Genes + Environment

Multiple SclerosisA look at genetic and environmental factors

Lauren E. Hansen

[email protected]

2008

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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

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…

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

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


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


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

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)

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

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

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

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

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

Environmental Risk Factors

• Epstein-Barr Virus (EBV)

• Human herpesvirus 6 (HHV-6)

• Vitamin D

• Smoking

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

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

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

Revised Hygiene Hypothesis


• Individuals infected with EBV who subsequently develop mononucelosis are 2 to 3 times more likely to develop MS

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

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

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)

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

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


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.

Genes + Environment

Health & Medicine

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