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Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis

Nature Reviews Neurology volume 13, pages 25–36 (2017)Cite this article

Subjects

Key Points

  • Epstein–Barr virus (EBV) infection, smoking, low vitamin D and lack of sun exposure are well established factors associated with risk of multiple sclerosis (MS); recently, adolescent obesity has been added to this list

  • Less established factors include exposure to organic solvents and night shift work, which associate with increased risk, whereas oral tobacco use, cytomegalovirus infection, alcohol use and coffee consumption associate with decreased risk

  • Some of these factors should be considered in primary prevention

  • Most lifestyle and environmental factors seem to have the greatest effect during a particular time window — adolescence

  • Certain factors, such as EBV infection, smoking and adolescent obesity interact with human leukocyte antigen MS risk genes, with substantial risk increases in individuals who carry genes that predispose them to MS

  • The interaction with these immune response genes provides strong evidence that these lifestyle and environmental factors act on adaptive immunity, leading to autoimmune attack on the nervous system

Abstract

Genetic predisposition to multiple sclerosis (MS) only explains a fraction of the disease risk; lifestyle and environmental factors are key contributors to the risk of MS. Importantly, these nongenetic factors can influence pathogenetic pathways, and some of them can be modified. Besides established MS-associated risk factors — high latitude, female sex, smoking, low vitamin D levels caused by insufficient sun exposure and/or dietary intake, and Epstein–Barr virus (EBV) infection — strong evidence now supports obesity during adolescence as a factor increasing MS risk. Organic solvents and shift work have also been reported to confer increased risk of the disease, whereas factors such as use of nicotine or alcohol, cytomegalovirus infection and a high coffee consumption are associated with a reduced risk. Certain factors — smoking, EBV infection and obesity — interact with HLA risk genes, pointing at a pathogenetic pathway involving adaptive immunity. All of the described risk factors for MS can influence adaptive and/or innate immunity, which is thought to be the main pathway modulated by MS risk alleles. Unlike genetic risk factors, many environmental and lifestyle factors can be modified, with potential for prevention, particularly for people at the greatest risk, such as relatives of individuals with MS. Here, we review recent data on environmental and lifestyle factors, with a focus on gene–environment interactions.

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Figure 1: Evolution of multiple sclerosis.
Figure 2: Principles of additive interactions between risk factors.
Figure 3: Hypothetical mechanisms of smoking-associated processes that contribute to risk of multiple sclerosis.
Figure 4: Lifestyle and environmental factors affect the immune system to trigger and/or perpetuate multiple sclerosis.

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Acknowledgements

We thank Mohsen Khademi for preparing the schematic figures and Maja Jagodic for input on the epigenetics section. The original studies by T.O. cited in the text have been supported by the Swedish Research Council, the Knut and Alice Wallenberg foundation, the AFA foundation, the Swedish Brain Foundation, Margareta af Ugglas Foundation and the EUfp7 Neurinox 2012–278611. L.A. has received grants for multiple sclerosis research from the Swedish Research Council, the Swedish Research Council for Health, Working Life and Welfare and the Swedish Brain Foundation.

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Authors and Affiliations

  1. Neuroimmunology Unit, Center for Molecular Medicine, L8:04, Karolinska University Hospital (Solna), Stockholm, 17176, Sweden

    Tomas Olsson

  2. Genetic Epidemiology and Genomics Laboratory, California Institute for Quantitative Biosciences (QB3), Office: 308D Stanley Hall, University of California, Berkeley, 94720–3220, CA

    Lisa F. Barcellos

  3. Institute of Environmental Medicine, Karolinska Institutet, Box 210, Stockholm, 171 77, Sweden

    Lars Alfredsson

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  1. Tomas Olsson
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  2. Lisa F. Barcellos
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  3. Lars Alfredsson
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All authors researched data for article, and provided substantial contribution to discussion of content, writing, reviewing and editing of the manuscript.

Corresponding author

Correspondence to Tomas Olsson.

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Competing interests

T.O. has received honoraria for lectures and/or advisory boards as well as unrestricted multiple sclerosis research grants from Allmiral, Astrazeneca, Biogen, Genzyme, Merck and Novartis. L.A. has received lecture honoraria from Biogen and Teva.

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Glossary

Latitude gradient

A gradual decrease in incidence and prevalence of MS from north to south in the northern hemisphere, and in the opposite direction in the southern hemisphere.

HLA complex

A region on human chromosome 6 containing ∼ 200 genes, most of which have functions in the immune system; of these, class II genes encode molecules that bind and present peptide antigens to CD4+ TH cells, and class I genes encode molecules that present peptide antigens to CD8+ cytotoxic T cells.

Genome-wide association studies (GWAS)

Single-nucleotide polymorphisms (SNPs) are identified throughout the genome, usually several hundreds of thousands of SNPs, in very large case–control cohorts, allowing identification of associations between diseases and discrete genome loci.

Experimental autoimmune encephalomyelitis

A model disease induced in experimental animals, commonly mice or rats, by immunizing the animal with CNS components that induce an autoimmune attack against the CNS that mimics many aspects of MS; can also be induced by transfer of CNS autoreactive T cells.

Molecular mimicry

A phenomenon in which parts of a microbial agent have a molecular structure similar to a host molecule, thereby eliciting an immune response that is autoreactive against the host.

Mendelian randomization

A method to determine causal effects of modifiable factors that takes advantage of the fact that gene variants for certain traits are independently segregated and randomly assigned at meiosis, thereby minimizing bias such as confounding.

Epiphysioectomy

Surgical removal of the epiphysis (also known as the pineal gland), the main source of melatonin.

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Olsson, T., Barcellos, L. & Alfredsson, L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol 13, 25–36 (2017). https://doi.org/10.1038/nrneurol.2016.187

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