Genes + Environment

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

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  • Genes + Environment

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

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