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A look at genetic and environmental factors involved in multiple sclerosis.

A look at genetic and environmental factors involved in multiple sclerosis.

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  • 1. Multiple Sclerosis A look at genetic and environmental factors Lauren E. Hansen [email_address] 2008 This work is licensed under the Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ or send a letter to Creative Commons, 171 Second Street, Suite 300, San Francisco, California, 94105, USA.
  • 2. Multiple Sclerosis Defined
    • Immune system attacks the body’s central nervous system (brain, spinal cord, optic nerves)
      • CD4+ T cells initiate the attack on the myelin coating of the axons of the CNS and scar tissue (sclerosis) is formed
      • Scars result in slowed or blocked function of the affected nerves, causing symptoms
      • Specific antigen not known
    McFarland & Martin, 2007
  • 3. Symptoms of MS
    • Vary over time and by severity and by person
    • May include:
      • Numbness, paralysis, loss of coordination, loss of vision, fatigue, balance problems, bladder & bowel dysfunction, dizziness, pain, cognitive difficulty, emotional changes, depression, and many others…
  • 4. Types of MS
    • Relapsing-Remitting (85%)
    • Primary-Progressive (10%)
    • Secondary-Progressive (50% of RR w/in 10 yrs)
    • Progressive-Relapsing (5%)
    National Multiple Sclerosis Society
  • 5. Diagnosis of MS
    • No definitive diagnostic test
    • Tests used to indicated presence of MS
      • Medical History & Neurologic Exam
      • MRI of brain and/or spinal cord
      • Visual evoked potential (VEP)
      • Cerebrospinal fluid analysis (spinal tap)
        • Presence of oligoclonal bands (90-95%)
      • Blood tests to rule out other conditions
    National Multiple Sclerosis Society
  • 6. Demographics of MS
    • 2.5 mil. Worldwide; 400,000 in the U.S.
      • 200 people diagnosed every week in U.S.
    • 2-3 times more common in women
    • Most diagnosed between 20 and 50 years of age
      • Later onset associated with more progressive form
    • Most common in Caucasians of N. European ancestry
      • But also present in those of African, Asian & Hispanic ethnicity
      • Not present in Inuit, Aborigine, Maori populations
    National Multiple Sclerosis Society
  • 7. Demographics of MS
    • Heredity plays a factor
      • Risk in general population = 1/750
      • Risk if close relative is affected = 1/40
      • Risk if identical twin is affected = 1/25
  • 8. Treatments
    • No cure exists
    • Exacerbations may be treated with corticosteroids
    • 6 Disease-Modifying Drugs
      • Avonex (interferon beta-1a)
      • Rebif (interferon beta-1a)
      • Betaseron (interferon beta-1b)
      • Copaxone (glatiramer acetate)
      • Novatrone (mitoxantrone)
      • Tysabri (natalizumab)
  • 9. Genetic Risk Factors
    • Three major players have been found so far
      • HLA-DRB1*1501 locus on the HLA
      • IL7R
      • IL2R
    • These factors combined account for 50% of the inheritability found for MS
    Gregory et al. 2007
  • 10. Human Leukocyte Antigen
    • Protein on the surface of cells that controls how the immune system identifies foreign tissue
    • HLA-DRB1*1501 locus associated with MS
      • OR=5.80 (95%CI, 3.53 to 9.53; P=1.83x10 -17 )
      • Gene dosage effect: homozygosity for this allele results in greater risk compared to heterozygosity
    The International Multiple Sclerosis Genetics Consortium, 2007
  • 11. Interleukins
    • Cytokines (messenger proteins) that regulate immune cells (T, B and natural killer cells)
      • Evidence of dysfunction of regulatory T cells (which have power to turn off immune system attacks) in MS
    • Genome-wide study indicates MS is a polygenic autoimmune disorder
      • Lots of common gene variations that each confer small risk
    The International Multiple Sclerosis Genetics Consortium, 2007
  • 12. Interleukin 7 receptor  chain
    • rs6897932 SNP in the IL7R gene is associated with a small increase in risk of developing MS
      • OR=1.18; 95%CI, 1.11 to 1.26; P=2.94x10 -7
    • IL7R aids in development of gamma & delta T cells (some of earliest T cells observed in inflammatory lesions of MS)
    The International Multiple Sclerosis Consortium, 2007
  • 13. Interleukin 2 receptor  chain
    • rs12722489 SNP
      • OR=1.25; 95%CI, 1.16 to 1.36; P=2.96x10 -8
    • rs2104286 SNP
      • OR=1.19; 95%CI, 1.11 to 1.26; P=2.16x10 -7
    • In studies using a monoclonal antibody to target the IL2R chain, clinical efficacy was observed
    The International Multiple Sclerosis Consortium, 2007
  • 14. Environmental Risk Factors
    • Epstein-Barr Virus (EBV)
    • Human herpesvirus 6 (HHV-6)
    • Vitamin D
    • Smoking
  • 15. Epstein-Barr Virus
    • EBV is a B-lymphotropic human DNA herpesvirus that can cause asymptomatic latent infections and infectious mononucleosis.
    • Serafini et al. (2007) found abnormal accumulation of EBV infected B cells and plasma cells in the brains of nearly 100% MS patients studied
      • Not seen in any other inflammatory neurological disorders
  • 16. Epstein-Barr Virus
    • IgG antibodies to EBNA -1 and EBNA-complex can be found an average of 5 years before MS onset
    • 4-fold increase in EBNA-1 and ENBA-complex titers corresponds to a 3-fold increase in risk of developing MS
      • (EBNA complex: RR 3.0; 95% CI, 1.3-6.5; P=.007)
      • (EBNA-1: RR 3.0; 95% CI, 1.2-7.3; P=.01)
    Levin et al. 2005
  • 17. Hygiene Hypothesis
    • Pro: Early EBV infection is associated with a reduced risk of MS.
      • Found in developing countries, the tropics, Asia and among Eskimos in Greenland
    • Con: Those who are EBV negative are 10 times less likely to develop MS
    Ascherio & Munger, 2008
  • 18. Revised Hygiene Hypothesis
    • Individuals infected with EBV who subsequently develop mononucelosis are 2 to 3 times more likely to develop MS
    Ascherio & Munger, 2008
  • 19. Human herpesvirus 6
    • Virtanen et al. (2007) found seroprevalence to HHV-6A in 100% of patients with MS versus 69.2% of patients with other autoimmune disorders
    • Levels found in those with MS higher than those without
    Virtanen et al. 2007
  • 20. Vitamin D and risk of MS
    • Vitamin D intake > 400 IU/d, RR=.59
    • (95% CI = .38 to .91, p=.006)
    • Munger et al. 2004
    • Serum levels of vitamin D > 99nmol/L, RR=.38
    • Munger et al. 2006
  • 21. Islam et al. 2007
    • Examined sun exposure as explanation for latitude gradient
    • Surveyed 193 disease-discordant twin pairs
    • Compared survey answers to calculated sun index (SI)
    • For each 1 unit increase in SI, risk decreased by 25%
      • OR=.75; 95%CI, .62-.90; p=.004 (adjusted for potential confounders)
  • 22. Vitamin D - additional findings
    • Latitude gradient for MS
      • Risk of MS for migrants is equal to the average risk of birthplace and final residence
    • Reduced risk of MS in Norway coastal villages
    • Injection of vitamin D prevents EAE (experimental autoimmune encephalomyelitis), while vitamin D deficiency accelerates onset
    Ascherio & Munger 2008
  • 23. Smoking
    • Combined longitudinal studies report increase risk of MS from smoking (p<.0001)
    • Risk of MS among women reporting 25 or more pack-years was 70% higher than those who never smoked (p<.01)
    • Increased risk of transition from relapsing-remitting MS to secondary-progressive MS
    • Smoking shown to be risk factor for other autoimmune disorders as well
    Ascherio & Munger, 2008
  • 24. Resources
    • Ascherio, A. & Munger, K. (2008) Epidemiology of multiple sclerosis: from risk factors to prevention. Seminars in Neurology, 28 (1), 17-28.
    • Gregory, G., Schmidt, S., Seth, P. et al. (2007). Interleukin 7 receptor a chain (IL7R) shows allelic and functional association with multiple sclerosis. Nature Genetics, (39) 9, 1083-1091.
    • The International Multiple Sclerosis Genetics Consortium (2007). Risk alleles for multiple sclerosis identified by a genomewide study. The New England Journal of Medicine, 357 (9), 851-862.
    • Islam, T., Gauderman, W.J., Cozen, W. & Mack, T.M. (2007). Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology, 69, 381-388.
    • Levin, L.I., Munger, K.L., Rubertone, M.V. et al. (2005). Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA, 293 (20), 2496-2500.
    • McFarland, H.F. & Martin R. (2007). Multiple sclerosis: a complicated picture of autoimmunity. Nature Immunology, 8 (9), 913-919.
    • The National Multiple Sclerosis Society www.nmss.org
    • Serafini, B., Rosicarelli, B., Franciotta, D. et al. (2007). Dysregulated Epsetin-Barr virus infection in the multiple sclerosis brain. The Journal of Experimental Medicine, 201 (12), 2899-2912.
    • Virtanen, J.O., Farkkila, M., Multanen, J. et al. (2007). Evidence for human herpesvirus 6 variant A antibodies in multiple sclerosis: diagnostic and therapeutic implications. Journal of NeuroVirology, 13, 347-352.