Multiple Sclerosis-Genetics or Environment or Both

Multiple Sclerosis-Genetics or Environment or Both?

INTRODUCTION

http://www.nlm.nih.gov/medlineplus/tutorials/_instruct/instructions.html?ModuleURL=multiplesclerosis&LMModuleID=nr229101&x=74&y=25

OVERVIEW

http://mscenter.ucsf.edu/faq.htm

GENETIC EVIDENCE

http://www.ucsf.edu/msdb/r_ms_genetic_disease.html

Research Papers

	Multiple Sclerosis candidate genes

Candidate Gene (Updated May 2002)	Chromosomal Location	Study Design	Representative References
Glutathione S-transferase mu	1p13.3	case-control	Mann, 2000
Interleukin-12 receptor beta 2	1p31	family-based	Reboul, 2000
T cell specific adapter protein (TDAd)	1q21	case-control	Dai, 2001
Fas Ligand	1q23	case-control	Zayas, 2001
Interleukin 10	1q31-q32	family-based	He, 1997; Reboul, 2000
Interleukin 10	1q31-q32	case-control	He, 1997; Pickard, 1999; Maurer, 2000
Protein tyrosine phosphatase receptor type C (CD45)	1q31-32	family-based	Barcellos, 2001
Protein tyrosine phosphatase receptor type C (CD45)	1q31-32	case-control	Jacobsen, 2001
Transforming growth factor (TGF) B2	1q31	family-based	He, 1997; Mertens, 1998
Transforming growth factor (TGF) B2	1q31	case-control	He, 1997; McDonnell, 1999
HRES-1 retro-element	1q32-q42	case-control	Rasmussen, 1997; Rasmussen, 2000
Transforming growth factor BR3	1p32-p33	family-based	Mertens, 1998
Rhesus blood group	1p36.2-p34	case-control	Roberts, 1979

Apolipoprotein (APO) B	2p23-24	family-based	Chataway, 1999a
Interleukin 1 receptor antagonist/ interleukin-1B (IL-1ra/IL-1b)	2q14.2	family-based	Wansen, 1997; Semana, 1997; Schrijver, 1999; Feakes, 2000
Interleukin 1 receptor antagonist/ interleukin-1B (IL-1ra/IL-1b)	2q14.2	case-control	Crusius, 1995; Wansen, 1997; Semana, 1997; de la Concha, 1997; McDonnell, 2000
Cytotoxic T-lymphocyte-associated protein 4 (CTLA4)	2q33	case-control	Harbo, 1999; Ligers, 1999; Fukazawa, 2000 Rasmussen, 2001; Dyment, 2002
Erb-B4	2q34	family-based	Mertens, 1998
Natural resistance-associated macrophage protein-1 (NRAMP1)	2q35	case-control	Kotze, 2001

Chemokine receptor 5 (CCR5)	3p21	case-control	Bennetts, 1997
Transforming growth factor BR2	3p22	family-based	Mertens, 1998
B7-1	3q13.3-q21	Case-control	Weinshenker, 2000
Interleukin 12p35	3q25-q26.2	family-based	Reboul, 2000

Fibroblast growth factor Re	4p16.3	family-based	Mertens, 1998
Platelet derived growth factor Ra	4q11-q12	family-based	Mertens, 1998
Vitamin D binding protein	4q12	family-based	Reboul, 2000
Fibroblast growth factor 2	4q25-q27	family-based	Mertens, 1998
Interleukin 2	4q26-q27	family-based	He, 1997; Reboul, 2000; Feakes, 2000
Interleukin 2	4q26-q27	case-control	He, 1997; McDonnell, 2000

Microtubule associated protein 1B	5q13	family-based	Chataway, 1999
Interleukin 4	5q23-31	family-based	He, 1997; Reboul, 2000
Interleukin 4	5q23-31	case-control	Vandenbroeck, 1997; He, 1997; McDonnell, 2000
Interleukin 9	5q23-31	case-control	McDonnell, 2000
Fibroblast growth factor 1	5q31.3-q33.2	family-based	Mertens, 1998
Interferon regulatory factor 1 (IRF1)	5q31	family-based	Vandenbroeck, 2000
Interleukin 12p40	5q33	family-based	Reboul, 2000

Pc 1 Duarte	6p21	case-control	Comings, 1979
HLA-DR	6p21.3	family-based	Haines, 1998
HLA-DR	6p21.3	case-control	Seboun, 1996 (review)
HLA-DQ	6p21.3	case-control	Seboun, 1996 (review)
HLA-DP	6p21.3	case-control	Fugger, 1990
HLA-DM	6p21.3	case-control	Ristori, 1997
HLA-DRA promoter	6p21.3	Case-control	Bennetts, 1999
Complement C4/CYP21	6p21.3	case-control	Franciotta, 1995
Tumor necrosis factor alpha	6p21.3	case-control	Garcia-Merino, 1996; Huizinga, 1997; Fernandez-Arquero, 1999
Transporters associated with antigen processing	6p21.3	case-control	Liblau, 1993; Spurkland, 1994; Bell, 1995
Myelin oligodendrocyte glycoprotein (MOG)	6p21.3	case-control	Hilton, 1995; Roth, 1995; Rodriguez, 1997
Myelin oligodendrocyte glycoprotein (MOG)	6p21.3	family-based	Seboun, 1999
Heat shock protein 70	6p21.3	case-control	Ramachandran, 1995; Cascino, 1994
Interferon gamma receptor 1	6q23-q24	family-based	Reboul, 2000
Estrogen receptor a	6q25.1	case-control	Niino, 2000

Erb-B	7p12	family-based	Mertens, 1998
Interleukin 6	7p15-p21	case-control	Schmidt, 2000
Platelet derived growth factor a	7p22	family-based	Mertens, 1998
Plasminogen activator inhibitor 1	7q22-31	Case-control	Luomala, 2000
T cell antigen receptor (TCR) B	7q35	family-based	Seboun, 1989; Lynch, 1991; Wansen, 1997; Hockertz, 1998
T cell antigen receptor (TCR) B	7q35	case-control	Beall, 1989; Fugger, 1990; Epplen, 1997; Wansen, 1997; Buhler, 2000
ERV3 retro-element	7	case-control	Rasmussen, 1996

Fibroblast growth factor R1	8p12	family-based	Mertens, 1998
Glial growth factor	8p21	family-based	Mertens, 1998

Interferons alpha/beta	9p21	family-based	Bergkvist, 1996
Interferons alpha/beta	9p21	case-control	Miterski, 1999
Transforming growth factor BR1	9q33-q34	family-based	Mertens, 1998

Interleukin-2R alpha	10p15	family-based	Reboul, 2000
Fas Apo-1 antigen	10q24.1	case-control	Cascino, 1998; Huang, 2000
Fibroblast growth factor BR2	10q25.3-q26	family-based	Mertens, 1998

Ciliary neurotrophic factor (CNTF)	11q22.2	case-control	Giess, 2002; Hoffmann, 2002
Interleukin-10 receptor	11q23.3	family-based	Reboul, 2000
Glutathione S-transferase pi	11	case-control	Mann, 2000
Interleukin 12p40 (IL12b)	11	case-control	Van Veen, 2001

Neurotrophin-3	12p13	family-based	Mertens, 1998
Alpha-2-macroglobulin (A2M)	12p13.3	case-control	Schweer, 2001
Erb-B3	12p	family-based	Mertens, 1998
Vitamin D receptor	12q13-q14	family-based	Steckley, 2000
Vitamin D receptor	12q13-q14	case control	Fukazawa, 1999
Low-density lipoprotein receptor (LRP)	12q13-q14	case-control	Schweer, 2001
25(OH)D3 1 alpha-hydroxilase	12q13	family-based	Steckley, 2000
Interferon gamma	12q14-15	family-based	Wansen, 1997; He, 1997; Dai, 2001
Interferon gamma	12q14-15	case-control	Wansen, 1997; He, 1997; Goris, 1999
Spinocerebellar ataxia 2 (SAC2)	12q21-23	case-control	Miterski, 2000
Insulin-like growth factor 1	12q23	family-based	Mertens, 1998
Nitric oxide synthase (NOS1)	12q24.2-24.31	family-based	Xu, 1999

T cell antigen receptor (TCR) A/D	14q11.2	family-based	Lynch, 1992
T cell antigen receptor (TCR) A/D	14q11.2	case-control	Oksenberg, 1989; Hashimoto, 1992
Transforming growth factor B3	14q24	family-based	Mertens, 1998
Immunoglobulin G heavy chain	14q32	family-based	Wansen, 1997; Wood, 1995
Immunoglobulin G heavy chain	14q32	case-control	Wansen, 1997
Immunoglobulin constant region	14q32	case-control	Gaiser, 1987
Immunoglobulin variable region	14q32	family-based	Hashimoto, 1993; Ligers, 1997; Feakes, 2000
Immunoglobulin variable region	14q32	case-control	Walter, 1991
Alpha-1 antitrypsin	14q24	case-control	McCombe, 1985

Insulin-like growth factor 1R	15q25-qter	family-based	Mertens, 1998
TRK-C	15q24-q25	family-based	Mertens, 1998

Interleukin 4 receptor	16p12.1-p11.2	family-based	He, 1997; Reboul, 2000
Interleukin 4 receptor	16p12.1-p11.2	case-control	He, 1997; Hackstein, 2001
MHC Class II transactivator	16p13	case-control	Rasmussen, 2001

2'3'-cyclic nucleotide 3'-phosphodiesterase	17q21	family-based	Thompson, 1996; He, 1997, Chataway, 1999a
2'3'-cyclic nucleotide 3'-phosphodiesterase	17q21	case-control	Thompson, 1996; He, 1997
Myeloperoxidase	17q23.1	case-control	Nagra, 1997; Nelissen, 2000 (b)
Myeloperoxidase	17q21.3-23.1	family-based	Chataway, 1999 (a); Nelissen, 2000 (b)
RIalpha of cAMP-dependent protein kinase (PRKAR1A)	17q21-q24	case-control	Nelissen, 2000 (b)
RIalpha of cAMP-dependent protein kinase (PRKAR1A)	17q21-q24	family-based	Nelissen, 2000 (b)
phenylethanolamine N-methyltransferase	17q21-q22	case-control	Mann, 2002
Apoplipoprotein (APO) H	17q22	family-based	Chataway, 1999 (a); Nelissen, 2000 (b)
Platelet/endothelial cell adhesion molecule (PECAM-1)	17q23	case-control	Sciacca, 2000; Nelissen, 2000 (b)
Monocyte chemotactic protein (MCP)-3	17q11.2	case-control	Fiten, 1999
Oligodendrocyte myelin glycoprotein (OMGP)	17q11.2	family-based	He, 1997; Seboun, 1999
Oligodendrocyte myelin glycoprotein (OMGP)	17q11.2	case-control	Hinks, 1995; He, 1997
Erb-B2	17q11.2	family-based	Mertens, 1998
Ecotropic viral integration	17q11	case-control	Hinks, 1995

Myelin basic protein (MBP)	18q22-qter	case-control	Boylan, 1991; Tienari, 1992; Ibsen, 1996
Myelin basic protein (MBP)	18q22-qter	family-based	Tienari, 1998; Choppin, 2001

Third component of complement (C3)	19p13-tel	case-control	Bernal, 1986; Bulman, 1991
Intracellular adhesion molecule 1 (ICAM-1)	19p13.3-p13.2	case-control	Mycko, 1998; Luomala, 1999
Notch3	19p13.2-p13.1	Family-based	Broadley, 2001
Apolipoprotein (APO) E	19q13	case-control	Rubinsztein, 1994; Gaillard, 1998; Evangelou, 1999; Olivery, 1999; Chapman, 2000; Weatherby, 2000; Chapman, 2001; Fazekas, 2001
Apolipoprotein (APO) E	19q13	family-based	Schmidt, 2002

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Last updated 08/01/2002.

ENVIRONMENTAL EVIDENCE

Journal article discussing environmental influences:

http://www.jneurovirol.com/pdf/6(s2)/s141-s146.pdf

MS prevalence data for selected countries

Much of the data in the following table is based on estimates by national MS Societies and others and extrapolations of survey data for regions within the countries. It does however give a feel for the overall distribution of the disease. Data on multiple sclerosis issued by the World Health Organisation is notably flawed, asserting that more men than women have the disease and that it is widespread in the tropics - perhaps this reflects the importance that this organisation places on a disease the affects over one million people worldwide.

Country	Number of people with MS	Prevalance (PwMS per 100,000)
Argentina	5,000	13.6
Australia	12,000	63.8
Austria	7,000	86.4
Belgium	8,900	87.5
Brazil	7,000	4.0
Bulgaria	3,200	39.3
Canada	35,000	111.0
Cyprus	350	46.7
Czech Republic	10,000	97.1
Denmark	6,000	112.0
Estonia	725	51.0
Finland	5,000	98.0
France	50,000	84.9
Germany	110,000	99.0
Greece	5,000	46.7
Hong Kong	50	0.88
Hungary	6,600	65.0
Iceland	285	105.1
Ireland	4,500	125.0
Israel	4,500	80.4
Italy	50,000	88.2
Japan	5,000	4.0
Libya	290	5.9
Luxembourg	400	94.1
Mexico	8,000	8.1
Netherlands	15,000	94.9
New Zealand	3,000	81.3
Norway	3,800	86.4
Poland	30,000	77.1
Portugal	5,000	50.5
Romania	7,500	33.4
South Africa	1,500	3.5
Spain	30,000	76.7
Sweden	12,000	134.8
Taiwan	175	0.8
Turkey	30,000	46.4
UK	85,000	143.8
USA	250,000	91.7
Zimbabwe	50	0.45

GENETIC AND ENVIRONMENTAL EVIDENCE

Studies of twins provide the clearest evidence for both genes and environment having a role. These studies look at pairs of twins in which at least one twin has MS. The table below shows the results of one such study [ 3].

Type of twin pair	Number of twin pairs	Twin pairs in which both twins had MS ("concordance rate")
Identical twins	44	25% (11 of 44 pairs)
Non-identical twins	61	3.3% (2 of 61 pairs)

If MS were governed only by genes, then every time one identical twin has MS, the other should have it, too. (Because identical twins have the same genes.) In other words, the "concordance rate" should be 100%. The table shows, however, that instead of a 100% concordance, there is a 25% concordance between identical twins. This shows that MS has an environmental component.

If MS were purely an environmental condition, then genes should make no difference at all. The concordance rate would be the same for identical twins and non-identical twins. The table shows, however, that the concordance rate is 7 to 8 times higher in identical twins (25%) than in non-identical twins (3.3%). This shows that MS has a genetic component.

3. Mumford CJ; Wood NW; Kellar-Wood H; Thorpe JW; Miller DH; Compston DA. The British Isles survey of multiple sclerosis in twins. Neurology 1994 Jan;44(1):11-15. [Medline]

CONCLUSION – SUMMARY TABLE OF DEBATE

Genetic	Environmental
Heredity	Geography
Specific Genes	Trauma
Molecular Biology Evidence	Pathogens
Twin Study	Twin Study

TREATMENTS

CONVENTIONAL

Treatments

Current Disease-Modifying Drugs

Brand Name	Chemical Name
Avonex®	Interferon beta 1-a
Betaseron®	Interferon beta 1-b
Copaxone®	Glatiramer acetate
Rebif®	Interferon beta-1a
Novantrone®	Mitoxantrone

ALTERNATIVE

Acupuncture
   Asian Herbal Medicine
   Asian Proprietary Medicine
   Aspartame (NutraSweet)
   Cognition
   Cold and Flu
     Echinacea
     Goldenseal
     Vitamin C
     Zinc
     Garlic
     Homeopathy
   Cooling
   Fatigue
   Humor Therapy
   Injection Site Reactions
   Marijuana
   Osteoporosis
   Prayer and Spirituality
   Prokarin
   Trad. Chinese Medicine
   Vitamin D

Preliminary Reviews of Other Alternate Therapies
   Androstenedione
   Antioxidant Vitamins Generally
   Calcium EAP
   Coenzyme Q 10
   Cranberry
   Creatine
   DHEA
   Evening Primrose Oil
   Garlic
   Ginkgo Biloba
   Ginseng
   Grape Seed Extract
   Herbs
   Hippotherapy
   Homeopathy
   Kava Kava
   Melatonin

REFERENCES

http://www.nmss.org/

http://www.ucsf.edu/msdb/aboutus.html

http://www.ninds.nih.gov/

http://health.discovery.com/minisites/dna/ms.html

http://www.ms-cam.org/index.html

Page Developed by Genetics 342 Group #2 Project (Summer 2004):

Please add your names!!

Jeanne Bohm