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MS research update - What causes MS? - 03 July 2013

Summary

This study used information from previously published studies of twins, some of whom had MS, and the people around them, to develop a mathematical model of how genetic and environmental factors add up to cause MS.

The researchers concluded that having certain genes is the first step towards possibly getting MS. However, having these genes is not enough to get MS and they say that "for all practical purposes, purely genetic MS does not exist".

They also concluded that there are at least three different environmental events which are needed to cause MS in people who are already genetically susceptible.

The complexity of the results shows that the causes of MS are still difficult to pin down. Consequently, it will take much more research to find out exactly what is going on and then work out how this knowledge can be used to prevent MS.

Background

The cause of MS is not well understood but it probably involves several factors coming together.

MS is not inherited like some conditions where someone carrying a faulty gene will go on to develop a medical condition whereas someone with the normal gene will not. Examples of these are Duchenne muscular dystrophy and haemophilia.

In MS, it is thought that some genes make it more likely that someone will get MS but that having a particular gene, or combination of genes, is definitely not enough on its own.

It seems that other factors in the environment are needed to cause MS in someone who already carries certain genes that make them susceptible. There is evidence that a wide range of environmental factors may play a part including lack of sunshine, lack of vitamin D (which is linked to lack of sunshine) and exposure to certain viruses.

How this study was carried out

This study used information from previously published studies of twins, some of whom had MS, and the people around them, to develop a mathematical model.

A mathematical model can help to explain what is going on in a complex situation. It can also be used tease out the different factors that may interact in a complicated way to produce the end result (in this case, getting MS). This model was designed so that the researchers could work out how much genes contributed to the risk of developing MS and how much the environment played a role.

Studies of twins were chosen because, in truly inherited conditions, identical twins will be identical in having (or not having) the inherited condition because they have identical genes. This does not happen in MS as, if one identical twin has MS, the other has a one in four chance. This is part of the evidence that other factors play a role, not just genes.

What was found

Genetic factors

The researchers found that, to get MS, the vast majority of people have to carry genes which would make them susceptible. This was true for at least 94% of people but they speculate that it might be 100%. This means that having certain genes is the first step towards possibly getting MS. However, having these genes is not enough to get MS and the researchers say that "for all practical purposes, purely genetic MS does not exist".

They report that men are more likely to be genetically susceptible than women. However, genetically susceptible women are more than twice as likely to go on to develop MS compared with susceptible men. This is because women are more responsive to the environmental factors that are involved in causing MS. This combination of genetic and environmental susceptibility accounts for the current ratio of MS which is about three times more women than men.

There are a large number of different genes which seem to confer susceptibility to MS. The most important is a variant (known in scientific terms as an allele) of the HLA gene called DRB1*1501. However, less than one in 20 people who carry this variant of this gene are genetically susceptible to MS so this gene is not the only genetic factor. Also, for those people who do carry this gene and do go on to have MS, the researchers estimate that the gene only contributed to susceptibility for two out of five of them.

To complicate things even further, people could have a copy of this variant of the gene from their mother and/or one from their father and these act independently to change someone's individual risk.

Environmental factors

The researchers concluded that there are at least three different environmental events which are needed to cause MS in people who are already genetically susceptible.

However, over two thirds of the general population (at least 69%) experience environmental exposure which is enough to produce MS although not all of them will be genetically susceptible so not all will go on to develop MS.

What does it mean?

This research shows that using published data from epidemiological studies, especially those in twins, can usefully included in a mathematical model to tease out the different risk factors for MS.

The complexity of the results shows that the causes of MS are still difficult to pin down. In particular, that genetic risk factors have to be combined with several different environmental risk factors to cause MS in a way that is not clear at the moment. It will take much more research to find out what is going on and then work out how this knowledge can be used to prevent MS.

Comment

The results of this scientific paper illustrate how difficult it is to identify and then explain all the risk factors for getting MS.

Like points on your license?

Here is one way to think about how risks stack up to cause MS: a bit like being given penalty points on your driving license.

In the UK, you can be given penalty points on your licence if you are convicted of a motoring offence. You can be disqualified from driving if you build up 12 or more penalty points.

Being born with genes that make you susceptible to MS might be the equivalent of being given three points on your license. Three points is not enough to lose your license (get MS) but it is a start in that direction.

Each environmental factor that you are exposed to that can contribute to causing MS, is another three points on your license. If you are exposed to three different environmental factors, that's another nine points.

If you already have three points because you are genetically susceptible, that's a total of 12 points. This adds up to losing your license or, in this case, getting MS.

Goodin DS.
The genetic and environmental bases of complex human-disease: extending the utility of twin-studies..
PLoS One. 2012;7(12):e47875.
abstract
Read the full text of this paper

More about causes of MS

You can read more about the possible causes of MS and the risk of MS for an individual in the A to Z of MS. Risk factors, such as lack of vitamin D, smoking and exposure to certain viruses including Epstein Barr virus, are discussed.

NHS Choices has information on how purely genetic conditions, like Duchenne muscular dystrophy and haemophilia, are inherited as well as general information on how lifestyle and environmental factors influence the risk of getting some conditions, for example, coronary heart disease. These conditions provide a useful comparison with MS.

Research by topic areas...

Symptoms and symptom management

Shaygannejad V, Ardestani PE, Ghasemi M, et al.
Restless legs syndrome in Iranian multiple sclerosis patients: a case-control study.
Int J Prev Med. 2013 May;4(Suppl 2):S189-93.
abstract
Read the full text of this paper

Pardini M, Bonzano L, Roccatagliata L, et al.
The fatigue-motor performance paradox in multiple sclerosis.
Sci Rep. 2013 Jun 18;3:2001.
abstract
Read the full text of this paper

MS relapses

Stellmann JP, Neuhaus A, Herich L, et al.
Placebo cohorts in phase-3 MS treatment trials - predictors for on-trial disease activity 1990-2010 based on a meta-analysis and individual case data.
PLoS One. 2012;7(11):e50347.
abstract
Read the full text of this paper

Disease modifying treatments

Reuss R..
PEGylated interferon beta-1a in the treatment of multiple sclerosis - an update.
Biologics. 2013;7:131-8.
abstract
Read the full text of this paper

Bar-Or A, Gold R, Kappos L, et al.
Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing-remitting multiple sclerosis: subgroup analyses of the DEFINE study.
J Neurol. 2013 Jun 25. [Epub ahead of print]
abstract

Jones JL, Scheidt DJ, Kaushal RS, et al.
Assessing the role of patient support services on adherence rates in patients using glatiramer acetate for relapsing-remitting multiple sclerosis.
J Med Econ. 2013;16(2):213-20.
abstract

Other treatments

Solaro C, Bergamaschi R, Rezzani C, et al.
Duloxetine is effective in treating depression in multiple sclerosis patients: an open-label multicenter study.
Clin Neuropharmacol. 2013 Jun 17. [Epub ahead of print]
abstract

Bergenheim AT, Asplund P, Linderoth B.
Percutaneous retrogasserian balloon compression for trigeminal neuralgia: review of critical technical details and outcomes.
World Neurosurg. 2013 Feb;79(2):359-68.
abstract

Assessment tools

Leddy S, Hadavi S, McCarren A, et al.
Validating a novel web-based method to capture disease progression outcomes in multiple sclerosis.
J Neurol. 2013 Jun 27. [Epub ahead of print]
abstract

Sidovar MF, Limone BL, Lee S, et al.
Mapping the 12-item multiple sclerosis walking scale to the EuroQol 5-dimension index measure in North American multiple sclerosis patients.
BMJ Open. 2013 May 28;3(5).
abstract
Read the full text of this paper

Learmonth YC, Dlugonski D, Pilutti LA, et al.
Psychometric properties of the Fatigue Severity Scale and the Modified Fatigue Impact Scale.
J Neurol Sci. 2013 Jun 20. doi:pii: S0022-510X(13)00230-X.10.1016/j.jns.2013.05.023. [Epub ahead of print]
abstract

Grand'maison F, Bhan V, Freedman MS, et al.
Utility of the Canadian Treatment Optimization Recommendations (TOR) in MS Care.
Can J Neurol Sci. 2013 Jul;40(4):527-35.
abstract

Honan CA, Brown RF, Hine DW.
The Multiple Sclerosis Work DifficultiesQuestionnaire (MSWDQ): development of a shortened scale.
Disabil Rehabil. 2013 Jun 20. [Epub ahead of print]
abstract

Quality of life

Jones KH, Ford DV, Jones PA, et al.
How people with multiple sclerosis rate their quality of life: an EQ-5D survey via the UK MS Register.
PLoS One. 2013 Jun 11;8(6):e65640.
abstract
Read the full text of this paper

Klevan G, Jacobsen CO, Aarseth JH, et al.
Health related quality of life in patients recently diagnosed with multiple sclerosis.
Acta Neurol Scand. 2013 Jun 15. doi:10.1111/ane.12142. [Epub ahead of print]
abstract

Vitamin D

Golan D, Halhal B, Glass-Marmor L, et al.
Vitamin D supplementation for patients with multiple sclerosis treated with interferon-beta: a randomized controlled trial assessing the effect on flu-like symptoms and immunomodulatory properties.
BMC Neurol. 2013 Jun 14;13(1):60. [Epub ahead of print]
abstract
Read the full text of this paper

Genetics

Sadovnick AD.
Differential effects of genetic susceptibility factors in males and females with multiple sclerosis.
Clin Immunol. 2013 May 11. doi:pii: S1521-6616(13)00122-8. 10.1016/j.clim.2013.05.002. [Epub ahead of print]
abstract

Psychological aspects

Mäntynen A, Rosti-Otajärvi E, Koivisto K, et al.
Neuropsychological rehabilitation does not improve cognitive performance but reduces perceived cognitive deficits in patients with multiple sclerosis: a randomised, controlled, multi-centre trial.
Mult Scler. 2013 Jun 26. [Epub ahead of print]
abstract

Velázquez-Cardoso J, Marosi-Holczberger E, Rodríguez-Agudelo Y, et al.
Recall strategies for the verbal fluency test in patients with multiple sclerosis.
Neurologia. 2013 Jun 21. doi:pii: S0213-4853(13)00104-7. 10.1016/j.nrl.2013.03.007. [Epub ahead of print]
abstract

Hankomäki E, Multanen J, Kinnunen E, et al.
The progress of cognitive decline in newly diagnosed MS patients.
Acta Neurol Scand. 2013 Jun 15. doi:10.1111/ane.12161. [Epub ahead of print]
abstract

Physical activity

Pilutti LA, Greenlee TA, Motl RW, et al.
Effects of exercise training on fatigue in multiple sclerosis: a meta-analysis.
Psychosom Med. 2013 Jun 20. [Epub ahead of print]
abstract

Latimer-Cheung AE, Martin Ginis KA, Hicks AL, et al.
Development of evidence-informed physical activity guidelines for adults with multiple sclerosis.
Arch Phys Med Rehabil. 2013 Jun 11. doi:pii: S0003-9993(13)00425-5. 10.1016/j.apmr.2013.05.015. [Epub ahead of print]
abstract

Kasser SL, Rizzo T.
An exploratory study of fitness practitioner intentions toward exercise programming for individuals with multiple sclerosis.
Disabil Health J. 2013 Jul;6(3):188-94.
abstract

Hormones and MS

Trenova AG, Slavov GS, Manova MG, et al.
Female sex hormones and cytokine secretion in women with multiple sclerosis.
Neurol Res. 2013 Jan;35(1):95-9.
abstract

Pathophysiology

Schneider E, Zimmermann H, Oberwahrenbrock T, et al.
Optical coherence tomography reveals distinct patterns of retinal damage in neuromyelitis optica and multiple sclerosis.
PLoS One. 2013 Jun 21;8(6):e66151.
abstract
Read the full text of this paper

Hofstetter L, Naegelin Y, Filli L, et al.
Progression in disability and regional grey matter atrophy in relapsing-remitting multiple sclerosis.
Mult Scler. 2013 Jun 26. [Epub ahead of print]
abstract

Work

Horwitz H, Ahlgren B, Nærum E.
Effect of occupation on risk of developing MS: an insurance cohort study.
BMJ Open. 2013 Jun 20;3(6).
abstract
Read the full text of this paper

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