Mitochondrial genome and risk of multiple sclerosis

Mitochondrial DNA (mtDNA) polymorphism makes a certain contribution to the formation of a genetic risk of multiple sclerosis (MS).

Objective: to analyze the frequency of mtDNA variants in patients with MS and control individuals in the Russian population. A similar study was conducted for the first time.

Patients and methods. The polymorphism of mtDNA was studied in the Russian population: in 283 unrelated patients with relapsing-remitting MS and in 290 unrelated healthy controls matched for gender and age.

Results and discussion. The frequency of haplogroup J in the patients with MS was twice higher than that in the control group (p=0.0055) (odds ratio (OR) 2.00; 95% confidence interval (CI). 1.21–3.41). This association was mostly observed in women (p=0.0083) (OR 2.20; 95% CI, 1.19–4.03). There was also a significant association of the A allele of MT-ND5 (m. 13708G>A) with MS (p=0.03) (OR 1.89; 95% CI 1.11–3.32). Sex stratification showed that the association with MS was significant only in women (p=0.009; OR, 2.52; 95% CI, 1.29–5.14). Further investigations will aim to analyze mtDNA variability (at the level of individual polymorphisms, haplogroups, and whole genome) in patients with relapsing-remitting MS and in those with primary progressive MS versus healthy individuals and patients with relapsing-remitting MS according to disease severity.

Conclusion. The data obtained in the Russian population suggest that mtDNA variations are involved in MS risk, to a greater extent in women. 

1. Goodin DS. The epidemiology of multiple sclerosis: insights to a causal cascade. Handb Clin Neurol. 2016;138:173-206. doi: 10.1016/B978-0-12-802973-2.00011-2.

2. Atlas of MS 2013. http://www.msif.org/wpcontent/uploads/2014/09/Atlas-of-MS.pdf

3. Thompson AJ, Baranzini SE, Geurts J, et al. Multiple sclerosis. Lancet. 2018 Apr 21; 391(10130):1622-1636. doi: 10.1016/S0140- 6736(18)30481-1. Epub 2018 Mar 23.

4. Harirchian MH, Fatehi F, Sarraf P, et al. Worldwide prevalence of familial multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord. 2018 Feb;20:43-47. doi: 10.1016/j.msard.2017.12.015. Epub 2017 Dec 24.

5. Sadovnick AD, Yee IM, Guimond C, et al. Age of onset in concordant twins and other relative pairs with multiple sclerosis. Am J Epidemiol. 2009 Aug 1;170(3):289-96. doi: 10.1093/aje/kwp143. Epub 2009 Jun 22.

6. Baranzini SE, Oksenberg JR. The genetics of multiple sclerosis: from 0 to 200 in 50 years. Trends Genet. 2017 Dec;33(12):960-970. doi: 10.1016/j.tig.2017.09.004. Epub 2017 Oct 5.

7. Bashinskaya VV, Kulakova OG, Boyko AN, et al. A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches. Hum Genet. 2015 Nov;134(11-12):1143-62. doi: 10.1007/s00439-015-1601-2. Epub 2015 Sep 25.

8. Boiko AN, Gusev EI, Sudomoina MA, et al. Association and linkage of juvenile MS with HLA-DR2(15) in Russians. Neurology. 2002 Feb 26;58(4):658-60.

9. Lill CM. Recent advances and future challenges in the genetics of multiple sclerosis. Front Neurol. 2014 Jul 14;5:130. doi: 10.3389/fneur.2014.00130. eCollection 2014.

10. Baulina N, Kulakova O, Kiselev I, et al . Immune-related miRNA expression patterns in peripheral blood mononuclear cells differ in multiple sclerosis relapse and remission. J Neuroimmunol. 2018 Apr 15;317:67-76. doi: 10.1016/j.jneuroim.2018.01.005. Epub 2018 Jan 5.

11. Kulakova OG, Kabilov MR, Danilova LV, et al. Whole-genome DNA methylation analysis of peripheral blood mononuclear cells in multiple sclerosis patients with different disease courses. Acta Naturae. 2016 Jul-Sep;8(3):103-110.

12. Kiselev I, Bashinskaya V, Kulakova O, et al. Variants of microRNA genes: gender-specific associations with multiple sclerosis risk and severity. Int J Mol Sci. 2015 Aug 24;16(8): 20067-81. doi: 10.3390/ijms160820067.

13. Veit Rothhammer V, Quintana FJ. Environmental control of autoimmune inflammation in the central nervous system. Curr Opin Immunol. 2016 Dec;43:46-53. doi: 10.1016/j.coi.2016.09.002. Epub 2016 Oct 4.

14. Campbell GR, Ziabreva I, Reeve AK, et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol. 2011 Mar;69(3):481-92. doi: 10.1002/ana.22109. Epub 2010 Nov 8.

15. Huang Y, Halliday GM. Aspects of innate immunity and Parkinson's disease. Front Pharmacol. 2012 Mar 8;3:33. doi: 10.3389/fphar.2012.00033. eCollection 2012.

16. McGuire PJ. Mitochondrial dysfunction and the aging immune system. Biology (Basel). 2019 May 11;8(2). pii: E26. doi: 10.3390/biology8020026.

17. Pacella I, Piconese S. Immunometabolic checkpoints of Treg dynamics: adaptation to microenvironmental opportunities and challenges. Front Immunol. 2019 Aug 27;10: 1889. doi: 10.3389/fimmu.2019.01889. eCollection 2019.

18. Varhaug KN, Vedeler CA, Myhr KM, et al. Increased levels of cell-free mitochondrial DNA in the cerebrospinal fluid of patients with multiple sclerosis. Mitochondrion. 2017 May;34:32-35. doi: 10.1016/j.mito.2016.12.003. Epub 2016 Dec 23.

19. Lowes H, Pyle A, Duddy M, Hudson G. Cell-free mitochondrial DNA in progressive multiple sclerosis. Mitochondrion. 2019 May;46: 307-312. doi: 10.1016/j.mito.2018.07.008. Epub 2018 Aug 8.

20. DeBalsi KL, Hoff KE, Copeland WC. Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res Rev. 2017 Jan;33:89-104. doi: 10.1016/j.arr.2016.04.006. Epub 2016 Apr 30.

21. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292-302. doi: 10.1002/ana.22366.

22. Favorova OO, Favorov AV, Boiko AN, et al. Three allele combinations associated with Multiple Sclerosis. BMC Med Genet. 2006 Jul 26;7:63.

23. Kozin MS, Kulakova OO, Kiselev IS, et al. Variants of mitochondrial genome and Risk of Multiple Sclerosis Development in Russians. Acta Naturae. 2018 Oct-Dec;10(4):79-86.

24. Kozin MS, Kulakova OO, Kiselev IS, et al. Combination input of several mitochondrial and nuclear gens in MS risk. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2019;(5):517-8. (In Russ.).

25. Yao L, Xu Z, Wan L. Whole mitochondrial DNA sequencing analysis in 47 Han populations in Southwest China. Med Sci Monit. 2019 Aug 29;25:6482-6490. doi: 10.12659/MSM.916275.

26. Bereiter-Hahn J. Mitochondrial dynamics in aging and disease. Prog Mol Biol Transl Sci. 2014;127:93-131. doi: 10.1016/B978-0-12-394625-6.00004-0.

27. Pakendorf B, Stoneking M. Mitochondrial DNA and human evolution. Annu Rev Genomics Hum Genet. 2005;6:165-83.

28. Hassani-Kumleh H, Houshmand M, Panahi MS, et al. Mitochondrial D-loop variation in Persian multiple sclerosis patients: K and A haplogroups as a risk factor. Cell Mol Neurobiol. 2006 Mar;26(2):119-25. Epub 2006 May 6.

29. Houshmand M, Sanati MH, Babrzadeh F, et al. Population screening for association of mitochondrial haplogroups BM, J, K and M with multiple sclerosis: interrelation between haplogroup J and MS in Persian patients. Mult Scler. 2005 Dec;11(6):728-30.

30. Vyshkina T, Sylvester A, Sadiq S, et al. Association of common mitochondrial DNA variants with multiple sclerosis and systemic lupus erythematosus., Clin Immunol. 2008 Oct; 129(1):31-5. doi: 10.1016/j.clim.2008.07.011. Epub 2008 Aug 16.

31. Yu X, Koczan D, Sulonen AM, et al. mtDNA nt13708A variant increases the risk of multiple sclerosis. PLoS One. 2008 Feb 13;3(2): e1530. doi: 10.1371/journal.pone.0001530.

32. Tranah GJ, Santaniello A, Caillier SJ, et al. Mitochondrial DNA sequence variation in multiple sclerosis. Neurology. 2015 Jul 28;85(4): 325-30. doi: 10.1212/WNL.0000000000001744. Epub 2015 Jul 1.

33. Otaegui D, Saenz A, Martinez-Zabaleta M, et al. Mitochondrial haplogroups in Basque multiple sclerosis patients. Mult Scler. 2004 Oct;10(5):532-5.

34. Mihailova SM, Ivanova MI, Quin LM, Naumova EJ. Mitochondrial DNA variants in Bulgarian patients affected by multiple sclerosis. J Neurol. 2007 Jan;14(1):44-7.

35. Slee M, Finkemeyer J, Krupa M, et al. A novel mitochondrial DNA deletion producing progressive external ophthalmoplegia associated with multiple sclerosis. J Clin Neurosci. 2011 Oct;18(10):1318-24. doi: 10.1016/j.jocn.2011. 02.019. Epub 2011 Jul 26.

36. Wilichowski E, Ohlenbusch A, Hanefeld F. Characterization of the mitochondrial genome in childhood multiple sclerosis. II. Multiple sclerosis without optic neuritis and LHON-associated genes. Neuropediatrics. 1998 Dec;29(6):307-312.

37. Poursadegh Zonouzi A, Ghorbian S, Abkar M, et al. Mitochondrial complex I gene variations; as a potential genetic risk factor in pathogenesis of multiple sclerosis. J Neurol Sci. 2014 Oct 15;345(1-2):220-3. doi: 10.1016/j.jns.2014.07.051. Epub 2014 Jul 28.

38. Andalib S, Emamhadi M, YousefzadehChabok S, et al. MtDNA T4216C variation in multiple sclerosis: a systematic review and meta-analysis. Acta Neurol Belg. 2016 Dec; 116(4):439-443. Epub 2016 Jul 25.

39. Andalib S, Talebi M, Sakhinia E, et al. Mitochondrial DNA T4216C and A4917G variations in Multiple Sclerosis. J Neurol Sci. 2015 Sep 15;356(1-2):55-60. doi: 10.1016/j.jns.2015.04.050. Epub 2015 May 7.

40. Andalib S, Talebi M, Sakhinia E, et al. No evidence of association between optic neuritis and secondary LHON mtDNA mutations in patients with multiple sclerosis. Mitochondrion. 2017 Sep;36:182-185. doi: 10.1016/j.mito.2017.08.005. Epub 2017 Aug 10.

41. Hudson G, Gomez-Duran A, Wilson IJ, Chinnery PF. Recent mitochondrial DNA mutations increase the risk of developing common late-onset human diseases. PLoS Genet. 2014 May 22;10(5):e1004369. doi: 10.1371/journal.pgen.1004369. eCollection 2014 May.

42. Fetisova EK, Muntyan MS, Lyamzaev KG, Chernyak BV. Therapeutic effect of the mitochondria-targeted antioxidant SkQ1 on the culture model of multiple sclerosis. Oxid Med Cell Longev. 2019 Jul 1;2019:2082561. doi: 10.1155/2019/2082561. eCollection 2019.