, while susceptibility to MS [5]. The disease progression of MS is
others may experience a more steady progression of the highly variable and is likely to depend on complex heritable
disease. genetic and environmental factors [6, 8]. According to recent
studies, Ms is believed to result from the interaction of allelic
Major Causes for MS variants of several yet unknown genes. Incomplete penetrance,
Studies have shown variety of possible causes for MS. The epigenetic changes and many environmental factors determine
most popular theory involves a commonly known slow acting the susceptibility of the disease. Epidemiological studies
virus such as measles, herpes, human T-cell lymphoma, and indicate that 1.9–4.7 % of MS patients have another MS
Epstein-Barr. After being exposed to one of these viruses, patient in their families. The risk of MS is 30 times higher in
some researchers explained that MS may develop in first-degree relatives. The most convincing evidence comes
genetically susceptible people. Some scientists are also from twin studies [5]. Multiplex families seem to possess the
looking for a connection between MS and nutritional factors, same susceptibility genes as sporadic cases of MS, albeit in
including deficiencies in vitamin D and fish oil. greater number [6, 7]. It has been estimated that there are
potentially 350 candidate susceptibility genes outside the
Role of Immune system MHC [8]. The most recent association studies find there are
Immune mechanisms are believed to play an important role in now over 50 genetic loci having confirmed association, with
the disease process. Focal demyelinated plaques are infiltrated many other candidate loci identified at lower probabilities
by heterogeneous populations of immune cells and soluble awaiting confirmation with larger scale studies [9, 11], including

55 
 
genes involved in vitamin D metabolism [12, 13]. However, the stimulator, and large electromagnet. An MRI picture looks
identified associations explain only a small fraction of the like an x-ray, but a magnet and radio waves are used to
familial aggregation of MS [14, 15]. produce a picture of the brain. For those with MS, the MRI is
used to show the size and location of active lesions and
Epigenetic Face of MS plaques. Sometimes dye is given to the person with MS to
Epigenetics represents all heritable or non-heritable changes better illuminate areas of inflammation. Disease modifying
that are not related to modified DNA sequences and lead to therapies may be more effective if started earlier in the course
altered expression or translation of the genome. It operates of the disease and the diagnostic criteria have been recently
using many mechanisms including DNA methylation, histone revised to recognize the importance of early treatment [22].
modifications and RNA interference. Epigenetic changes are However due to the clinical complexity of the disease, the
specific to tissues and cannot be detected by association or heterogeneity of the tissues used in expression studies, as well
linkage studies that are based on conventional DNA as the variable DNA chips used for the gene profiling, it is
amplification methods. MS is twice as common in females difficult to interpret the available information. A large number
than males. This obvious gender influence also underscores a of aetiological factors have been identified to play a role in
possible epigenetic effect in MS since none of the MS including genetic susceptibility, smoking [23], exposure to
predisposing genes are located in the X chromosome. the Epstein-Barr virus (EBV) [24] and low exposure to sunlight
Moreover, MS is more often transmitted to the next generation which presumed to be mediated through vitamin D
by mothers than by fathers [16]. This parent-of-origin effect insufficiency [25, 26]. Although this information is essential for
might be mediated through the HLA-DRB1*15 allele, since the understanding of the pathogenesis of MS, it is difficult to
mothers are more likely than fathers to transmit their HLA- decipher and define the gene pathways involved in the
DRB1*15 allele to their children [17]. disorder.

Prevalence of MS Conclusion
MS affects mainly young adults with predominance for Understanding the clinical course and molecular pathways
females and prevalence in the USA and northern Europe of involved in MS are highly variable and should lead to
100 per 100000 people [18]. From 250,000 to 350,000 patients therapies that target these specific pathways. This also
in the U.S. have MS and 50% of patients will need help depends on complex genetic and environmental factors.
walking within 15 years after the onset of the disease [19]. Emerging evidence has established a preliminary role for
Twice as many women are affected as men, and persons of epigenetic mechanisms in MS. Despite advances in
Northern European descent appear to be at highest risk for MS understanding the immunopathogenesis of MS and the
[20]
. The disease is diagnosed on the basis of clinical findings availability of innovative therapeutic strategies, efficacious
and supporting evidence from ancillary tests, such as magnetic treatment of MS remains an unmet need. Characterization of
resonance imaging (MRI) of the brain and examination of the epigenetic factors that can be used in prediction of treatment
cerebrospinal fluid (CSF). MS typically presents in adults 20 responsive and non-responsive MS patients will meet an
to 45 years of age; occasionally, it presents in childhood or important deficiency in this field. A number of different
late middle age. The cause is unknown, but it appears to experiments for gene expression studies through microarrays
involve a combination of genetic susceptibility and a non revealed hundreds of significantly altered expressed genes.
genetic trigger, such as a virus, metabolism, or environmental Some of these genes have been further investigated and have
factors, that together result in a self-sustaining autoimmune provided increased understanding of the complex pathological
disorder that leads to recurrent immune attacks on the CNS mechanisms involved in MS. Many more genes need further
[21]
. analysis and represent an interesting and exciting future in MS
research. Novel approaches to repair of the damaged nervous
Discussion system may also be suggested. It may even be possible to
Multiple sclerosis is a chronic inflammatory demyelinating begin to understand how to interrupt MS before it begins.
disease of central nervous system white matter. A widely
accepted view of the process of demyelination suggests that T References
cells, immunoglobulin and complement components have 1. Martin R, McFarland HF, McFarlin DE. Immunological
roles in pathogenesis. Adhesion molecules, cytokines, aspects of demyelinating diseases. A. Rev. Immunol,
chemokines and HLA molecules are critical participants in the 1992; 10:153-187.
development of the inflammatory response in brain. MS 2. Dyment DA, Sadovnick AD, Ebers GC, Sadnovich AD.
diagnosis is based upon an individual’s history of clinical Genetics of multiple sclerosis. Hum. Mol. Genet, 1997l;
symptoms and neurological examinations. A qualified 6:1693-1698.
physician often a neurologist must thoroughly review all 3. Sawcer S, Goodfellow PN, Compston A. The genetic
symptoms experienced by an individual to suspect MS. Other analysis of multiple sclerosis. Trends Genet, 1997;
conditions with similar symptoms often require various lab 13:234-239.
tests. Treatments have been available for MS since the late 4. Zamvil SS, Steinman L. Diverse targets for intervention
1980s, based on immune suppression strategies. These during inflammatory and neurodegenerative phases of
treatments do not stop the inflammatory process within the multiple sclerosis. Neuron 2003; 38(5):685-688.
CNS seen on magnetic resonance imaging (MRI) which has 5. Gourraud PA, Harbo HF, Hauser SL. Baranzini SE. The
been used to assist in the diagnosis of MS for more than 20 genetics of multiple sclerosis: An up-to-date review.
years. The MRI consists of a computer, radiofrequency Immunological Reviews, 2012; 248:87-103.

56 
 
6. Urdinguio RG, Sanchez-Mut JV, Esteller M. Epigenetic sclerosis: 2010 revisions to the McDonald criteria. Ann.
mechanisms in neurological diseases: Genes, syndromes Neurol. 2011; 69:292-302.
and therapies. Lancet Neurology, 2009; 8:1056-1072. 23. Handel AE, Williamson AJ, Disanto G, Dobson R,
7. Lauer K. Environmental risk factors in multiple sclerosis. Giovannoni G, Ramagopalan SV. Smoking and multiple
Expert Review of Neurotherapeutics, 2010; 10:421-440. sclerosis: An updated meta-analysis. PLoS One. 2011;
8. Oksenberg JR, Baranzini SE. Multiple sclerosis 6:e16-149.
genetics—Is the glass half full, or half empty? Nature 24. Handel AE, Williamson AJ, Disanto G, Handunnetthi L,
Reviews Neurology, 2010; 6:429-437. Giovannoni G, Ramagopalan SV. An updated meta-
9. D’Netto MJ, Ward H, Morrison KM, Ramagopalan SV, analysis of risk of multiple sclerosis following infectious
Dyment DA, DeLuca GC, et al. Risk alleles for multiple mononucleosis. PLoS One. 2010; 5:e12-496.
sclerosis in multiplex families. Neurology. 2009; 25. Islam T, Gauderman WJ, Cozen W, Mack TM. Childhood
72:1984-1988. sun exposure influences risk of multiple sclerosis in
10. Gourraud PA, McElroy JP, Caillier SJ, Johnson BA, monozygotic twins. Neurology. 2007; 69:381-388.
Santaniello A, Hauser SL, et al. Aggregation of multiple 26. Van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L,
sclerosis genetic risk variants in multiple and single case Simmons R, Taylor BV, et al. Past exposure to sun, skin
families. Ann. Neurol. 2011; 69:65-74. phenotype, and risk of multiple sclerosis: Case-control
11. Wang JH, Pappas D, de Jager PL, Pelletier D, de Bakker study. Br. Med. J. 2003; 327:316.
PI, Kappos L, et al. Modeling the cumulative genetic risk
for multiple sclerosis from genome-wide association data.
Genome Med. 2011; 3:3.
12. Sawcer S, Hellenthal G, Pirinen M, Spencer CC,
Patsopoulos NA, Moutsianas L, et al. Genetic risk and a
primary role for cell-mediated immune mechanisms in
multiple sclerosis. Nature. 2011; 476:214-219.
13. Patsopoulos NA, de Bakker PIW. Bayer Pharma MS
Genetics Working Group; Steering Committees of Studies
Evaluating IFNβ-1b and a CCR1-Antagonist; ANZgene
Consortium; GeneMSA; International Multiple Sclerosis
Genetics Consortium. Genome-wide meta-analysis
identifies novel multiple sclerosis susceptibility loci. Ann.
Neurol. 2011; 70:897-912.
14. Australia and New Zealand Multiple Sclerosis Genetics
Consortium (ANZgene) Genome-wide association study
identifies new multiple sclerosis susceptibility loci on
chromosomes 12 and 20. Nat. Genet. 2009; 41:824-828.
15. Bush WS, Sawcer SJ, de Jager PL, Oksenberg JR,
McCauley JL, Pericak-Vance MA, et al. Evidence for
polygenic susceptibility to multiple sclerosis—The shape
of things to come. Am. J Hum. Genet. 2010; 86:621-625.
16. Ebers GC. Parent-of-origin effect in multiple sclerosis:
Observations in half-siblings. Lancet, 2004; 363:1773-
1774.
17. Ramagopalan SV, Dobson R, Meier UC, Giovannoni G.
Multiple sclerosis: Risk factors, prodromes, and potential
causal pathways. Lancet Neurology, 2010; 9:727-739.
18. Noseworthy JH, Lucchinetti C, Rodriguez M,
Weinshenker BG. Multiple sclerosis. New Engl. J Med,
2000; 343:938-952.
19. Singh VK, Mehrotra S, Agarwal SS. The paradigm of Th1
and Th2 cytokines: Its relevance to autoimmunity and
allergy. Immunol Res. 1999; 20:147-161.
20. Hauser SL, Goodwin DS. Multiple sclerosis and other
demyelinating diseases. In: Fauci AS, Braunwald E,
Kasper DL, Hauser SL, editors. Harrison’s Principles of
Internal Medicine. 17th ed. II. New York: McGraw-Hill
Medical; 2008, 2611-2621.
21. Cree BAC. Multiple sclerosis. In: Brust JCM, editor.
Current Diagnosis and Treatment in Neurology. New
York: Lange Medical Books/McGraw-Hill Medical;
2007.
22. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen
JA, Filippi M, et al. Diagnostic criteria for multiple
57