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PHM142 Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
Multiple Sclerosis Genes
Sarah To
Ying Amy Zhao
Hui (Lily) Zhou
Multiple Sclerosis
• Autoimmune disorder
• Destruction of myelin →
lesions on brain and spinal
Causes of Multiple Sclerosis
Pathophysiology of Multiple Sclerosis
• Geographic Location
• Smoking
• Exposure to Infectious Disease
• HLA genes
• Non-HLA genes
Genes of MS
• Inheritance pattern unknown
• Increased familial risk and heritability
• Affect MS susceptibility, disease severity and other aspects of
clinical phenotype
• Interaction among multiple polymorphic genes → each
increasing risk of MS by small factor
• Location: 6p21.32
Found in class II subregion of the HLA complex
• Responsible for producing beta chain of MHC
class II molecules
MHC class II molecules expressed by APCs, present
antigens to T cells
• Polymorphic gene
Variants of HLA-DRB1 can interact to affect MS
HLA-DRB1 variants
• HLA-DRB1*1501:
main allele
associated with
MS susceptibility
• Different allele
combinations can
increase or
decrease risk of
developing MS
HLA-DRB1 and T cell Selection
• HLA-DRB1 variants differ in amino acid sequence
• Differences in peptide-antigen binding region can affect affinity of antigen
• T cell development in thymus involves negative selection: T cells
that react strongly to self antigen-MHC complexes eliminated
• Unstable interaction between myelin antigen and MHC complex
results in few complexes
• T cells that react strongly to myelin antigen-MHC complex can
escape negative selection if they do not encounter myelinantigen-MHC complexes in thymus
Non-HLA genes
• Genes in T-cell regulation
• Genes affecting other cells of immune system
• Vitamin D metabolism
• Genes involved in neuronal surveillance and repair
• KIP1b, GPC5
IL-7RA and IL-2RA
• IL7RA and IL2RA code for the alpha chains of the interleukin2 receptor and interleukin-7 receptor
• Important in promoting the growth and differentiation of
• SNP significantly associated with MS
• SNP location: rs6897932 within exon 6 (C to T -> Thr to Ile at
position 244)
• Reduction of splicing of exon 6
• Less production of soluble IL-7Rα, which inhibit IL-7 activity in
CD8+ T cells
• Decrease level of expression leads to decreased activation
• Also known as CD25
• Main function: sensitization of activated T cells to IL-2
mediated proliferation
• SNPs: rs12722489 and rs2104286 within the IL2RA gene
• SNPs cause reduction of CD25 expression and thereby
reducing its likelihood of activation
• Loss in regulatory T cell confers MS susceptibility
• Also related to type I diabetes
Current and Further Research in MS genes
• Ongoing research into genetic factors that affect MS and the
mechanisms involved
• Focus on identifying specific causative gene
• Linkage disequilibrium makes it difficult to pinpoint causative gene
from candidate genes
• Determine if genetic variants associated with MS
susceptibility also affect progression, severity, response to
HLA-DRB1 variants can interact to increase or decrease MS susceptibility
HLA-DRB1*1501 is the main HLA-DRB1 allele associated with MS susceptibility
Different MHC class II molecules resulting from HLA-DRB1 variants may bind to
self-antigens with different affinities
Unstable self-antigen-MHC complexes may allow strongly autoreactive T
cells to escape negative selection
IL-7RA and IL-2RA are two non-HLA MS linked genes that are associated with
MS susceptibility
In IL-7RA, the identified SNP reduces splicing of exon 6, which reduces
expression of the receptor and thereby reducing activation
In IL-2RA, the identified SNP reduces likelihood of activation and causes loss in
regulatory T cells
Axisa, P., & Hafler, D. A. (2016, June). Multiple sclerosis: Genetics, biomarkers, treatments. Current Opinion in Neurology, 29(3), 345-353.
Barcellos, L. F., Oksenberg, J. R., Green, A. J., Bucher, P., Rimmler, J. B., Schmidt, S., . . . Hauser, S. L. (2002, January). Genetic basis
for clinical expression in multiple sclerosis. Brain, 125(1), 150-158. doi:10.1093/brain/awf009
Goverman, J. M. (2011). Immune tolerance in multiple sclerosis. Immunological Reviews, 241(1), 228-240. doi:10.1111/j.1600065x.2011.01016.x
HLA-DRB1 gene. (2016, November 8). Retrieved November 11, 2016, from
Hoe, E., Mckay, F., Schibeci, S., Heard, R., Stewart, G., & Booth, D. (2010). Interleukin 7 Receptor Alpha Chain Haplotypes Vary in Their
Influence on Multiple Sclerosis Susceptibility and Response to Interferon Beta. Journal of Interferon & Cytokine Research, 30(5), 291-298.
Hoppenbrouwers, I. A., & Hintzen, R. Q. (2011, February). Genetics of multiple sclerosis. Biochimica Et Biophysica Acta (BBA) - Molecular
Basis of Disease, 1812(2), 194-201. doi:10.1016/j.bbadis.2010.09.017
Ramagopalan, S. V., & Ebers, G. C. (2009). Multiple sclerosis: Major histocompatibility complexity and antigen presentation. Genome
Medicine Genome Med, 1(11), 105. doi:10.1186/gm105
Schmidt, H., Williamson, D., & Ashley-Koch, A. (2007). HLA-DR15 Haplotype and Multiple Sclerosis: A HuGE Review. American Journal
of Epidemiology, 165(10), 1097-1109. doi:10.1093/aje/kwk118