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

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. Access through your institution Buy or subscribe This is a preview of subscription content,

access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn

more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS

OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE INCREASED RISK OF MULTIPLE SCLEROSIS

ASSOCIATED WITH HLA-DRB1*15:01 AND SMOKING IS MODIFIED BY ALCOHOL CONSUMPTION Article Open access 27 October 2021 NO EVIDENCE FOR AN ASSOCIATION BETWEEN ALCOHOL CONSUMPTION AND MULTIPLE

SCLEROSIS RISK: A UK BIOBANK STUDY Article Open access 22 December 2022 ELEVATED GENETIC RISK FOR MULTIPLE SCLEROSIS EMERGED IN STEPPE PASTORALIST POPULATIONS Article Open access 10 January

2024 REFERENCES * Marrie, R. A., Yu, N., Wei, Y., Elliott, L. & Blanchard, J. High rates of physician services utilization at least five years before multiple sclerosis diagnosis. _Mult.

Scler._ 19, 1113–1119 (2013). Article  PubMed  Google Scholar  * Hughes, A. M. _ et al_. Early-life hygiene-related factors affect risk of central nervous system demyelination and asthma

differentially. _Clin. Exp. Immunol._ 172, 466–474 (2013). Article  PubMed  PubMed Central  Google Scholar  * Hedstrom, A. K., Hillert, J., Olsson, T. & Alfredsson, L. Reverse causality

behind the association between reproductive history and MS. _Mult. Scler._ 20, 406–411 (2014). Article  CAS  PubMed  Google Scholar  * Nielsen, N. M. _ et al_. Reproductive history and risk

of multiple sclerosis. _Epidemiology_ 22, 546–552 (2011). Article  PubMed  Google Scholar  * Ascherio, A., Munger, K. L. & Lunemann, J. D. The initiation and prevention of multiple

sclerosis. _Nat. Rev. Neurol._ 8, 602–612 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lucas, R. M., Byrne, S. N., Correale, J., Ilschner, S. & Hart, P. H. Ultraviolet

radiation, vitamin D and multiple sclerosis. _Neurodegener. Dis. Manag._ 5, 413–424 (2015). Article  PubMed  Google Scholar  * Sawcer, S. The complex genetics of multiple sclerosis:

pitfalls and prospects. _Brain_ 131, 3118–3131 (2008). Article  PubMed  PubMed Central  Google Scholar  * van der Mei, I. _ et al_. Population attributable fractions and joint effects of key

risk factors for multiple sclerosis. _Mult. Scler._ 22, 461–469 (2016). Article  CAS  PubMed  Google Scholar  * O'Gorman, C., Lin, R., Stankovich, J. & Broadley, S. A. Modelling

genetic susceptibility to multiple sclerosis with family data. _Neuroepidemiology_ 40, 1–12 (2013). Article  PubMed  Google Scholar  * Westerlind, H. _ et al_. Modest familial risks for

multiple sclerosis: a registry-based study of the population of Sweden. _Brain_ 137, 770–778 (2014). Article  PubMed  PubMed Central  Google Scholar  * Westerlind, H. _ et al_.

Identity-by-descent mapping in a Scandinavian multiple sclerosis cohort. _Eur. J. Hum. Genet._ 23, 688–692 (2015). Article  CAS  PubMed  Google Scholar  * Simpson, S. _ et al_. Latitude is

significantly associated with the prevalence of multiple sclerosis: a meta-analysis. _J. Neurol. Neurosurg. Psychiatry_ 82, 1132–1141 (2011). Article  PubMed  Google Scholar  * Gale, C. R.

& Martyn, C. N. Migrant studies in multiple sclerosis. _Prog. Neurobiol._ 47, 425–448 (1995). Article  CAS  PubMed  Google Scholar  * Berg-Hansen, P. _ et al_. Prevalence of multiple

sclerosis among immigrants in Norway. _Mult. Scler._ 21, 695–702 (2015). Article  PubMed  Google Scholar  * Ahlgren, C., Oden, A. & Lycke, J. A nationwide survey of the prevalence of

multiple sclerosis in immigrant populations of Sweden. _Mult. Scler._ 18, 1099–1107 (2012). Article  PubMed  Google Scholar  * Ahlgren, C., Lycke, J., Oden, A. & Andersen, O. High risk

of MS in Iranian immigrants in Gothenburg, Sweden. _Mult. Scler._ 16, 1079–1082 (2010). Article  CAS  PubMed  Google Scholar  * Montgomery, S. M., Lambe, M., Olsson, T. & Ekbom, A.

Parental age, family size, and risk of multiple sclerosis. _Epidemiology_ 15, 717–723 (2004). Article  PubMed  Google Scholar  * van der Mei, I. A. _ et al_. Human leukocyte antigen-DR15,

low infant sibling exposure and multiple sclerosis: gene-environment interaction. _Ann. Neurol._ 67, 261–265 (2010). Article  PubMed  Google Scholar  * Barnett, M. H., McLeod, J. G.,

Hammond, S. R. & Kurtzke, J. F. Migration and multiple sclerosis in immigrants from United Kingdom and Ireland to Australia: a reassessment. III: risk of multiple sclerosis in UKI

immigrants and Australian-born in Hobart, Tasmania. _J. Neurol._ 263, 792–798 (2016). Article  PubMed  Google Scholar  * Koch-Henriksen, N. & Sorensen, P. S. The changing demographic

pattern of multiple sclerosis epidemiology. _Lancet Neurol._ 9, 520–532 (2010). Article  PubMed  Google Scholar  * Westerlind, H. _ et al_. New data identify an increasing sex ratio of

multiple sclerosis in Sweden. _Mult. Scler._ 20, 1578–1583 (2014). Article  PubMed  PubMed Central  Google Scholar  * Ponsonby, A. L. _ et al_. Offspring number, pregnancy, and risk of a

first clinical demyelinating event: the AusImmune Study. _Neurology_ 78, 867–874 (2012). Article  PubMed  Google Scholar  * Magyari, M., Koch-Henriksen, N., Pfleger, C. C. & Sorensen, P.

S. Reproduction and the risk of multiple sclerosis. _Mult. Scler._ 19, 1604–1609 (2013). Article  PubMed  Google Scholar  * Brodin, P. _ et al_. Variation in the human immune system is

largely driven by non-heritable influences. _Cell_ 160, 37–47 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Roshanisefat, H., Bahmanyar, S., Hillert, J., Olsson, T. &

Montgomery, S. Shared genetic factors may not explain the raised risk of comorbid inflammatory diseases in multiple sclerosis. _Mult. Scler._ 18, 1430–1436 (2012). Article  CAS  PubMed 

Google Scholar  * Sawcer, S. _ et al_. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. _Nature_ 476, 214–219 (2011). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Brynedal, B. _ et al_. _HLA-A_ confers an _HLA-DRB1_ independent influence on the risk of multiple sclerosis. _PLoS ONE_ 2, e664 (2007). Article  CAS  PubMed 

PubMed Central  Google Scholar  * Beecham, A. H. _ et al_. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. _Nat. Genet._ 45, 1353–1360

(2013). Article  CAS  PubMed  PubMed Central  Google Scholar  * Moutsianas, L. _ et al_. Class II HLA interactions modulate genetic risk for multiple sclerosis. _Nat. Genet._ 47, 1107–1113

(2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Rothman, K. J., Greenland, S. & Walker, A. M. Concepts of interaction. _Am. J. Epidemiol._ 112, 467–470 (1980). Article 

CAS  PubMed  Google Scholar  * Rothman, K. J., Greenland, S. & Lash, T. L. (eds) in _Modern Epidemiology_. 3rd edn Ch. 3 pp. 71–83 (Lippincott Williams & Wilkins, 2008). Google

Scholar  * Hawkes, C. H. Smoking is a risk factor for multiple sclerosis: a metanalysis. _Mult. Scler._ 13, 610–615 (2007). Article  CAS  PubMed  Google Scholar  * Handel, A. E. _ et al_.

Smoking and multiple sclerosis: an updated meta-analysis. _PLoS ONE_ 6, e16149 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hedstrom, A. K., Baarnhielm, M., Olsson, T.

& Alfredsson, L. Tobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis. _Neurology_ 73, 696–701 (2009). Article  PubMed  Google Scholar  * Ghadirian, P.,

Dadgostar, B., Azani, R. & Maisonneuve, P. A case-control study of the association between socio-demographic, lifestyle and medical history factors and multiple sclerosis. _Can. J.

Public Health_ 92, 281–285 (2001). Article  CAS  PubMed  Google Scholar  * Salzer, J. _ et al_. Smoking as a risk factor for multiple sclerosis. _Mult. Scler._ 19, 1022–1027 (2013). Article

  PubMed  Google Scholar  * Hedstrom, A. K., Baarnhielm, M., Olsson, T. & Alfredsson, L. Exposure to environmental tobacco smoke is associated with increased risk for multiple sclerosis.

_Mult. Scler._ 17, 788–793 (2011). Article  CAS  PubMed  Google Scholar  * Heydarpour, P. _ et al_. Potential impact of air pollution on multiple sclerosis in Tehran, Iran.

_Neuroepidemiology_ 43, 233–238 (2014). Article  PubMed  Google Scholar  * Barragan-Martinez, C. _ et al_. Organic solvents as risk factor for autoimmune diseases: a systematic review and

meta-analysis. _PLoS ONE_ 7, e51506 (2012). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hedstrom, A. _ et al_. Smokers run increased risk of developing anti-natalizumab

antibodies. _Mult. Scler._ 20, 1081–1085 (2013). Article  CAS  PubMed  Google Scholar  * Hedstrom, A. K. _ et al_. Smoking and risk of treatment-induced neutralizing antibodies to interferon

β-1a. _Mult. Scler._ 20, 445–450 (2014). Article  CAS  PubMed  Google Scholar  * Chinoy, H. _ et al_. Interaction of HLA-DRB1*03 and smoking for the development of anti-Jo-1 antibodies in

adult idiopathic inflammatory myopathies: a European-wide case study. _Ann. Rheum. Dis._ 71, 961–965 (2012). Article  CAS  PubMed  Google Scholar  * Klareskog, L., Catrina, A. I. &

Paget, S. Rheumatoid arthritis. _Lancet_ 373, 659–672 (2009). Article  CAS  PubMed  Google Scholar  * Hedstrom, A. K., Hillert, J., Olsson, T. & Alfredsson, L. Nicotine might have a

protective effect in the etiology of multiple sclerosis. _Mult. Scler._ 19, 1009–1013 (2013). Article  CAS  PubMed  Google Scholar  * Nizri, E. _ et al_. Activation of the cholinergic

anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of TH1 and TH17 responses. _J. Immunol._ 183, 6681–6688 (2009). Article  CAS  PubMed  Google Scholar  *

Shan, M. _ et al_. Lung myeloid dendritic cells coordinately induce TH1 and TH17 responses in human emphysema. _Sci. Transl. Med._ 1, 4ra10 (2009). Article  CAS  PubMed  Google Scholar  *

Odoardi, F. _ et al_. T cells become licensed in the lung to enter the central nervous system. _Nature_ 488, 675–679 (2012). Article  CAS  PubMed  Google Scholar  * Hedstrom, A. K. _ et al_.

Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. _Brain_ 134, 653–664 (2011). Article  PubMed  Google Scholar  * Hedstrom, A. K. _ et al_.

Interaction between passive smoking and two HLA genes with regard to multiple sclerosis risk. _Int. J. Epidemiol._ 43, 1791–1798 (2014). Article  PubMed  PubMed Central  Google Scholar  *

Briggs, F. B. _ et al_. Smoking and risk of multiple sclerosis: evidence of modification by _NAT1_ variants. _Epidemiology_ 25, 605–614 (2014). Article  PubMed  Google Scholar  * Friese, M.

A. & Fugger, L. Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? _Brain_ 128, 1747–1763 (2005). Article  PubMed  Google Scholar  * Friese, M. A. _ et al_.

Opposing effects of HLA class I molecules in tuning autoreactive CD8+ T cells in multiple sclerosis. _Nat. Med._ 14, 1227–1235 (2008). Article  CAS  PubMed  Google Scholar  * Dendrou, C. A.,

Fugger, L. & Friese, M. A. Immunopathology of multiple sclerosis. _Nat. Rev. Immunol._ 15, 545–558 (2015). Article  CAS  PubMed  Google Scholar  * Mustafa, M. _ et al_. The major

histocompatibility complex influences myelin basic protein 63-88-induced T cell cytokine profile and experimental autoimmune encephalomyelitis. _Eur. J. Immunol._ 23, 3089–3095 (1993).

Article  CAS  PubMed  Google Scholar  * Mustafa, M. _ et al_. Protective influences on experimental autoimmune encephalomyelitis by MHC class I and class II alleles. _J. Immunol._ 153,

3337–3344 (1994). CAS  PubMed  Google Scholar  * Issazadeh, S., Kjellen, P., Olsson, T., Mustafa, M. & Holmdahl, R. Major histocompatibility complex-controlled protective influences on

experimental autoimmune encephalomyelitis are peptide specific. _Eur. J. Immunol._ 27, 1584–1587 (1997). Article  CAS  PubMed  Google Scholar  * Hedstrom, A. K., Olsson, T. & Alfredsson,

L. Smoking is a major preventable risk factor for multiple sclerosis. _Mult. Scler._ 22, 1021–1026 (2016). Article  CAS  PubMed  Google Scholar  * Sundstrom, P. & Nystrom, L. Smoking

worsens the prognosis in multiple sclerosis. _Mult. Scler._ 14, 1031–1035 (2008). Article  CAS  PubMed  Google Scholar  * Correale, J. & Farez, M. F. Smoking worsens multiple sclerosis

prognosis: two different pathways are involved. _J. Neuroimmunol._ 281, 23–34 (2015). Article  CAS  PubMed  Google Scholar  * Di Pauli, F. _ et al_. Smoking is a risk factor for early

conversion to clinically definite multiple sclerosis. _Mult. Scler._ 14, 1026–1030 (2008). Article  CAS  PubMed  Google Scholar  * Healy, B. C. _ et al_. Smoking and disease progression in

multiple sclerosis. _Arch. Neurol._ 66, 858–864 (2009). Article  PubMed  PubMed Central  Google Scholar  * Hernan, M. A. _ et al_. Cigarette smoking and the progression of multiple

sclerosis. _Brain_ 128, 1461–1465 (2005). Article  PubMed  Google Scholar  * Pittas, F. _ et al_. Smoking is associated with progressive disease course and increased progression in clinical

disability in a prospective cohort of people with multiple sclerosis. _J. Neurol._ 256, 577–585 (2009). Article  PubMed  Google Scholar  * Manouchehrinia, A. _ et al_. Tobacco smoking and

disability progression in multiple sclerosis: United Kingdom cohort study. _Brain_ 136, 2298–2304 (2013). Article  PubMed  PubMed Central  Google Scholar  * Zivadinov, R. _ et al_. Smoking

is associated with increased lesion volumes and brain atrophy in multiple sclerosis. _Neurology_ 73, 504–510 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Manouchehrinia,

A., Weston, M., Tench, C. R., Britton, J. & Constantinescu, C. S. Tobacco smoking and excess mortality in multiple sclerosis: a cohort study. _J. Neurol. Neurosurg. Psychiatry_ 85,

1091–1095 (2014). Article  PubMed  PubMed Central  Google Scholar  * Ramanujam, R. _ et al_. Effect of smoking cessation on multiple sclerosis prognosis. _JAMA Neurol._ 72, 1117–1123 (2015).

Article  PubMed  Google Scholar  * Handel, A. E. _ et al_. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. _PLoS ONE_ 5, e12496 (2010). Article 

CAS  PubMed  PubMed Central  Google Scholar  * Sundstrom, P., Nystrom, M., Ruuth, K. & Lundgren, E. Antibodies to specific EBNA-1 domains and _HLA DRB1*1501_ interact as risk factors for

multiple sclerosis. _J. Neuroimmunol._ 215, 102–107 (2009). Article  CAS  PubMed  Google Scholar  * Sundqvist, E. _ et al_. Epstein-Barr virus and multiple sclerosis: interaction with HLA.

_Genes Immun._ 13, 14–20 (2012). Article  CAS  PubMed  Google Scholar  * Levin, L. I., Munger, K. L., O'Reilly, E. J., Falk, K. I. & Ascherio, A. Primary infection with the

Epstein-Barr virus and risk of multiple sclerosis. _Ann. Neurol._ 67, 824–830 (2010). PubMed  PubMed Central  Google Scholar  * Ascherio, A. & Munger, K. L. EBV and autoimmunity. _Curr.

Top. Microbiol. Immunol._ 390, 365–385 (2015). CAS  PubMed  Google Scholar  * Makhani, N. _ et al_. Viral exposures and MS outcome in a prospective cohort of children with acquired

demyelination. _Mult. Scler._ 22, 385–388 (2016). Article  CAS  PubMed  Google Scholar  * Zhou, Y. _ et al_. Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of

multiple sclerosis. _Mult. Scler._ (2016). * Nielsen, T. R. _ et al_. Effects of infectious mononucleosis and _HLA-DRB1*15_ in multiple sclerosis. _Mult. Scler._ 15, 431–436 (2009). Article

  CAS  PubMed  Google Scholar  * Hedstrom, A. K., Lima Bomfim, I., Hillert, J., Olsson, T. & Alfredsson, L. Obesity interacts with infectious mononucleosis in risk of multiple sclerosis.

_Eur. J. Neurol._ 22, 578–e538 (2015). Article  CAS  PubMed  Google Scholar  * Serafini, B. _ et al_. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. _J. Exp.

Med._ 204, 2899–2912 (2007). Article  CAS  PubMed  PubMed Central  Google Scholar  * Lassmann, H., Niedobitek, G., Aloisi, F. & Middeldorp, J. M. Epstein–Barr virus in the multiple

sclerosis brain: a controversial issue—report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. _Brain_ 134, 2772–2786 (2011). Article

  PubMed  PubMed Central  Google Scholar  * Hauser, S. L. _ et al_. B-Cell depletion with rituximab in relapsing-remitting multiple sclerosis. _N. Engl. J. Med._ 358, 676–688 (2008). Article

  CAS  PubMed  Google Scholar  * Sundqvist, E. _ et al_. JC polyomavirus infection is strongly controlled by human leucocyte antigen class II variants. _PLoS Pathog._ 10, e1004084 (2014).

Article  PubMed  PubMed Central  Google Scholar  * Staras, S. A. _ et al_. Seroprevalence of cytomegalovirus infection in the United States, 1988–1994. _Clin. Infect. Dis._ 43, 1143–1151

(2006). Article  PubMed  Google Scholar  * Waubant, E. _ et al_. Common viruses associated with lower pediatric multiple sclerosis risk. _Neurology_ 76, 1989–1995 (2011). Article  CAS 

PubMed  PubMed Central  Google Scholar  * Waubant, E. _ et al_. Antibody response to common viruses and human leukocyte antigen-DRB1 in pediatric multiple sclerosis. _Mult. Scler._ 19,

891–895 (2013). Article  CAS  PubMed  Google Scholar  * Sundqvist, E. _ et al_. Cytomegalovirus seropositivity is negatively associated with multiple sclerosis. _Mult. Scler._ 20, 165–173

(2014). Article  CAS  PubMed  Google Scholar  * Ascherio, A. _ et al_. Epstein–Barr virus antibodies and risk of multiple sclerosis: a prospective study. _JAMA_ 286, 3083–3088 (2001).

Article  CAS  PubMed  Google Scholar  * Levin, L. I. _ et al_. Temporal relationship between elevation of Epstein–Barr virus antibody titers and initial onset of neurological symptoms in

multiple sclerosis. _JAMA_ 293, 2496–2500 (2005). Article  CAS  PubMed  Google Scholar  * DeLorenze, G. N. _ et al_. Epstein–Barr virus and multiple sclerosis: evidence of association from a

prospective study with long-term follow-up. _Arch. Neurol._ 63, 839–844 (2006). Article  PubMed  Google Scholar  * Chidrawar, S. _ et al_. Cytomegalovirus-seropositivity has a profound

influence on the magnitude of major lymphoid subsets within healthy individuals. _Clin. Exp. Immunol._ 155, 423–432 (2009). Article  CAS  PubMed  PubMed Central  Google Scholar  * Munger, K.

L. _ et al_. Molecular mechanism underlying the impact of vitamin D on disease activity of MS. _Ann. Clin. Transl. Neurol._ 1, 605–617 (2014). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Kampman, M. T., Wilsgaard, T. & Mellgren, S. I. Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle. _J. Neurol._ 254, 471–477

(2007). Article  CAS  PubMed  Google Scholar  * Baarnhielm, M. _ et al_. Sunlight is associated with decreased multiple sclerosis risk: no interaction with human leukocyte antigen-DRB1*15.

_Eur. J. Neurol._ 19, 955–962 (2012). Article  CAS  PubMed  Google Scholar  * Becklund, B. R., Severson, K. S., Vang, S. V. & DeLuca, H. F. UV radiation suppresses experimental

autoimmune encephalomyelitis independent of vitamin D production. _Proc. Natl. Acad. Sci. U. S. A._ 107, 6418–6423 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Rana, S.,

Rogers, L. J. & Halliday, G. M. Systemic low-dose UVB inhibits CD8 T cells and skin inflammation by alternative and novel mechanisms. _Am. J. Pathol._ 178, 2783–2791 (2011). Article  CAS

  PubMed  PubMed Central  Google Scholar  * Breuer, J. _ et al_. Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. _Ann. Neurol._ 75,

739–758 (2014). Article  CAS  PubMed  Google Scholar  * Navid, F. _ et al_. The aryl hydrocarbon receptor is involved in UVR-induced immunosuppression. _J. Invest. Dermatol._ 133, 2763–2770

(2013). Article  CAS  PubMed  Google Scholar  * Correale, J. & Farez, M. F. Modulation of multiple sclerosis by sunlight exposure: role of _cis_-urocanic acid. _J. Neuroimmunol._ 261,

134–140 (2013). Article  CAS  PubMed  Google Scholar  * Munger, K. L., Levin, L. I., Hollis, B. W., Howard, N. S. & Ascherio, A. Serum 25-hydroxyvitamin D levels and risk of multiple

sclerosis. _JAMA_ 296, 2832–2838 (2006). Article  CAS  PubMed  Google Scholar  * Cortese, M. _ et al_. Timing of use of cod liver oil, a vitamin D source, and multiple sclerosis risk: the

EnvIMS study. _Mult. Scler._ 21, 1856–1864 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Bjornevik, K. _ et al_. Sun exposure and multiple sclerosis risk in Norway and

Italy: the EnvIMS study. _Mult. Scler._ 20, 1042–1049 (2014). Article  PubMed  Google Scholar  * Baarnhielm, M., Olsson, T. & Alfredsson, L. Fatty fish intake is associated with

decreased occurrence of multiple sclerosis. _Mult. Scler._ 20, 726–732 (2014). Article  CAS  PubMed  Google Scholar  * Sandberg, L. _ et al_. Vitamin D and axonal injury in multiple

sclerosis. _Mult. Scler._ 22, 1027–1031 (2015). Article  CAS  PubMed  Google Scholar  * Ueda, P. _ et al_. Neonatal vitamin D status and risk of multiple sclerosis. _Ann. Neurol._ 76,

338–346 (2014). Article  CAS  PubMed  Google Scholar  * Adzemovic, M. Z., Zeitelhofer, M., Hochmeister, S., Gustafsson, S. A. & Jagodic, M. Efficacy of vitamin D in treating multiple

sclerosis-like neuroinflammation depends on developmental stage. _Exp. Neurol._ 249, 39–48 (2013). Article  CAS  PubMed  Google Scholar  * Munger, K. L. _ et al_. Vitamin D status during

pregnancy and risk of multiple sclerosis in offspring of women in the Finnish maternity cohort. _JAMA Neurol._ 73, 515–519 (2016). Article  PubMed  PubMed Central  Google Scholar  * Staples,

J., Ponsonby, A. L. & Lim, L. Low maternal exposure to ultraviolet radiation in pregnancy, month of birth, and risk of multiple sclerosis in offspring: longitudinal analysis. _BMJ_ 340,

c1640 (2010). PubMed  PubMed Central  Google Scholar  * Sundqvist, E. _ et al_. Confirmation of association between multiple sclerosis and CYP27B1. _Eur. J. Hum. Genet._ 18, 1349–1352

(2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Rhead, B. _ et al_. Mendelian randomization shows a causal effect of low vitamin D on multiple sclerosis risk. _Neurol.

Genet._ 2, e97 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Mokry, L. E. _ et al_. Vitamin D and risk of multiple sclerosis: a Mendelian randomization study. _PLoS Med._

12, e1001866 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Handunnetthi, L., Ramagopalan, S. V. & Ebers, G. C. Multiple sclerosis, vitamin D, and _HLA-DRB1*15_.

_Neurology_ 74, 1905–1910 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Ascherio, A. _ et al_. Vitamin D as an early predictor of multiple sclerosis activity and

progression. _JAMA Neurol._ 71, 306–314 (2014). Article  PubMed  PubMed Central  Google Scholar  * Fitzgerald, K. C. _ et al_. Association of vitamin D levels with multiple sclerosis

activity and progression in patients receiving interferon Beta-1b. _JAMA Neurol._ 72, 1458–1465 (2015). Article  PubMed  Google Scholar  * Munger, K. L., Chitnis, T. & Ascherio, A. Body

size and risk of MS in two cohorts of US women. _Neurology_ 73, 1543–1550 (2009). Article  PubMed  PubMed Central  Google Scholar  * Munger, K. L. _ et al_. Childhood body mass index and

multiple sclerosis risk: a long-term cohort study. _Mult. Scler._ 19, 1323–1329 (2013). Article  PubMed  PubMed Central  Google Scholar  * Hedstrom, A. K. _ et al_. Interaction between

adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. _Neurology_ 82, 865–872 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Gianfrancesco, M. A. _ et

al_. Obesity during childhood and adolescence increases susceptibility to multiple sclerosis after accounting for established genetic and environmental risk factors. _Obes. Res. Clin.

Pract._ 8, e435–447 (2014). Article  PubMed  PubMed Central  Google Scholar  * Langer-Gould, A., Brara, S. M., Beaber, B. E. & Koebnick, C. Childhood obesity and risk of pediatric

multiple sclerosis and clinically isolated syndrome. _Neurology_ 80, 548–552 (2013). Article  PubMed  PubMed Central  Google Scholar  * Hedstrom, A. K., Olsson, T. & Alfredsson, L. Body

mass index during adolescence, rather than childhood, is critical in determining MS risk. _Mult. Scler._ 22, 878–883 (2016). Article  CAS  PubMed  Google Scholar  * Wesnes, K. _ et al_. Body

size and the risk of multiple sclerosis in Norway and Italy: the EnvIMS study. _Mult. Scler._ 21, 388–395 (2015). Article  PubMed  Google Scholar  * Mokry, L. E. _ et al_. Obesity and

multiple sclerosis: a Mendelian randomization study. _PLoS Med._ 13, e1002053 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Gianfrancesco, M. A. _ et al_. Genetic variants

associated with body mass index demonstrate a causal effect on multiple sclerosis susceptibility. _Am. J. Epidemiol._ In press http://dx.doi.org/10.1093/aje/kww120 (2016). * Lumeng, C. N.,

Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. _J. Clin. Invest._ 117, 175–184 (2007). Article  CAS  PubMed  PubMed Central

  Google Scholar  * Procaccini, C., Pucino, V., Mantzoros, C. S. & Matarese, G. Leptin in autoimmune diseases. _Metabolism_ 64, 92–104 (2015). Article  CAS  PubMed  Google Scholar  *

Matarese, G. _ et al_. Leptin increase in multiple sclerosis associates with reduced number of CD4+CD25+ regulatory T cells. _Proc. Natl Acad. Sci. USA._ 102, 5150–5155 (2005). Article  CAS

  PubMed  Google Scholar  * Matarese, G., Carrieri, P. B., Montella, S., De Rosa, V. & La Cava, A. Leptin as a metabolic link to multiple sclerosis. _Nat. Rev. Neurol._ 6, 455–461

(2010). Article  CAS  PubMed  Google Scholar  * Wortsman, J., Matsuoka, L. Y., Chen, T. C., Lu, Z. & Holick, M. F. Decreased bioavailability of vitamin D in obesity. _Am. J. Clin. Nutr._

72, 690–693 (2000). Article  CAS  PubMed  Google Scholar  * Karlsson, E. A. & Beck, M. A. The burden of obesity on infectious disease. _Exp. Biol. Med. (Maywood)_ 235, 1412–1424 (2010).

Article  CAS  Google Scholar  * Paich, H. A. _ et al_. Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 influenza A virus. _Obesity (Silver

Spring)_ 21, 2377–2386 (2013). Article  CAS  Google Scholar  * Magrini, A. _ et al_. Shift work and autoimmune thyroid disorders. _Int. J. Immunopathol. Pharmacol._ 19, 31–36 (2006). CAS 

PubMed  Google Scholar  * Hedstrom, A. K., Akerstedt, T., Hillert, J., Olsson, T. & Alfredsson, L. Shift work at young age is associated with increased risk for multiple sclerosis. _Ann.

Neurol._ 70, 733–741 (2011). Article  PubMed  Google Scholar  * Hedstrom, A., Akerstedt, T., Olsson, T. & Alfredsson, L. Shift work influences multiple sclerosis risk. _Mult. Scler._

21, 1195–1199 (2015). Article  CAS  PubMed  Google Scholar  * Hansson, I., Holmdahl, R. & Mattsson, R. Constant darkness enhances autoimmunity to type II collagen and exaggerates

development of collagen-induced arthritis in DBA/1 mice. _J. Neuroimmunol._ 27, 79–84 (1990). Article  CAS  PubMed  Google Scholar  * Farez, M. F. _ et al_. Melatonin contributes to the

seasonality of multiple sclerosis relapses. _Cell_ 162, 1338–1352 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  * Hansson, I., Holmdahl, R. & Mattsson, R. Pinealectomy

ameliorates collagen II-induced arthritis in mice. _Clin. Exp. Immunol._ 92, 432–436 (1993). Article  CAS  PubMed  PubMed Central  Google Scholar  * Massa, J., O'Reilly, E. J., Munger,

K. L. & Ascherio, A. Caffeine and alcohol intakes have no association with risk of multiple sclerosis. _Mult. Scler._ 19, 53–58 (2013). Article  CAS  PubMed  Google Scholar  * Hedstrom,

A. K., Hillert, J., Olsson, T. & Alfredsson, L. Alcohol as a modifiable lifestyle factor affecting multiple sclerosis risk. _JAMA Neurol._ 71, 300–305 (2014). Article  PubMed  Google

Scholar  * Kallberg, H. _ et al_. Alcohol consumption is associated with decreased risk of rheumatoid arthritis: results from two Scandinavian case-control studies. _Ann. Rheum. Dis._ 68,

222–227 (2009). Article  CAS  PubMed  Google Scholar  * Hedstrom, A. K. _ et al_. High consumption of coffee is associated with decreased multiple sclerosis risk; results from two

independent studies. _J. Neurol. Neurosurg. Psychiatry_ 87, 454–460 (2016). Article  CAS  PubMed  PubMed Central  Google Scholar  * Chen, G. Q. _ et al_. Chronic caffeine treatment

attenuates experimental autoimmune encephalomyelitis induced by guinea pig spinal cord homogenates in Wistar rats. _Brain Res._ 1309, 116–125 (2010). Article  CAS  PubMed  Google Scholar  *

Horrigan, L. A., Kelly, J. P. & Connor, T. J. Immunomodulatory effects of caffeine: friend or foe? _Pharmacol. Ther._ 111, 877–892 (2006). Article  CAS  PubMed  Google Scholar  *

Kleinewietfeld, M. _ et al_. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. _Nature_ 496, 518–522 (2013). Article  CAS  PubMed  PubMed Central  Google

Scholar  * Wu, C. _ et al_. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. _Nature_ 496, 513–517 (2013). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Farez, M. F., Fiol, M. P., Gaitan, M. I., Quintana, F. J. & Correale, J. Sodium intake is associated with increased disease activity in multiple sclerosis. _J. Neurol. Neurosurg.

Psychiatry_ 86, 26–31 (2015). Article  PubMed  Google Scholar  * Berer, K. _ et al_. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. _Nature_ 479,

538–541 (2011). Article  CAS  PubMed  Google Scholar  * Correale, J. & Farez, M. F. The impact of environmental infections (parasites) on MS activity. _Mult. Scler._ 17, 1162–1169

(2011). Article  CAS  PubMed  Google Scholar  * Zhang, D. _ et al_. Genetic control of individual differences in gene-specific methylation in human brain. _Am. J. Hum. Genet._ 86, 411–419

(2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Liu, Y. _ et al_. GeMes, clusters of DNA methylation under genetic control, can inform genetic and epigenetic analysis of

disease. _Am. J. Hum. Genet._ 94, 485–495 (2014). Article  CAS  PubMed  PubMed Central  Google Scholar  * Gao, X., Jia, M., Zhang, Y., Breitling, L. P. & Brenner, H. DNA methylation

changes of whole blood cells in response to active smoking exposure in adults: a systematic review of DNA methylation studies. _Clin. Epigenetics_ 7, 113 (2015). Article  CAS  PubMed  PubMed

Central  Google Scholar  * Mastronardi, F. G. _ et al_. Increased citrullination of histone H3 in multiple sclerosis brain and animal models of demyelination: a role for tumor necrosis

factor-induced peptidylarginine deiminase 4 translocation. _J. Neurosci._ 26, 11387–11396 (2006). Article  CAS  PubMed  PubMed Central  Google Scholar  * Baranzini, S. E. _ et al_. Genome,

epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. _Nature_ 464, 1351–1356 (2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Pedre, X. _ et

al_. Changed histone acetylation patterns in normal-appearing white matter and early multiple sclerosis lesions. _J. Neurosci._ 31, 3435–3445 (2011). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Graves, M. C. _ et al_. Methylation differences at the HLA-DRB1 locus in CD4+ T-Cells are associated with multiple sclerosis. _Mult. Scler._ 20, 1033–1041 (2014). Article 

CAS  PubMed  Google Scholar  * Huynh, J. L. _ et al_. Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. _Nat. Neurosci._ 17, 121–130 (2014). Article

  CAS  PubMed  Google Scholar  * Bos, S. D. _ et al_. Genome-wide DNA methylation profiles indicate CD8+ T cell hypermethylation in multiple sclerosis. _PLoS ONE_ 10, e0117403 (2015).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Maltby, V. E. _ et al_. Genome-wide DNA methylation profiling of CD8+ T cells shows a distinct epigenetic signature to CD4+ T cells in

multiple sclerosis patients. _Clin. Epigenetics_ 7, 118 (2015). Article  CAS  PubMed  PubMed Central  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS

AND AFFILIATIONS * Neuroimmunology Unit, Center for Molecular Medicine, L8:04, Karolinska University Hospital (Solna), Stockholm, 17176, Sweden Tomas Olsson * 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 * Institute of

Environmental Medicine, Karolinska Institutet, Box 210, Stockholm, 171 77, Sweden Lars Alfredsson Authors * Tomas Olsson View author publications You can also search for this author inPubMed

 Google Scholar * Lisa F. Barcellos View author publications You can also search for this author inPubMed Google Scholar * Lars Alfredsson View author publications You can also search for

this author inPubMed Google Scholar CONTRIBUTIONS 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. ETHICS DECLARATIONS 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. POWERPOINT SLIDES

POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR TABLE 1 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE 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 Download citation * Published: 09 December 2016 * Issue Date: January 2017 * DOI: https://doi.org/10.1038/nrneurol.2016.187 SHARE THIS ARTICLE

Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided

by the Springer Nature SharedIt content-sharing initiative