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 options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    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 

  2. 2

    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 

  3. 3

    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).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Nielsen, N. M. et al. Reproductive history and risk of multiple sclerosis. Epidemiology 22, 546–552 (2011).

    Article  PubMed  Google Scholar 

  5. 5

    Ascherio, A., Munger, K. L. & Lunemann, J. D. The initiation and prevention of multiple sclerosis. Nat. Rev. Neurol. 8, 602–612 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6

    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 

  7. 7

    Sawcer, S. The complex genetics of multiple sclerosis: pitfalls and prospects. Brain 131, 3118–3131 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    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).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    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 

  10. 10

    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 

  11. 11

    Westerlind, H. et al. Identity-by-descent mapping in a Scandinavian multiple sclerosis cohort. Eur. J. Hum. Genet. 23, 688–692 (2015).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    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 

  13. 13

    Gale, C. R. & Martyn, C. N. Migrant studies in multiple sclerosis. Prog. Neurobiol. 47, 425–448 (1995).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Berg-Hansen, P. et al. Prevalence of multiple sclerosis among immigrants in Norway. Mult. Scler. 21, 695–702 (2015).

    Article  PubMed  Google Scholar 

  15. 15

    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 

  16. 16

    Ahlgren, C., Lycke, J., Oden, A. & Andersen, O. High risk of MS in Iranian immigrants in Gothenburg, Sweden. Mult. Scler. 16, 1079–1082 (2010).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    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 

  18. 18

    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 

  19. 19

    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 

  20. 20

    Koch-Henriksen, N. & Sorensen, P. S. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol. 9, 520–532 (2010).

    Article  PubMed  Google Scholar 

  21. 21

    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 

  22. 22

    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 

  23. 23

    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 

  24. 24

    Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    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).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Sawcer, S. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    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 

  28. 28

    Beecham, A. H. et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat. Genet. 45, 1353–1360 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Moutsianas, L. et al. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat. Genet. 47, 1107–1113 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Rothman, K. J., Greenland, S. & Walker, A. M. Concepts of interaction. Am. J. Epidemiol. 112, 467–470 (1980).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    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 

  32. 32

    Hawkes, C. H. Smoking is a risk factor for multiple sclerosis: a metanalysis. Mult. Scler. 13, 610–615 (2007).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Handel, A. E. et al. Smoking and multiple sclerosis: an updated meta-analysis. PLoS ONE 6, e16149 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    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 

  35. 35

    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).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Salzer, J. et al. Smoking as a risk factor for multiple sclerosis. Mult. Scler. 19, 1022–1027 (2013).

    Article  PubMed  Google Scholar 

  37. 37

    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).

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Heydarpour, P. et al. Potential impact of air pollution on multiple sclerosis in Tehran, Iran. Neuroepidemiology 43, 233–238 (2014).

    Article  PubMed  Google Scholar 

  39. 39

    Barragan-Martinez, C. et al. Organic solvents as risk factor for autoimmune diseases: a systematic review and meta-analysis. PLoS ONE 7, e51506 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Hedstrom, A. et al. Smokers run increased risk of developing anti-natalizumab antibodies. Mult. Scler. 20, 1081–1085 (2013).

    Article  CAS  PubMed  Google Scholar 

  41. 41

    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 

  42. 42

    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).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Klareskog, L., Catrina, A. I. & Paget, S. Rheumatoid arthritis. Lancet 373, 659–672 (2009).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    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).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    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).

    CAS  Article  PubMed  Google Scholar 

  46. 46

    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 

  47. 47

    Odoardi, F. et al. T cells become licensed in the lung to enter the central nervous system. Nature 488, 675–679 (2012).

    CAS  Article  PubMed  Google Scholar 

  48. 48

    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 

  49. 49

    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 

  50. 50

    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 

  51. 51

    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 

  52. 52

    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).

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Dendrou, C. A., Fugger, L. & Friese, M. A. Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 15, 545–558 (2015).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    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).

    CAS  Article  PubMed  Google Scholar 

  55. 55

    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 

  56. 56

    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).

    CAS  Article  PubMed  Google Scholar 

  57. 57

    Hedstrom, A. K., Olsson, T. & Alfredsson, L. Smoking is a major preventable risk factor for multiple sclerosis. Mult. Scler. 22, 1021–1026 (2016).

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Sundstrom, P. & Nystrom, L. Smoking worsens the prognosis in multiple sclerosis. Mult. Scler. 14, 1031–1035 (2008).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Correale, J. & Farez, M. F. Smoking worsens multiple sclerosis prognosis: two different pathways are involved. J. Neuroimmunol. 281, 23–34 (2015).

    CAS  Article  PubMed  Google Scholar 

  60. 60

    Di Pauli, F. et al. Smoking is a risk factor for early conversion to clinically definite multiple sclerosis. Mult. Scler. 14, 1026–1030 (2008).

    CAS  Article  PubMed  Google Scholar 

  61. 61

    Healy, B. C. et al. Smoking and disease progression in multiple sclerosis. Arch. Neurol. 66, 858–864 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Hernan, M. A. et al. Cigarette smoking and the progression of multiple sclerosis. Brain 128, 1461–1465 (2005).

    Article  PubMed  Google Scholar 

  63. 63

    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 

  64. 64

    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 

  65. 65

    Zivadinov, R. et al. Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis. Neurology 73, 504–510 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    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 

  67. 67

    Ramanujam, R. et al. Effect of smoking cessation on multiple sclerosis prognosis. JAMA Neurol. 72, 1117–1123 (2015).

    Article  PubMed  Google Scholar 

  68. 68

    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 

  69. 69

    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 

  70. 70

    Sundqvist, E. et al. Epstein-Barr virus and multiple sclerosis: interaction with HLA. Genes Immun. 13, 14–20 (2012).

    CAS  Article  PubMed  Google Scholar 

  71. 71

    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 

  72. 72

    Ascherio, A. & Munger, K. L. EBV and autoimmunity. Curr. Top. Microbiol. Immunol. 390, 365–385 (2015).

    CAS  PubMed  Google Scholar 

  73. 73

    Makhani, N. et al. Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination. Mult. Scler. 22, 385–388 (2016).

    CAS  Article  PubMed  Google Scholar 

  74. 74

    Zhou, Y. et al. Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis. Mult. Scler. (2016).

  75. 75

    Nielsen, T. R. et al. Effects of infectious mononucleosis and HLA-DRB1*15 in multiple sclerosis. Mult. Scler. 15, 431–436 (2009).

    CAS  Article  PubMed  Google Scholar 

  76. 76

    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).

    CAS  Article  PubMed  Google Scholar 

  77. 77

    Serafini, B. et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J. Exp. Med. 204, 2899–2912 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    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 

  79. 79

    Hauser, S. L. et al. B-Cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008).

    CAS  Article  PubMed  Google Scholar 

  80. 80

    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 

  81. 81

    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 

  82. 82

    Waubant, E. et al. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 76, 1989–1995 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    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 

  84. 84

    Sundqvist, E. et al. Cytomegalovirus seropositivity is negatively associated with multiple sclerosis. Mult. Scler. 20, 165–173 (2014).

    CAS  Article  PubMed  Google Scholar 

  85. 85

    Ascherio, A. et al. Epstein–Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 286, 3083–3088 (2001).

    CAS  Article  PubMed  Google Scholar 

  86. 86

    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).

    CAS  Article  PubMed  Google Scholar 

  87. 87

    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 

  88. 88

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    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).

    CAS  Article  PubMed  Google Scholar 

  91. 91

    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).

    CAS  Article  PubMed  Google Scholar 

  92. 92

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    Breuer, J. et al. Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. Ann. Neurol. 75, 739–758 (2014).

    CAS  Article  PubMed  Google Scholar 

  95. 95

    Navid, F. et al. The aryl hydrocarbon receptor is involved in UVR-induced immunosuppression. J. Invest. Dermatol. 133, 2763–2770 (2013).

    CAS  Article  PubMed  Google Scholar 

  96. 96

    Correale, J. & Farez, M. F. Modulation of multiple sclerosis by sunlight exposure: role of cis-urocanic acid. J. Neuroimmunol. 261, 134–140 (2013).

    CAS  Article  PubMed  Google Scholar 

  97. 97

    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).

    CAS  Article  PubMed  Google Scholar 

  98. 98

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    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 

  100. 100

    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 

  101. 101

    Sandberg, L. et al. Vitamin D and axonal injury in multiple sclerosis. Mult. Scler. 22, 1027–1031 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Ueda, P. et al. Neonatal vitamin D status and risk of multiple sclerosis. Ann. Neurol. 76, 338–346 (2014).

    CAS  Article  PubMed  Google Scholar 

  103. 103

    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).

    CAS  Article  PubMed  Google Scholar 

  104. 104

    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 

  105. 105

    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 

  106. 106

    Sundqvist, E. et al. Confirmation of association between multiple sclerosis and CYP27B1. Eur. J. Hum. Genet. 18, 1349–1352 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    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 

  108. 108

    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 

  109. 109

    Handunnetthi, L., Ramagopalan, S. V. & Ebers, G. C. Multiple sclerosis, vitamin D, and HLA-DRB1*15. Neurology 74, 1905–1910 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    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 

  111. 111

    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 

  112. 112

    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 

  113. 113

    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 

  114. 114

    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 

  115. 115

    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 

  116. 116

    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 

  117. 117

    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).

    CAS  Article  PubMed  Google Scholar 

  118. 118

    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 

  119. 119

    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 

  120. 120

    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).

  121. 121

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Procaccini, C., Pucino, V., Mantzoros, C. S. & Matarese, G. Leptin in autoimmune diseases. Metabolism 64, 92–104 (2015).

    CAS  Article  PubMed  Google Scholar 

  123. 123

    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).

    CAS  Article  PubMed  Google Scholar 

  124. 124

    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).

    CAS  Article  PubMed  Google Scholar 

  125. 125

    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).

    CAS  Article  PubMed  Google Scholar 

  126. 126

    Karlsson, E. A. & Beck, M. A. The burden of obesity on infectious disease. Exp. Biol. Med. (Maywood) 235, 1412–1424 (2010).

    CAS  Article  Google Scholar 

  127. 127

    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).

    CAS  Article  Google Scholar 

  128. 128

    Magrini, A. et al. Shift work and autoimmune thyroid disorders. Int. J. Immunopathol. Pharmacol. 19, 31–36 (2006).

    CAS  PubMed  Google Scholar 

  129. 129

    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 

  130. 130

    Hedstrom, A., Akerstedt, T., Olsson, T. & Alfredsson, L. Shift work influences multiple sclerosis risk. Mult. Scler. 21, 1195–1199 (2015).

    CAS  Article  PubMed  Google Scholar 

  131. 131

    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).

    CAS  Article  PubMed  Google Scholar 

  132. 132

    Farez, M. F. et al. Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell 162, 1338–1352 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    Hansson, I., Holmdahl, R. & Mattsson, R. Pinealectomy ameliorates collagen II-induced arthritis in mice. Clin. Exp. Immunol. 92, 432–436 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    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).

    CAS  Article  PubMed  Google Scholar 

  135. 135

    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 

  136. 136

    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).

    CAS  Article  PubMed  Google Scholar 

  137. 137

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    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).

    CAS  Article  PubMed  Google Scholar 

  139. 139

    Horrigan, L. A., Kelly, J. P. & Connor, T. J. Immunomodulatory effects of caffeine: friend or foe? Pharmacol. Ther. 111, 877–892 (2006).

    CAS  Article  PubMed  Google Scholar 

  140. 140

    Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    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 

  143. 143

    Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).

    CAS  Article  PubMed  Google Scholar 

  144. 144

    Correale, J. & Farez, M. F. The impact of environmental infections (parasites) on MS activity. Mult. Scler. 17, 1162–1169 (2011).

    CAS  Article  PubMed  Google Scholar 

  145. 145

    Zhang, D. et al. Genetic control of individual differences in gene-specific methylation in human brain. Am. J. Hum. Genet. 86, 411–419 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    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 

  148. 148

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Baranzini, S. E. et al. Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464, 1351–1356 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. 150

    Pedre, X. et al. Changed histone acetylation patterns in normal-appearing white matter and early multiple sclerosis lesions. J. Neurosci. 31, 3435–3445 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151

    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).

    CAS  Article  PubMed  Google Scholar 

  152. 152

    Huynh, J. L. et al. Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat. Neurosci. 17, 121–130 (2014).

    CAS  Article  PubMed  Google Scholar 

  153. 153

    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 

  154. 154

    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

Affiliations

Authors

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

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

Verify currency and authenticity via CrossMark

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

Further reading

Search

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing