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Genetics and Epigenetics of Multiple Sclerosis

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Epigenetics and Gene Expression in Cancer, Inflammatory and Immune Diseases

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

Multiple sclerosis (MS), a chronic inflammatory neurodegenerative disease of the central nervous system (CNS), mainly affects young adults between 20 and 40 years of age and, therefore, presents an important health burden in the active population. Disease etiology is still largely unknown and different “omic” approaches, some of them available only in the last few years, are considered to be of great importance for deciphering the pathophysiology, progression and different subtypes of the disease. Combining results from exome sequencing, genome-wide association studies, transcriptome and epigenome levels, we gained insights into different levels of whole genome cell specific changes. The integratomic approach provides evidence for dysregulated JAK-STAT signaling pathway in MS, which is shown to be different in MS patients when compared to controls in all abovementioned different genome-wide approaches.

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References

  1. Ascherio A (2013) Environmental factors in multiple sclerosis. Expert Rev Neurother 13(12 Suppl):3–9. doi:10.1586/14737175.2013.865866

    Article  PubMed  Google Scholar 

  2. Marrie RA, Cohen J, Stuve O, Trojano M, Sorensen PS, Reingold S, Cutter G, Reider N (2015) A systematic review of the incidence and prevalence of comorbidity in multiple sclerosis: overview. Mult Scler 21(3):263–281. doi:10.1177/1352458514564491

    Article  PubMed  PubMed Central  Google Scholar 

  3. Dyment DA, Yee IM, Ebers GC, Sadovnick AD, Canadian Collaborative Study Group (2006) Multiple sclerosis in stepsiblings: recurrence risk and ascertainment. J Neurol Neurosurg Psychiatry 77(2):258–259. doi:10.1136/jnnp.2005.063008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. O’Gorman C, Lin R, Stankovich J, Broadley SA (2013) Modelling genetic susceptibility to multiple sclerosis with family data. Neuroepidemiology 40(1):1–12. doi:10.1159/000341902

    Article  PubMed  Google Scholar 

  5. Simpson S Jr, Taylor BV, van der Mei I (2015) The role of epidemiology in MS research: past successes, current challenges and future potential. Mult Scler 21(8):969–977. doi:10.1177/1352458515574896

    Article  PubMed  Google Scholar 

  6. Naito S, Namerow N, Mickey MR, Terasaki PI (1972) Multiple sclerosis: association with HL-A3. Tissue Antigens 2(1):1–4

    Article  CAS  PubMed  Google Scholar 

  7. Oksenberg JR, Baranzini SE (2010) Multiple sclerosis genetics—is the glass half full, or half empty? Nat Rev Neurol 6(8):429–437. doi:10.1038/nrneurol.2010.91

    Article  PubMed  Google Scholar 

  8. Sawcer S, Franklin RJ, Ban M (2014) Multiple sclerosis genetics. Lancet Neurol 13(7):700–709. doi:10.1016/S1474-4422(14)70041-9

    Article  CAS  PubMed  Google Scholar 

  9. International Multiple Sclerosis Genetics Consortium, Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357(9):851–862, doi: NEJMoa073493 [pii] 10.1056/NEJMoa073493

    Article  Google Scholar 

  10. Hartmann FJ, Khademi M, Aram J, Ammann S, Kockum I, Constantinescu C, Gran B, Piehl F, Olsson T, Codarri L, Becher B (2014) Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells. Nat Commun 5:5056. doi:10.1038/ncomms6056

    Article  CAS  PubMed  Google Scholar 

  11. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium, Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S, Gray E, Booth DR, Potter SC, Goris A, Band G, Oturai AB, Strange A, Saarela J, Bellenguez C, Fontaine B, Gillman M, Hemmer B, Gwilliam R, Zipp F, Jayakumar A, Martin R, Leslie S, Hawkins S, Giannoulatou E, D’Alfonso S, Blackburn H, Martinelli Boneschi F, Liddle J, Harbo HF, Perez ML, Spurkland A, Waller MJ, Mycko MP, Ricketts M, Comabella M, Hammond N, Kockum I, McCann OT, Ban M, Whittaker P, Kemppinen A, Weston P, Hawkins C, Widaa S, Zajicek J, Dronov S, Robertson N, Bumpstead SJ, Barcellos LF, Ravindrarajah R, Abraham R, Alfredsson L, Ardlie K, Aubin C, Baker A, Baker K, Baranzini SE, Bergamaschi L, Bergamaschi R, Bernstein A, Berthele A, Boggild M, Bradfield JP, Brassat D, Broadley SA, Buck D, Butzkueven H, Capra R, Carroll WM, Cavalla P, Celius EG, Cepok S, Chiavacci R, Clerget-Darpoux F, Clysters K, Comi G, Cossburn M, Cournu-Rebeix I, Cox MB, Cozen W, Cree BA, Cross AH, Cusi D, Daly MJ, Davis E, de Bakker PI, Debouverie M, D’Hooghe MB, Dixon K, Dobosi R, Dubois B, Ellinghaus D, Elovaara I, Esposito F, Fontenille C, Foote S, Franke A, Galimberti D, Ghezzi A, Glessner J, Gomez R, Gout O, Graham C, Grant SF, Guerini FR, Hakonarson H, Hall P, Hamsten A, Hartung HP, Heard RN, Heath S, Hobart J, Hoshi M, Infante-Duarte C, Ingram G, Ingram W, Islam T, Jagodic M, Kabesch M, Kermode AG, Kilpatrick TJ, Kim C, Klopp N, Koivisto K, Larsson M, Lathrop M, Lechner-Scott JS, Leone MA, Leppa V, Liljedahl U, Bomfim IL, Lincoln RR, Link J, Liu J, Lorentzen AR, Lupoli S, Macciardi F, Mack T, Marriott M, Martinelli V, Mason D, McCauley JL, Mentch F, Mero IL, Mihalova T, Montalban X, Mottershead J, Myhr KM, Naldi P, Ollier W, Page A, Palotie A, Pelletier J, Piccio L, Pickersgill T, Piehl F, Pobywajlo S, Quach HL, Ramsay PP, Reunanen M, Reynolds R, Rioux JD, Rodegher M, Roesner S, Rubio JP, Ruckert IM, Salvetti M, Salvi E, Santaniello A, Schaefer CA, Schreiber S, Schulze C, Scott RJ, Sellebjerg F, Selmaj KW, Sexton D, Shen L, Simms-Acuna B, Skidmore S, Sleiman PM, Smestad C, Sorensen PS, Sondergaard HB, Stankovich J, Strange RC, Sulonen AM, Sundqvist E, Syvanen AC, Taddeo F, Taylor B, Blackwell JM, Tienari P, Bramon E, Tourbah A, Brown MA, Tronczynska E, Casas JP, Tubridy N, Corvin A, Vickery J, Jankowski J, Villoslada P, Markus HS, Wang K, Mathew CG, Wason J, Palmer CN, Wichmann HE, Plomin R, Willoughby E, Rautanen A, Winkelmann J, Wittig M, Trembath RC, Yaouanq J, Viswanathan AC, Zhang H, Wood NW, Zuvich R, Deloukas P, Langford C, Duncanson A, Oksenberg JR, Pericak-Vance MA, Haines JL, Olsson T, Hillert J, Ivinson AJ, De Jager PL, Peltonen L, Stewart GJ, Hafler DA, Hauser SL, McVean G, Donnelly P, Compston A (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359):214–219. doi:10.1038/nature10251

    Article  Google Scholar 

  12. International Multiple Sclerosis Genetics Consortium, Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A, Cotsapas C, Shah TS, Spencer C, Booth D, Goris A, Oturai A, Saarela J, Fontaine B, Hemmer B, Martin C, Zipp F, D’Alfonso S, Martinelli-Boneschi F, Taylor B, Harbo HF, Kockum I, Hillert J, Olsson T, Ban M, Oksenberg JR, Hintzen R, Barcellos LF, Wellcome Trust Case Control C, International IBDGC, Agliardi C, Alfredsson L, Alizadeh M, Anderson C, Andrews R, Sondergaard HB, Baker A, Band G, Baranzini SE, Barizzone N, Barrett J, Bellenguez C, Bergamaschi L, Bernardinelli L, Berthele A, Biberacher V, Binder TM, Blackburn H, Bomfim IL, Brambilla P, Broadley S, Brochet B, Brundin L, Buck D, Butzkueven H, Caillier SJ, Camu W, Carpentier W, Cavalla P, Celius EG, Coman I, Comi G, Corrado L, Cosemans L, Cournu-Rebeix I, Cree BA, Cusi D, Damotte V, Defer G, Delgado SR, Deloukas P, di Sapio A, Dilthey AT, Donnelly P, Dubois B, Duddy M, Edkins S, Elovaara I, Esposito F, Evangelou N, Fiddes B, Field J, Franke A, Freeman C, Frohlich IY, Galimberti D, Gieger C, Gourraud PA, Graetz C, Graham A, Grummel V, Guaschino C, Hadjixenofontos A, Hakonarson H, Halfpenny C, Hall G, Hall P, Hamsten A, Harley J, Harrower T, Hawkins C, Hellenthal G, Hillier C, Hobart J, Hoshi M, Hunt SE, Jagodic M, Jelcic I, Jochim A, Kendall B, Kermode A, Kilpatrick T, Koivisto K, Konidari I, Korn T, Kronsbein H, Langford C, Larsson M, Lathrop M, Lebrun-Frenay C, Lechner-Scott J, Lee MH, Leone MA, Leppa V, Liberatore G, Lie BA, Lill CM, Linden M, Link J, Luessi F, Lycke J, Macciardi F, Mannisto S, Manrique CP, Martin R, Martinelli V, Mason D, Mazibrada G, McCabe C, Mero IL, Mescheriakova J, Moutsianas L, Myhr KM, Nagels G, Nicholas R, Nilsson P, Piehl F, Pirinen M, Price SE, Quach H, Reunanen M, Robberecht W, Robertson NP, Rodegher M, Rog D, Salvetti M, Schnetz-Boutaud NC, Sellebjerg F, Selter RC, Schaefer C, Shaunak S, Shen L, Shields S, Siffrin V, Slee M, Sorensen PS, Sorosina M, Sospedra M, Spurkland A, Strange A, Sundqvist E, Thijs V, Thorpe J, Ticca A, Tienari P, van Duijn C, Visser EM, Vucic S, Westerlind H, Wiley JS, Wilkins A, Wilson JF, Winkelmann J, Zajicek J, Zindler E, Haines JL, Pericak-Vance MA, Ivinson AJ, Stewart G, Hafler D, Hauser SL, Compston A, McVean G, De Jager P, Sawcer SJ, McCauley JL (2013) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet 45(11):1353–1360. doi:10.1038/ng.2770

    Article  Google Scholar 

  13. Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM, Berlanga-Taylor AJ, Handel A, De Luca GC, Sadovnick AD, Lepage P, Montpetit A, Ebers GC (2011) Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol 70(6):881–886. doi:10.1002/ana.22678

    Article  CAS  PubMed  Google Scholar 

  14. Dyment DA, Cader MZ, Chao MJ, Lincoln MR, Morrison KM, Disanto G, Morahan JM, De Luca GC, Sadovnick AD, Lepage P, Montpetit A, Ebers GC, Ramagopalan SV (2012) Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene. Neurology 79(5):406–411. doi:10.1212/WNL.0b013e3182616fc4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mele M, Ferreira PG, Reverter F, DeLuca DS, Monlong J, Sammeth M, Young TR, Goldmann JM, Pervouchine DD, Sullivan TJ, Johnson R, Segre AV, Djebali S, Niarchou A, Consortium GT, Wright FA, Lappalainen T, Calvo M, Getz G, Dermitzakis ET, Ardlie KG, Guigo R (2015) Human genomics. the human transcriptome across tissues and individuals. Science 348(6235):660–665. doi:10.1126/science.aaa0355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kemppinen AK, Kaprio J, Palotie A, Saarela J (2011) Systematic review of genome-wide expression studies in multiple sclerosis. BMJ Open 1(1), e000053. doi:10.1136/bmjopen-2011-000053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338(5):278–285. doi:10.1056/NEJM199801293380502

    Article  CAS  PubMed  Google Scholar 

  18. van der Valk P, De Groot CJ (2000) Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS. Neuropathol Appl Neurobiol 26(1):2–10

    Article  PubMed  Google Scholar 

  19. Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T (1999) Cortical lesions in multiple sclerosis. Brain 122(Pt 1):17–26

    Article  PubMed  Google Scholar 

  20. Kutzelnigg A, Lassmann H (2005) Cortical lesions and brain atrophy in MS. J Neurol Sci 233(1–2):55–59. doi:10.1016/j.jns.2005.03.027

    Article  PubMed  Google Scholar 

  21. Whitney LW, Becker KG, Tresser NJ, Caballero-Ramos CI, Munson PJ, Prabhu VV, Trent JM, McFarland HF, Biddison WE (1999) Analysis of gene expression in multiple sclerosis lesions using cDNA microarrays. Ann Neurol 46(3):425–428

    Article  CAS  PubMed  Google Scholar 

  22. Whitney LW, Ludwin SK, McFarland HF, Biddison WE (2001) Microarray analysis of gene expression in multiple sclerosis and EAE identifies 5-lipoxygenase as a component of inflammatory lesions. J Neuroimmunol 121(1–2):40–48

    Article  CAS  PubMed  Google Scholar 

  23. Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, Sobel RA, Lock C, Karpuj M, Pedotti R, Heller R, Oksenberg JR, Steinman L (2001) The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294(5547):1731–1735. doi:10.1126/science.1062960

    Article  CAS  PubMed  Google Scholar 

  24. Blom T, Franzen A, Heinegard D, Holmdahl R (2003) Comment on “The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease”. Science 299(5614):1845. doi:10.1126/science.1078985, author reply 1845

    Article  CAS  PubMed  Google Scholar 

  25. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8(5):500–508. doi:10.1038/nm0502-500

    Article  CAS  PubMed  Google Scholar 

  26. Lindberg RL, De Groot CJ, Certa U, Ravid R, Hoffmann F, Kappos L, Leppert D (2004) Multiple sclerosis as a generalized CNS disease—comparative microarray analysis of normal appearing white matter and lesions in secondary progressive MS. J Neuroimmunol 152(1–2):154–167. doi:10.1016/j.jneuroim.2004.03.011

    Article  CAS  PubMed  Google Scholar 

  27. Tajouri L, Mellick AS, Ashton KJ, Tannenberg AEG, Nagra RM, Tourtellotte WW, Griffiths LR (2003) Quantitative and qualitative changes in gene expression patterns characterize the activity of plaques in multiple sclerosis. Mol Brain Res 119(2):170–183. doi:10.1016/j.molbrainres.2003.09.008

    Article  CAS  PubMed  Google Scholar 

  28. Mycko MP, Papoian R, Boschert U, Raine CS, Selmaj KW (2003) cDNA microarray analysis in multiple sclerosis lesions: detection of genes associated with disease activity. Brain 126(Pt 5):1048–1057

    Article  PubMed  Google Scholar 

  29. Mycko MP, Papoian R, Boschert U, Raine CS, Selmaj KW (2004) Microarray gene expression profiling of chronic active and inactive lesions in multiple sclerosis. Clin Neurol Neurosurg 106(3):223–229. doi:10.1016/j.clineuro.2004.02.019

    Article  PubMed  Google Scholar 

  30. Liu X, Lee YS, Yu CR, Egwuagu CE (2008) Loss of STAT3 in CD4+ T cells prevents development of experimental autoimmune diseases. J Immunol 180(9):6070–6076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tsutsui S, Schnermann J, Noorbakhsh F, Henry S, Yong VW, Winston BW, Warren K, Power C (2004) A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. J Neurosci 24(6):1521–1529. doi:10.1523/JNEUROSCI.4271-03.2004

    Article  CAS  PubMed  Google Scholar 

  32. Graumann U, Reynolds R, Steck AJ, Schaeren-Wiemers N (2003) Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol 13(4):554–573

    Article  CAS  PubMed  Google Scholar 

  33. Zeis T, Graumann U, Reynolds R, Schaeren-Wiemers N (2008) Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection. Brain 131(Pt 1):288–303. doi:10.1093/brain/awm291

    PubMed  Google Scholar 

  34. Allen IV, McKeown SR (1979) A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis. J Neurol Sci 41(1):81–91

    Article  CAS  PubMed  Google Scholar 

  35. Dutta R, McDonough J, Yin X, Peterson J, Chang A, Torres T, Gudz T, Macklin WB, Lewis DA, Fox RJ, Rudick R, Mirnics K, Trapp BD (2006) Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 59(3):478–489. doi:10.1002/ana.20736

    Article  CAS  PubMed  Google Scholar 

  36. Dutta R, McDonough J, Chang A, Swamy L, Siu A, Kidd GJ, Rudick R, Mirnics K, Trapp BD (2007) Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients. Brain 130(Pt 10):2566–2576. doi:10.1093/brain/awm206

    Article  PubMed  Google Scholar 

  37. Zeis T, Allaman I, Gentner M, Schroder K, Tschopp J, Magistretti PJ, Schaeren-Wiemers N (2015) Metabolic gene expression changes in astrocytes in multiple sclerosis cerebral cortex are indicative of immune-mediated signaling. Brain Behav Immun. doi: 10.1016/j.bbi.2015.04.013

  38. Pellerin L, Magistretti PJ (2012) Sweet sixteen for ANLS. J Cereb Blood Flow Metab 32(7):1152–1166. doi:10.1038/jcbfm.2011.149

    Article  CAS  PubMed  Google Scholar 

  39. Torkildsen O, Stansberg C, Angelskar SM, Kooi EJ, Geurts JJ, van der Valk P, Myhr KM, Steen VM, Bo L (2010) Upregulation of immunoglobulin-related genes in cortical sections from multiple sclerosis patients. Brain Pathol 20(4):720–729. doi:10.1111/j.1750-3639.2009.00343.x

    Article  CAS  PubMed  Google Scholar 

  40. Chepelev I, Wei G, Tang Q, Zhao K (2009) Detection of single nucleotide variations in expressed exons of the human genome using RNA-Seq. Nucleic Acids Res 37(16), e106. doi:10.1093/nar/gkp507

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kucukali CI, Kurtuncu M, Coban A, Cebi M, Tuzun E (2015) Epigenetics of multiple sclerosis: an updated review. Neuromolecular Med 17(2):83–96. doi:10.1007/s12017-014-8298-6

    Article  CAS  PubMed  Google Scholar 

  42. Ebers GC, Sadovnick AD, Dyment DA, Yee IM, Willer CJ, Risch N (2004) Parent-of-origin effect in multiple sclerosis: observations in half-siblings. Lancet 363(9423):1773–1774. doi:10.1016/S0140-6736(04)16304-6

    Article  CAS  PubMed  Google Scholar 

  43. Ramagopalan SV, Dobson R, Meier UC, Giovannoni G (2010) Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol 9(7):727–739. doi:10.1016/S1474-4422(10)70094-6

    Article  PubMed  Google Scholar 

  44. Niller HH, Tarnai Z, Decsi G, Zsedenyi A, Banati F, Minarovits J (2014) Role of epigenetics in EBV regulation and pathogenesis. Future Microbiol 9(6):747–756. doi:10.2217/fmb.14.41

    Article  CAS  PubMed  Google Scholar 

  45. Calabrese R, Zampieri M, Mechelli R, Annibali V, Guastafierro T, Ciccarone F, Coarelli G, Umeton R, Salvetti M, Caiafa P (2012) Methylation-dependent PAD2 upregulation in multiple sclerosis peripheral blood. Mult Scler 18(3):299–304. doi:10.1177/1352458511421055

    Article  CAS  PubMed  Google Scholar 

  46. Kumagai C, Kalman B, Middleton FA, Vyshkina T, Massa PT (2012) Increased promoter methylation of the immune regulatory gene SHP-1 in leukocytes of multiple sclerosis subjects. J Neuroimmunol 246(1–2):51–57. doi:10.1016/j.jneuroim.2012.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pedre X, Mastronardi F, Bruck W, Lopez-Rodas G, Kuhlmann T, Casaccia P (2011) Changed histone acetylation patterns in normal-appearing white matter and early multiple sclerosis lesions. J Neurosci 31(9):3435–3445. doi:10.1523/JNEUROSCI.4507-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bos SD, Page CM, Andreassen BK, Elboudwarej E, Gustavsen MW, Briggs F, Quach H, Leikfoss IS, Bjolgerud A, Berge T, Harbo HF, Barcellos LF (2015) Genome-wide DNA methylation profiles indicate CD8+ T cell hypermethylation in multiple sclerosis. PLoS One 10(3):e0117403. doi:10.1371/journal.pone.0117403

    Article  PubMed  PubMed Central  Google Scholar 

  49. Baranzini SE, Mudge J, van Velkinburgh JC, Khankhanian P, Khrebtukova I, Miller NA, Zhang L, Farmer AD, Bell CJ, Kim RW, May GD, Woodward JE, Caillier SJ, McElroy JP, Gomez R, Pando MJ, Clendenen LE, Ganusova EE, Schilkey FD, Ramaraj T, Khan OA, Huntley JJ, Luo S, Kwok PY, Wu TD, Schroth GP, Oksenberg JR, Hauser SL, Kingsmore SF (2010) Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis. Nature 464(7293):1351–1356. doi:10.1038/nature08990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Huynh JL, Garg P, Thin TH, Yoo S, Dutta R, Trapp BD, Haroutunian V, Zhu J, Donovan MJ, Sharp AJ, Casaccia P (2014) Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat Neurosci 17(1):121–130. doi:10.1038/nn.3588

    Article  CAS  PubMed  Google Scholar 

  51. Junker JP, Ziegler F, Rief M (2009) Ligand-dependent equilibrium fluctuations of single calmodulin molecules. Science 323(5914):633–637. doi:10.1126/science.1166191

    Article  CAS  PubMed  Google Scholar 

  52. Noorbakhsh F, Ellestad KK, Maingat F, Warren KG, Han MH, Steinman L, Baker GB, Power C (2011) Impaired neurosteroid synthesis in multiple sclerosis. Brain 134(Pt 9):2703–2721. doi:10.1093/brain/awr200

    Article  PubMed  PubMed Central  Google Scholar 

  53. Han MH, Hwang SI, Roy DB, Lundgren DH, Price JV, Ousman SS, et al (2008) Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature. 451:1076.

    Google Scholar 

  54. Frisullo G, Angelucci F, Caggiula M, Nociti V, Iorio R, Patanella AK, Sancricca C, Mirabella M, Tonali PA, Batocchi AP (2006) pSTAT1, pSTAT3, and T-bet expression in peripheral blood mononuclear cells from relapsing-remitting multiple sclerosis patients correlates with disease activity. J Neurosci Res 84(5):1027–1036. doi:10.1002/jnr.20995

    Article  CAS  PubMed  Google Scholar 

  55. Frisullo G, Nociti V, Iorio R, Patanella AK, Marti A, Mirabella M, Tonali PA, Batocchi AP (2008) The persistency of high levels of pSTAT3 expression in circulating CD4+ T cells from CIS patients favors the early conversion to clinically defined multiple sclerosis. J Neuroimmunol 205(1–2):126–134. doi:10.1016/j.jneuroim.2008.09.003

    Article  CAS  PubMed  Google Scholar 

  56. Bright JJ, Du C, Sriram S (1999) Tyrphostin B42 inhibits IL-12-induced tyrosine phosphorylation and activation of Janus kinase-2 and prevents experimental allergic encephalomyelitis. J Immunol 162(10):6255–6262

    CAS  PubMed  Google Scholar 

  57. Liu Y, Holdbrooks AT, De Sarno P, Rowse AL, Yanagisawa LL, McFarland BC, Harrington LE, Raman C, Sabbaj S, Benveniste EN, Qin H (2014) Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis. J Immunol 192(1):59–72. doi:10.4049/jimmunol.1301513

    Article  CAS  PubMed  Google Scholar 

  58. Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Samani NJ, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskivina V, Nikolov I, O’Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Ball SG, Balmforth AJ, Barrett JH, Bishop TD, Iles MM, Maqbool A, Yuldasheva N, Hall AS, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Matthew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Lathrop MG, Connell J, Dominiczak A, Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Biologics in RAG, Genomics Study Syndicate Steering C, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hilder SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B, Frayling TM, Freathy RM, Lango H, Perry JR, Shields BM, Weedon MN, Hattersley AT, Hitman GA, Walker M, Elliott KS, Groves CJ, Lindgren CM, Rayner NW, Timpson NJ, Zeggini E, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Breast Cancer Susceptibility C, Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Newport M, Sirugo G, Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ, Davison D, Ferreira T, Pereira-Gale J, Hallgrimsdo’ttir IB, Howie BN, Su Z, Teo YY, Vukcevic D, Bentley D, Brown MA, Compston A, Farrall M, Hall AS, Hattersley AT, Hill AV, Parkes M, Pembrey M, Stratton MR, Mitchell SL, Newby PR, Brand OJ, Carr-Smith J, Pearce SH, McGinnis R, Keniry A, Deloukas P, Reveille JD, Zhou X, Sims AM, Dowling A, Taylor J, Doan T, Davis JC, Savage L, Ward MM, Learch TL, Weisman MH, Brown M (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39(11):1329–1337. doi: 10.1038/ng.2007.17

  59. Comabella M, Craig DW, Camina-Tato M, Morcillo C, Lopez C, Navarro A, Rio J, Biomarker MSSG, Montalban X, Martin R (2008) Identification of a novel risk locus for multiple sclerosis at 13q31.3 by a pooled genome-wide scan of 500,000 single nucleotide polymorphisms. PLoS One 3(10):e3490, doi: 10.1371/journal.pone.0003490

    Article  PubMed  PubMed Central  Google Scholar 

  60. Aulchenko YS, Hoppenbrouwers IA, Ramagopalan SV, Broer L, Jafari N, Hillert J, Link J, Lundstrom W, Greiner E, Dessa Sadovnick A, Goossens D, Van Broeckhoven C, Del-Favero J, Ebers GC, Oostra BA, van Duijn CM, Hintzen RQ (2008) Genetic variation in the KIF1B locus influences susceptibility to multiple sclerosis. Nat Genet 40(12):1402–1403. doi:10.1038/ng.251

    Article  CAS  PubMed  Google Scholar 

  61. Baranzini SE, Wang J, Gibson RA, Galwey N, Naegelin Y, Barkhof F, Radue EW, Lindberg RL, Uitdehaag BM, Johnson MR, Angelakopoulou A, Hall L, Richardson JC, Prinjha RK, Gass A, Geurts JJ, Kragt J, Sombekke M, Vrenken H, Qualley P, Lincoln RR, Gomez R, Caillier SJ, George MF, Mousavi H, Guerrero R, Okuda DT, Cree BA, Green AJ, Waubant E, Goodin DS, Pelletier D, Matthews PM, Hauser SL, Kappos L, Polman CH, Oksenberg JR (2009) Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet 18(4):767–778, doi:ddn388 [pii] 10.1093/hmg/ddn388

    Article  CAS  PubMed  Google Scholar 

  62. De Jager PL, Jia X, Wang J, de Bakker PI, Ottoboni L, Aggarwal NT, Piccio L, Raychaudhuri S, Tran D, Aubin C, Briskin R, Romano S, International MSGC, Baranzini SE, McCauley JL, Pericak-Vance MA, Haines JL, Gibson RA, Naeglin Y, Uitdehaag B, Matthews PM, Kappos L, Polman C, McArdle WL, Strachan DP, Evans D, Cross AH, Daly MJ, Compston A, Sawcer SJ, Weiner HL, Hauser SL, Hafler DA, Oksenberg JR (2009) Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 41(7):776–782, doi:ng.401 [pii] 10.1038/ng.401

    Article  PubMed  PubMed Central  Google Scholar 

  63. Australia, New Zealand Multiple Sclerosis Genetics Consortium (2009) Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet 41(7):824–828. doi:10.1038/ng.396

    Article  Google Scholar 

  64. Sanna S, Pitzalis M, Zoledziewska M, Zara I, Sidore C, Murru R, Whalen MB, Busonero F, Maschio A, Costa G, Melis MC, Deidda F, Poddie F, Morelli L, Farina G, Li Y, Dei M, Lai S, Mulas A, Cuccuru G, Porcu E, Liang L, Zavattari P, Moi L, Deriu E, Urru MF, Bajorek M, Satta MA, Cocco E, Ferrigno P, Sotgiu S, Pugliatti M, Traccis S, Angius A, Melis M, Rosati G, Abecasis GR, Uda M, Marrosu MG, Schlessinger D, Cucca F (2010) Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis. Nat Genet 42(6):495–497. doi:10.1038/ng.584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nischwitz S, Cepok S, Kroner A, Wolf C, Knop M, Muller-Sarnowski F, Pfister H, Roeske D, Rieckmann P, Hemmer B, Ising M, Uhr M, Bettecken T, Holsboer F, Muller-Myhsok B, Weber F (2010) Evidence for VAV2 and ZNF433 as susceptibility genes for multiple sclerosis. J Neuroimmunol 227(1–2):162–166. doi:10.1016/j.jneuroim.2010.06.003

    Article  CAS  PubMed  Google Scholar 

  66. Jakkula E, Leppa V, Sulonen AM, Varilo T, Kallio S, Kemppinen A, Purcell S, Koivisto K, Tienari P, Sumelahti ML, Elovaara I, Pirttila T, Reunanen M, Aromaa A, Oturai AB, Sondergaard HB, Harbo HF, Mero IL, Gabriel SB, Mirel DB, Hauser SL, Kappos L, Polman C, De Jager PL, Hafler DA, Daly MJ, Palotie A, Saarela J, Peltonen L (2010) Genome-wide association study in a high-risk isolate for multiple sclerosis reveals associated variants in STAT3 gene. Am J Hum Genet 86(2):285–291. doi:10.1016/j.ajhg.2010.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Matesanz F, Gonzalez-Perez A, Lucas M, Sanna S, Gayan J, Urcelay E, Zara I, Pitzalis M, Cavanillas ML, Arroyo R, Zoledziewska M, Marrosu M, Fernandez O, Leyva L, Alcina A, Fedetz M, Moreno-Rey C, Velasco J, Real LM, Ruiz-Pena JL, Cucca F, Ruiz A, Izquierdo G (2012) Genome-wide association study of multiple sclerosis confirms a novel locus at 5p13.1. PLoS One 7(5):e36140. doi:10.1371/journal.pone.0036140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Martinelli-Boneschi F, Esposito F, Brambilla P, Lindstrom E, Lavorgna G, Stankovich J, Rodegher M, Capra R, Ghezzi A, Coniglio G, Colombo B, Sorosina M, Martinelli V, Booth D, Oturai AB, Stewart G, Harbo HF, Kilpatrick TJ, Hillert J, Rubio JP, Abderrahim H, Wojcik J, Comi G (2012) A genome-wide association study in progressive multiple sclerosis. Mult Scler 18(10):1384–1394. doi:10.1177/1352458512439118

    Article  PubMed  Google Scholar 

  69. Mastronardi FG, Noor A, Wood DD, Paton T, Moscarello MA (2007) Peptidyl argininedeiminase 2 CpG island in multiple sclerosis white matter is hypomethylated. J Neurosci Res 85(9):2006–2016. doi:10.1002/jnr.21329

    Article  CAS  PubMed  Google Scholar 

  70. D’Souza CA, Wood DD, She YM, Moscarello MA (2005) Autocatalytic cleavage of myelin basic protein: an alternative to molecular mimicry. Biochemistry 44(38):12905–12913. doi:10.1021/bi051152f

    Article  PubMed  Google Scholar 

  71. Makar KW, Wilson CB (2004) DNA methylation is a nonredundant repressor of the Th2 effector program. J Immunol 173(7):4402–4406

    Article  CAS  PubMed  Google Scholar 

  72. Akimzhanov AM, Yang XO, Dong C (2007) Chromatin remodeling of interleukin-17 (IL-17)-IL-17 F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem 282(9):5969–5972. doi:10.1074/jbc.C600322200

    Article  CAS  PubMed  Google Scholar 

  73. Li H, He Y, Richardson WD, Casaccia P (2009) Two-tier transcriptional control of oligodendrocyte differentiation. Curr Opin Neurobiol 19(5):479–485. doi:10.1016/j.conb.2009.08.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mastronardi FG, Wood DD, Mei J, Raijmakers R, Tseveleki V, Dosch HM, Probert L, Casaccia-Bonnefil P, Moscarello MA (2006) 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(44):11387–11396. doi:10.1523/JNEUROSCI.3349-06.2006

    Article  CAS  PubMed  Google Scholar 

  75. Tegla CA, Cudrici CD, Azimzadeh P, Singh AK, Trippe R 3rd, Khan A, Chen H, Andrian-Albescu M, Royal W 3rd, Bever C, Rus V, Rus H (2013) Dual role of response gene to complement-32 in multiple sclerosis. Exp Mol Pathol 94(1):17–28. doi:10.1016/j.yexmp.2012.09.005

    Article  CAS  PubMed  Google Scholar 

  76. Gao B, Kong Q, Kemp K, Zhao YS, Fang D (2012) Analysis of sirtuin 1 expression reveals a molecular explanation of IL-2-mediated reversal of T-cell tolerance. Proc Natl Acad Sci U S A 109(3):899–904. doi:10.1073/pnas.1118462109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Li K, Seo KH, Gao T, Zheng Q, Qi RQ, Wang H, Weiland M, Dong Z, Mi QS, Zhou L (2011) Invariant NKT cell development and function in microRNA-223 knockout mice. Int Immunopharmacol 11(5):561–568. doi:10.1016/j.intimp.2010.11.004

    Article  CAS  PubMed  Google Scholar 

  78. Junker A, Krumbholz M, Eisele S, Mohan H, Augstein F, Bittner R, Lassmann H, Wekerle H, Hohlfeld R, Meinl E (2009) MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain 132(Pt 12):3342–3352. doi:10.1093/brain/awp300

    Article  PubMed  Google Scholar 

  79. Cox MB, Cairns MJ, Gandhi KS, Carroll AP, Moscovis S, Stewart GJ, Broadley S, Scott RJ, Booth DR, Lechner-Scott J, ANMSG Consortium (2010) MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood. PLoS One 5(8):e12132. doi:10.1371/journal.pone.0012132

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Clinical Institute of Medical Genetics, University Medical Center Ljubljana, Slajmerjeva 3, Ljubljana, 1000, Slovenia

    Borut Peterlin, Ales Maver, Vidmar Lovro & Luca Lovrečić

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  1. Borut Peterlin
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  2. Ales Maver
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  3. Vidmar Lovro
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  4. Luca Lovrečić
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Correspondence to Borut Peterlin .

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  1. Department of Nutrition Science, Purdue University, West Lafayette, Indiana, USA

    Barbara Stefanska

  2. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine University of Liverpool, Liverpool, United Kingdom

    David J. MacEwan

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Peterlin, B., Maver, A., Lovro, V., Lovrečić, L. (2017). Genetics and Epigenetics of Multiple Sclerosis. In: Stefanska, B., MacEwan, D. (eds) Epigenetics and Gene Expression in Cancer, Inflammatory and Immune Diseases. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6743-8_11

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