SIGNIFICANCE OF INTERACTIONS BETWEEN GENETIC AND ENVIRONMENTAL FACTORS IN ETIOLOGY OF MULTIPLE SCLEROSIS
Abstract
Multiple sclerosis (MS) is an immune-mediated disorder of central nervous system. It most frequently occurs in young female adults, and the prevalence increases with latitude. So far, over 200 genes, loci and single nucleotide polymorphisms (SNPs) have been linked with MS, although each one contributing only slightly in the overall etiology of the disease. The HLA-DRB1*15:01 haplotype has been shown to have the strongest association with MS occurrence risk in genome-wide association studies (GWAS), while HLA-A*02 has been shown to have a protective effect. The exact etiology of MS is still unclear, but there seems to exist interplay between genetic burden of an individual, and environmental factors which contribute to MS occurrence such as Epstein-Barr virus (EBV) infection, vitamin D levels, smoking status, and early life obesity. An interaction between HLA-DRB1*15:01 and EBV infection, the strongest environmental risk factor for MS, has been observed. It has been suggested that this interaction is a result of HLA-DRB1*15:01 acting as a coreceptor for EBV, thus providing a pathophysiological explanation connecting environmental with genetic MS risk factors. A recent study including participants from two case-control studies with over 13.000 individuals showed that an interaction exists between sun exposure, vitamin D levels, and HLA-DRB*15:01 carrier status, leading to increased risk of MS in individuals with lower sun exposure, vitamin D deficient, and HLA-DRB*15:01 positive. The interaction of HLA-DRB1*15:01 with smoking has been observed in a meta-analysis, while the same study only showed an interaction of smoking with the absence of HLA-A*02 in a subset of studies. The risk of MS has been show to vary in obese individuals, with obese individuals with the susceptible genotype (HLA-DRB1*15:01+, HLA-A*02-) having 16x higher odds of having MS compared with non-obese persons with a non-susceptible genotype.
References
1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-17.
2. Kobelt G, Thompson A, Berg J, Gannedahl M, Eriksson J, MSCOI Study Group, et al. New insights into the burden and costs of multiple sclerosis in Europe. Mult Scler 2017;23:1123–36.
3. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-73.
4. Klineova S, Lublin FD. Clinical Course of Multiple Sclerosis. Cold Spring Harb Perspect Med. 2018;8(9):a028928.
5. The Multiple Sclerosis International Federation, Atlas of MS, 3rd Edition; September, 2020.
6. Hauser SL, Cree BAC. Treatment of Multiple Sclerosis: A Review. Am J Med. 2020;133(12):1380-90.e2.
7. Simpson S Jr, Wang W, Otahal P, Blizzard L, van der Mei IAF, Taylor BV. Latitude continues to be significantly associated with the prevalence of multiple sclerosis: an updated meta-analysis. J Neurol Neurosurg Psychiatry. 2019;90(11):1193-200.
8. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 2007;61:288–99.
9. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Ann Neurol 2007;61:504–13.
10. Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. Lancet Neurol. 2010;9(6):599-612.
11. Hansen T, Skytthe A, Stenager E, Petersen HC, Bronnum-Hansen H, Kyvik KO. Concordance for multiple sclerosis in Danish twins: an update of a nationwide study. Mult Scler 2005;11(5):504-10.
12. Sadovnick AD, Dircks A, Ebers GC. Genetic counselling in multiple sclerosis: risks to sibs and children of affected individuals. Clin Genet 1999;56(2):118-22.
13. Ehtesham N, Rafie MZ, Mosallaei M. The global prevalence of familial multiple sclerosis: an updated systematic review and meta-analysis. BMC Neurol. 2021;21(1):246.
14. International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science 2019;365(6460):eaav7188.
15. Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214-9.
16. Brynedal B, Duvefelt K, Jonasdottir G, Roos IM, Akesson E, Palmgren J, et al. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS One 2007;2:e664.
17. Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol. 2017;13(1):25-36.
18. Ascherio A, Munger KL, Lennette ET, Spiegelman D, Hernán MA, Olek MJ, et al. Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA. 2001;286(24):3083-8.
19. Handel AE, Williamson AJ, Disanto G, Handunnetthi L, Giovannoni G, Ramagopalan SV. An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One 2010;5:e12496.
20. Nielsen TR, Rostgaard K, Nielsen NM, Koch-Henriksen N, Haahr S, Sørensen PS, et al. Multiple sclerosis after infectious mononucleosis. Arch Neurol. 2007;64(1):72-5.
21. Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301.
22. Bjornevik K, Münz C, Cohen JI, Ascherio A. Epstein-Barr virus as a leading cause of multiple sclerosis: mechanisms and implications. Nat Rev Neurol. 2023;19(3):160-71.
23. VanderWeele TJ, Ding P. Sensitivity Analysis in Observational Research: Introducing the E-Value. Ann Intern Med. 2017;167(4):268-74.
24. Jacobs BM, Giovannoni G, Cuzick J, Dobson R. Systematic review and meta-analysis of the association between Epstein-Barr virus, multiple sclerosis and other risk factors. Mult Scler. 2020;26(11):1281-97.
25. Sundqvist E, Sundström P, Lindén M, Hedström AK, Aloisi F, Hillert J, et al. Epstein-Barr virus and multiple sclerosis: interaction with HLA. Genes Immun. 2012;13(1):14-20.
26. Zdimerova H, Murer A, Engelmann C, Raykova A, Deng Y, Gujer C, et al. Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15. Eur J Immunol. 2021;51(1):64-75.
27. Menegatti J, Schub D, Schäfer M, Grässer FA, Ruprecht K. HLA-DRB1*15:01 is a co-receptor for Epstein-Barr virus, linking genetic and environmental risk factors for multiple sclerosis. Eur J Immunol. 2021;51(9):2348-50.
28. Munger KL, Zhang SM, O’Reilly E, Hernan MA, Olek MJ, Willett WC, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004;62:60–5.
29. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. J Am Med Assoc. 2006;296:2832–8.
30. Simpson S Jr, Taylor B, Blizzard L, Ponsonby AL, Pittas F, Tremlett H, et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol. 2010;68(2):193-203.
31. Handunnetthi L, Ramagopalan SV, Ebers GC. Multiple sclerosis, vitamin D, and HLA-DRB1*15. Neurology. 2010;74(23):1905-10.
32. Pierrot-Deseilligny C, Souberbielle JC. Vitamin D and multiple sclerosis: An update. Mult Scler Relat Disord. 2017;14:35-45.
33. Hedström AK, Olsson T, Kockum I, Hillert J, Alfredsson L. Low sun exposure increases multiple sclerosis risk both directly and indirectly. J Neurol. 2020;267(4):1045-52.
34. Ricigliano VA, Handel AE, Sandve GK, Annibali V, Ristori G, Mechelli R, et al. EBNA2 binds to genomic intervals associated with multiple sclerosis and overlaps with vitamin D receptor occupancy. PLoS ONE. 2015;10:e0119605.
35. Brütting C, Stangl GI, Staege MS. Vitamin D, Epstein-Barr virus, and endogenous retroviruses in multiple sclerosis - facts and hypotheses. J Integr Neurosci. 2021;20(1):233-38.
36. Pekmezovic T, Drulovic J, Milenkovic M, Jarebinski M, Stojsavljevic N, Mesaros S, et al. Lifestyle factors and multiple sclerosis: a case-control study in Belgrade. Neuroepidemiology 2006;27:212–16.
37. Manouchehrinia A, Huang J, Hillert J, Alfredsson L, Olsson T, Kockum I, et al. Smoking Attributable Risk in Multiple Sclerosis. Front Immunol. 2022;13:840158.
38. Poorolajal J, Bahrami M, Karami M, Hooshmand E. Effect of smoking on multiple sclerosis: a meta-analysis. J Public Health (Oxf). 2017;39(2):312-20.
39. Hedström AK, Sundqvist E, Bäärnhielm M, Nordin N, Hillert J, Kockum I, et al. Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain. 2011;134(Pt 3):653-64.
40. Sawcer S, Hellenthal G. The major histocompatibility complex and multiple sclerosis: a smoking gun? Brain 2011;134:638–40.
41. Simon KC, van der Mei IA, Munger KL, Ponsonby A, Dickinson J, Dwyer T, et al. Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk. Neurology. 2010;74(17):1365-71.
42. Sundqvist E, Sundström P, Lindén M, Hedström AK, Aloisi F, Hillert J, et al. Lack of replication of interaction between EBNA1 IgG and smoking in risk for multiple sclerosis. Neurology. 2012;79(13):1363-8.
43. Hedström AK, Katsoulis M, Hössjer O, Bomfim IL, Oturai A, Sondergaard HB, et al. The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement. Eur J Epidemiol. 2017;32(10):909-19.
44. Munger KL. Childhood obesity is a risk factor for multiple sclerosis. Mult Scler J. 2013;19:1800.
45. Schreiner TG, Genes TM. Obesity and Multiple Sclerosis-A Multifaceted Association. J Clin Med. 202;10(12):2689.
46. Alfredsson L, Olsson T. Lifestyle and Environmental Factors in Multiple Sclerosis. Cold Spring Harb Perspect Med. 2019;9:a028944.
47. Mokry LE, Ross S, Timpson NJ, Sawcer S, Davey Smith G, Richards JB. Obesity and Multiple Sclerosis: A Mendelian Randomization Study. PLoS Med. 2016;13:e1002053.
48. Harroud A, Mitchell RE, Richardson TG, Morris JA, Forgetta V, Davey Smith G, et al. Childhood obesity and multiple sclerosis: A Mendelian randomization study. Mult Scler J. 2021;27:2150-8.
49. Hedström AK, Lima Bomfim I, Barcellos L, Gianfrancesco M, Schaefer C, Kockum I, et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology. 2014;82(10):865-72.
50. Zeng R, Jiang R, Huang W, Wang J, Zhang L, Ma Y, et al. Dissecting shared genetic architecture between obesity and multiple sclerosis. EBioMedicine. 2023;93:104647.
51. Hedström AK, Lima Bomfim I, Hillert J, Olsson T, Alfredsson L. Obesity interacts with infectious mononucleosis in risk of multiple sclerosis. Eur J Neurol. 2015;22(3):578-e38.
52. O'Gorman C, Lucas R, Taylor B. Environmental risk factors for multiple sclerosis: a review with a focus on molecular mechanisms. Int J Mol Sci. 2012;13(9):11718-52.
53. Maple PA, Ascherio A, Cohen JI, Cutter G, Giovannoni G, Shannon-Lowe C, et al. The Potential for EBV Vaccines to Prevent Multiple Sclerosis. Front Neurol. 2022;13:887794.
54. Aloisi F, Giovannoni G, Salvetti M. Epstein-Barr virus as a cause of multiple sclerosis: opportunities for prevention and therapy. Lancet Neurol. 2023;22(4):338-49.
55. Ascherio A, Munger KL. Epidemiology of multiple sclerosis: from risk factors to prevention-an update. Semin Neurol. 2016;36:103–14.
56. Tremlett H, Munger KL, Makhani N. The Multiple Sclerosis Prodrome: Evidence to Action. Front Neurol. 2022;12:761408.
57. Zhao Y, Wijnands JMA, Hogg T, Kingwell E, Zhu F, Evans C, et al. Interrogation of the multiple sclerosis prodrome using high-dimensional health data. Neuroepidemiology. 2020;54:140.
58. Yusuf F, Wijnands JM, Kingwell E, Zhu F, Evans C, Fisk JD, et al. Fatigue, sleep disorders, anaemia and pain in the multiple sclerosis prodrome. Mult Scler. 2021;27:290–302.