Advertisement

Molecular Biology

, Volume 53, Issue 4, pp 513–534 | Cite as

Genetic Markers for Personalized Therapy of Polygenic Diseases: Pharmacogenetics of Multiple Sclerosis

  • E. Yu. Tsareva
  • O. O. Favorova
  • A. N. Boyko
  • O. G. KulakovaEmail author
REVIEWS

Abstract

Pharmacogenetics (PG) investigates the inherited variants of the human genome that underlie individual differences in drug metabolic transformation, delivery, and mechanism of action. Not only the contributions of individual genes, but also their cumulative effect should be considered in the case of polygenic diseases, which include the majority of human diseases. Multiple sclerosis (MS) is a severe autoimmune neurodegenerative disorder of the central nervous system (CNS) and is polygenic in nature. Understanding the role that the immune system plays in the pathogenesis of MS helped to design drugs for its pathogenetic therapy. These drugs are known as the disease-modifying treatments (DMTs). Among these are interferon β (IFN-β) and glatiramer acetate (GA), whose treatment efficacy and long-term safety have been proven in many clinical trials. However their efficacy on MS course varies from highly effective to lack of response. Prognostic genetic biomarkers of treatment efficacy can help to identify the MS patient groups where a particular drug is preferential or even strictly indicated to use. The review summarizes the findings from pharmacogenetic studies evaluating the efficacy of IFN-β and GA in MS patients, including the author’s original data.

Keywords:

polygenic diseases allelic polymorphism biomarker epistasis multiple sclerosis pharmacogenetics interferon-β glatiramer acetate 

Notes

ACKNOWLEDGMENTS

We are grateful to I.S. Kiselev for help in manuscript preparation.

FUNDING

This work was supported by the Russian Foundation for Basic Research (project no. 17-00-00206).

COMPLIANCE WITH ETHICAL STANDARDS

Conflict of interests. The authors declare that they have no conflict of interest.

Statement of compliance with standards of research involving humans as subjects. All procedures used in this work were in accordance with the ethical standards of the Institutional Ethics Committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

REFERENCES

  1. 1.
    Kalow W. 2002. Pharmacogenetics and personalised medicine. Fundam. Clin. Pharmacol. 16, 337–342.CrossRefPubMedGoogle Scholar
  2. 2.
    Seredenin S.B. 2004. Lectures in Pharmacogenetics. Moscow: MIA.Google Scholar
  3. 3.
    Stepanov V.A. 2010. Genomes, populations, diseases: Ethnic genomics and personilized medicine. Acta Nature. 4, 18–34.Google Scholar
  4. 4.
    Laing R.E., Hess P., Shen Y., Wang J., Hu S.X. 2011. The role and impact of SNPs in pharmacogenomics and personalized medicine. Curr. Drug. Metab. 12, 460–486.CrossRefPubMedGoogle Scholar
  5. 5.
    Sauna Z.E., Kimchi-Sarfaty C., Ambudkar S.V., Gottesman M.M. 2007. Silent polymorphisms speak: How they affect pharmacogenomics and the treatment of cancer. Cancer Res. 67, 9609–9612.CrossRefPubMedGoogle Scholar
  6. 6.
    Consortium E.P., Birney E., Stamatoyannopoulos J.A., Dutta A., Guigo R., Gingeras T.R., Margulies E.H., Weng Z., Snyder M., Dermitzakis E.T., Thurman R.E., Kuehn M.S., Taylor C.M., Neph S., Koch C.M., et al. 2007. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature. 447, 799–816.CrossRefGoogle Scholar
  7. 7.
    Bashinskaya V.V., Kulakova O.G., Boyko A.N., Favorov A.V., Favorova O.O. 2015. A review of genome-wide association studies for multiple sclerosis: Classical and hypothesis-driven approaches. Hum. Genet. 134, 1143–1162.CrossRefPubMedGoogle Scholar
  8. 8.
    Grossman I., Avidan N., Singer C., Goldstaub D., Hayardeny L., Eyal E., Ben-Asher E., Paperna T., Pe’er I., Lancet D., Beckmann J.S., Miller A. 2007. Pharmacogenetics of glatiramer acetate therapy for multiple sclerosis reveals drug-response markers. Pharmacogenet. Genomics. 17, 657–667.CrossRefPubMedGoogle Scholar
  9. 9.
    Gross R., Healy B.C., Cepok S., Chitnis T., Khoury S.J., Hemmer B., Weiner H.L., Hafler D.A., De Jager P.L. 2011. Population structure and HLA DRB1 1501 in the response of subjects with multiple sclerosis to first-line treatments. J. Neuroimmunol. 233, 168–174.CrossRefPubMedGoogle Scholar
  10. 10.
    Beaulieu M., De Denus S., Lachaine J. 2010. Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 11, 1573–1590.CrossRefPubMedGoogle Scholar
  11. 11.
    King C.R., Porche-Sorbet R.M., Gage B.F., Ridker P.M., Renaud Y., Phillips M.S., Eby C. 2008. Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose. Am. J. Clin. Pathol. 129, 876–883.CrossRefPubMedGoogle Scholar
  12. 12.
    Marin-Leblanc M., Perreault S., Bahroun I., Lapointe M., Mongrain I., Provost S., Turgeon J., Talajic M., Brugada R., Phillips M., Tardif J.C., Dube M.P. 2012. Validation of warfarin pharmacogenetic algorithms in clinical practice. Pharmacogenomics. 13, 21–29.CrossRefPubMedGoogle Scholar
  13. 13.
    Carlquist J.F., Anderson J.L. 2011. Using pharmacogenetics in real time to guide warfarin initiation: A clinician update. Circulation. 124, 2554–2559.CrossRefPubMedGoogle Scholar
  14. 14.
    Wellcome Trust Case Control C., Australo-Anglo-American Spondylitis C., Burton P.R., Clayton D.G., Cardon L.R., Craddock N., Deloukas P., Duncanson A., Kwiatkowski D.P., Mccarthy M.I., Ouwehand W.H., Samani N.J., Todd J.A., Donnelly P., Barrett J.C., et al. 2007. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39 (11), 1329–1337.CrossRefGoogle Scholar
  15. 15.
    Baecher-Allan C., Kaskow B.J., Weiner H.L. 2018. Multiple sclerosis: Mechanisms and immunotherapy. Neuron. 97, 742–768.CrossRefPubMedGoogle Scholar
  16. 16.
    Gusev E.I., Boiko A.N., Zavalishin I.A., Bykova O.V. 2004. Modern epidemiology of multiple sclerosis, in Rasseyannyi skleroz i drugie demieliniziruyushchie zabolevaniya (Multiple Sclerosis and Other Demyelinating Diseases). Eds. Gusev E.I., Zavalishin I.A., Boiko A.N. Moscow: Miklosh, pp. 8–29.Google Scholar
  17. 17.
    Gabibov A.G., Favorova O.O., Kulakova O.G., Boiko A.N., Belogurov A.A., Ponomarenko N.A., Gusev E.I. 2010. Multiple sclerosis, in Neirodegenerativnye zabolevaniya: fundamental’nye i prikladnye aspekty (Neurodegenerative Diseases: Fundamental and Appied Aspects). Ed. Ugryumov M.V. Moscow: Nauka, pp. 382–442.Google Scholar
  18. 18.
    Favorova, O.O., Kulakova O.G., Boiko A.N. 2010. Multiple sclerosis as a polygenic disease: An update. Russ. J. Genet. 46 (3), 265–275.CrossRefGoogle Scholar
  19. 19.
    Bjartmar C., Wujek J.R., Trapp B.D. 2003. Axonal loss in the pathology of MS: Consequences for understanding the progressive phase of the disease. J. Neurol. Sci. 206, 165–171.CrossRefPubMedGoogle Scholar
  20. 20.
    Ascherio A., Munger K.L. 2007. Environmental risk factors for multiple sclerosis: 1. The role of infection. Ann. Neurol. 61, 288–299.CrossRefPubMedGoogle Scholar
  21. 21.
    Ascherio A., Munger K.L. 2007. Environmental risk factors for multiple sclerosis: 2. Noninfectious factors. Ann. Neurol. 61, 504–513.CrossRefPubMedGoogle Scholar
  22. 22.
    Stadelmann C., Wegner C., Bruck W. 2011. Inflammation, demyelination, and degeneration: Recent insights from MS pathology. Biochim. Biophys. Acta. 1812, 275–282.CrossRefPubMedGoogle Scholar
  23. 23.
    Dendrou C.A., Fugger L., Friese M.A. 2015. Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 15, 545–558.CrossRefPubMedGoogle Scholar
  24. 24.
    Tauber S.C., Nau R., Gerber J. 2007. Systemic infections in multiple sclerosis and experimental autoimmune encephalomyelitis. Arch. Physiol. Biochem. 113, 124–130.CrossRefPubMedGoogle Scholar
  25. 25.
    Dobson R., Meier U.C., Giovannoni G. 2011. More to come: Humoral immune responses in MS. J. Neuroimmunol. 240241, 13–21.CrossRefPubMedGoogle Scholar
  26. 26.
    Lassmann H., Bradl M. 2017. Multiple sclerosis: Experimental models and reality. Acta Neuropathol. 133 (2), 223–244.CrossRefPubMedGoogle Scholar
  27. 27.
    Von Budingen H.C., Bar-Or A., Zamvil S.S. 2011. B cells in multiple sclerosis: Connecting the dots. Curr. Opin. Immunol. 23, 713–720.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Soelberg Sorensen P. 2017. Safety concerns and risk management of multiple sclerosis therapies. Acta Neurol. Scand. 136, 168–186.CrossRefPubMedGoogle Scholar
  29. 29.
    Hanson K.A., Agashivala N., Wyrwich K.W., Raimundo K., Kim E., Brandes D.W. 2014. Treatment selection and experience in multiple sclerosis: Survey of neurologists. Patient Prefer Adherence. 8, 415–422.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Uze G., Schreiber G., Piehler J., Pellegrini S. 2007. The receptor of the type I interferon family. Curr. Top. Microbiol. Immunol. 316, 71–95.PubMedGoogle Scholar
  31. 31.
    Jiang H., Milo R., Swoveland P., Johnson K.P., Panitch H., Dhib-Jalbut S. 1995. Interferon beta-1b reduces interferon gamma-induced antigen-presenting capacity of human glial and B cells. J. Neuroimmunol. 61, 17–25.CrossRefPubMedGoogle Scholar
  32. 32.
    Hallal-Longo D.E., Mirandola S.R., Oliveira E.C., Farias A.S., Pereira F.G., Metze I.L., Brandao C.O., Ruocco H.H., Damasceno B.P., Santos L.M. 2007. Diminished myelin-specific T cell activation associated with increase in CTLA4 and Fas molecules in multiple sclerosis patients treated with IFN-beta. J. Interferon Cytokine Res. 27, 865–873.CrossRefPubMedGoogle Scholar
  33. 33.
    Kieseier B.C. 2011. The mechanism of action of interferon-beta in relapsing multiple sclerosis. CNS Drugs. 25, 491–502.CrossRefPubMedGoogle Scholar
  34. 34.
    Namdar A., Nikbin B., Ghabaee M., Bayati A., Izad M. 2010. Effect of IFN-beta therapy on the frequency and function of CD4(+)CD25(+) regulatory T cells and Foxp3 gene expression in relapsing-remitting multiple sclerosis (RRMS): A preliminary study. J. Neuroimmunol. 218, 120–124.CrossRefPubMedGoogle Scholar
  35. 35.
    Korporal M., Haas J., Balint B., Fritzsching B., Schwarz A., Moeller S., Fritz B., Suri-Payer E., Wildemann B. 2008. Interferon beta-induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells. Arch. Neurol. 65, 1434–1439.CrossRefPubMedGoogle Scholar
  36. 36.
    Aristimuno C., De Andres C., Bartolome M., De Las Heras V., Martinez-Gines M.L., Arroyo R., Fernandez-Cruz E., Sanchez-Ramon S. 2010. IFNbeta-1a therapy for multiple sclerosis expands regulatory CD8+ T cells and decreases memory CD8+ subset: A longitudinal 1-year study. Clin. Immunol. 134, 148–157.CrossRefPubMedGoogle Scholar
  37. 37.
    Waubant E., Goodkin D., Bostrom A., Bacchetti P., Hietpas J., Lindberg R., Leppert D. 2003. IFNbeta lowers MMP-9/TIMP-1 ratio, which predicts new enhancing lesions in patients with SPMS. Neurology. 60, 52–57.CrossRefPubMedGoogle Scholar
  38. 38.
    Teleshova N., Pashenkov M., Huang Y.M., Soderstrom M., Kivisakk P., Kostulas V., Haglund M., Link H. 2002. Multiple sclerosis and optic neuritis: CCR5 and CXCR3 expressing T cells are augmented in blood and cerebrospinal fluid. J. Neurol. 249, 723–729.CrossRefPubMedGoogle Scholar
  39. 39.
    Biernacki K., Antel J.P., Blain M., Narayanan S., Arnold D.L., Prat A. 2005. Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis. Arch. Neurol. 62, 563–568.CrossRefPubMedGoogle Scholar
  40. 40.
    Arnon R. 1996. The development of Cop 1 (Copaxone), an innovative drug for the treatment of multiple sclerosis: Personal reflections. Immunol. Lett. 50, 1–15.CrossRefPubMedGoogle Scholar
  41. 41.
    Duda P.W., Schmied M.C., Cook S.L., Krieger J.I., Hafler D.A. 2000. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J. Clin. Invest. 105, 967–976.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Vieira P.L., Heystek H.C., Wormmeester J., Wierenga E.A., Kapsenberg M.L. 2003. Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. J. Immunol. 170, 4483–4488.CrossRefPubMedGoogle Scholar
  43. 43.
    Chen M., Gran B., Costello K., Johnson K., Martin R., Dhib-Jalbut S. 2001. Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS. Mult. Scler. 7, 209–219.CrossRefPubMedGoogle Scholar
  44. 44.
    Weder C., Baltariu G.M., Wyler K.A., Gober H.J., Lienert C., Schluep M., Radu E.W., De Libero G., Kappos L., Duda P.W. 2005. Clinical and immune responses correlate in glatiramer acetate therapy of multiple sclerosis. Eur. J. Neurol. 12, 869–878.CrossRefPubMedGoogle Scholar
  45. 45.
    Teitelbaum D., Milo R., Arnon R., Sela M. 1992. Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein. Proc. Natl. Acad. Sci. U. S. A. 89, 137–141.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Fridkis-Hareli M., Teitelbaum D., Gurevich E., Pecht I., Brautbar C., Kwon O.J., Brenner T., Arnon R., Sela M. 1994. Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells: Specificity and promiscuity. Proc. Natl. Acad. Sci. U. S. A. 91, 4872–4876.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Haas J., Korporal M., Balint B., Fritzsching B., Schwarz A., Wildemann B. 2009. Glatiramer acetate improves regulatory T-cell function by expansion of naive CD4(+)CD25(+)FOXP3(+)CD31(+) T-cells in patients with multiple sclerosis. J. Neuroimmunol. 216, 113–117.CrossRefPubMedGoogle Scholar
  48. 48.
    Hong J., Li N., Zhang X., Zheng B., Zhang J.Z. 2005. Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Proc. Natl. Acad. Sci. U. S. A. 102, 6449–6454.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Tennakoon D.K., Mehta R.S., Ortega S.B., Bhoj V., Racke M.K., Karandikar N.J. 2006. Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis. J. Immunol. 176, 7119–7129.CrossRefPubMedGoogle Scholar
  50. 50.
    Karandikar N.J., Crawford M.P., Yan X., Ratts R.B., Brenchley J.M., Ambrozak D.R., Lovett-Racke A.E., Frohman E.M., Stastny P., Douek D.C., Koup R.A., Racke M.K. 2002. Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in patients with multiple sclerosis. J. Clin. Invest. 109, 641–649.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Kala M., Rhodes S.N., Piao W.H., Shi F.D., Campagnolo D.I., Vollmer T.L. 2010. B cells from glatiramer acetate-treated mice suppress experimental autoimmune encephalomyelitis. Exp. Neurol. 221, 136–145.CrossRefPubMedGoogle Scholar
  52. 52.
    Ure D.R., Rodriguez M. 2002. Polyreactive antibodies to glatiramer acetate promote myelin repair in murine model of demyelinating disease. FASEB J. 16, 1260–1262.CrossRefPubMedGoogle Scholar
  53. 53.
    Aharoni R., Kayhan B., Eilam R., Sela M., Arnon R. 2003. Glatiramer acetate-specific T cells in the brain express T helper 2/3 cytokines and brain-derived neurotrophic factor in situ. Proc. Natl. Acad. Sci. U. S. A. 100, 14157–14162.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Ziemssen T., Kumpfel T., Schneider H., Klinkert W.E., Neuhaus O., Hohlfeld R. 2005. Secretion of brain-derived neurotrophic factor by glatiramer acetate-reactive T-helper cell lines: Implications for multiple sclerosis therapy. J. Neurol. Sci. 233, 109–112.CrossRefPubMedGoogle Scholar
  55. 55.
    Racke M.K., Lovett-Racke A.E., Karandikar N.J. 2010. The mechanism of action of glatiramer acetate treatment in multiple sclerosis. Neurology. 74 (Suppl. 1), S25–S30.CrossRefPubMedGoogle Scholar
  56. 56.
    Kappos L., Weinshenker B., Pozzilli C., Thompson A.J., Dahlke F., Beckmann K., Polman C., McFarland H., European Interferon Beta-1b in Secondary Progressive Multiple Sclerosis Trial Steering Committee, Independent Advisory Board, North American Interferon Beta-1b in Secondary Progressive Multiple Sclerosis Trial Steering Committee. Independent Advisory B. 2004. Interferon beta-1b in secondary progressive MS: A combined analysis of the two trials. Neurology. 63, 1779–1787.CrossRefPubMedGoogle Scholar
  57. 57.
    Kappos L., Traboulsee A., Constantinescu C., Eralinna J.P., Forrestal F., Jongen P., Pollard J., Sandberg-Wollheim M., Sindic C., Stubinski B., Uitdehaag B., Li D. 2006. Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology. 67, 944–953.CrossRefPubMedGoogle Scholar
  58. 58.
    Boiko A.N. Khachanova N.V., Buglak A.V., Demina T.L., Belyaeva I.A., Lashch N.V., Serkov S.V., Gusev E.I. 2000. Possibiliuties of using clinical genetic parameters and magnetic resonance tomography data for predicting the effects of multiple sclerosis treatment with beta-interferon-1b. Zh Nevrol. Psikhiatr. im. S.S. Korsakova. 100, 53–59.PubMedGoogle Scholar
  59. 59.
    Fusco C., Andreone V., Coppola G., Luongo V., Guerini F., Pace E., Florio C., Pirozzi G., Lanzillo R., Ferrante P., Vivo P., Mini M., Macri M., Orefice G., Lombardi M.L. 2001. HLA-DRB1*1501 and response to copolymer-1 therapy in relapsing-remitting multiple sclerosis. Neurology. 57, 1976–1979.CrossRefPubMedGoogle Scholar
  60. 60.
    Wergeland S., Beiske A., Nyland H., Hovdal H., Jensen D., Larsen J.P., Maroy T.H., Smievoll A.I., Vede-ler C.A., Myhr K.M. 2005. IL-10 promoter haplotype influence on interferon treatment response in multiple sclerosis. Eur. J. Neurol. 12, 171–175.CrossRefPubMedGoogle Scholar
  61. 61.
    Guerrero A.L., Tejero M.A., Gutierrez F., Martin-Polo J., Iglesias F., Laherran E., Martin-Serradilla J.I., Merino S. 2011. Influence of APOE gene polymorphisms on interferon-beta treatment response in multiple sclerosis. Neurologia. 26, 137–142.CrossRefPubMedGoogle Scholar
  62. 62.
    Bustamante M.F., Morcillo-Suarez C., Malhotra S., Rio J., Leyva L., Fernandez O., Zettl U.K., Killestein J., Brassat D., Garcia-Merino J.A., Sanchez A.J., Urcelay E., Alvarez-Lafuente R., Villar L.M., Alvarez-Cermeno J.C., et al. 2015. Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-beta. Neurol. Neuroimmunol. Neuroinflamm. 2, e154.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Konig I.R. 2011. Validation in genetic association studies. Brief. Bioinform. 12, 253–258.CrossRefPubMedGoogle Scholar
  64. 64.
    Vosslamber S., Van Der Voort L.F., Van Den Elskamp I.J., Heijmans R., Aubin C., Uitdehaag B.M., Crusius J.B., Van Der Pouw Kraan T.C., Comabella M., Montalban X., Hafler D.A., De Jager P.L., Killestein J., Polman C.H., Verweij C.L. 2011. Interferon regulatory factor 5 gene variants and pharmacological and clinical outcome of Interferon-β therapy in multiple sclerosis. Genes Immun. 12, 466–472.CrossRefPubMedGoogle Scholar
  65. 65.
    Vandenbroeck K., Alloza I., Swaminathan B., Antiguedad A., Otaegui D., Olascoaga J., Barcina M.G., De Las Heras V., Bartolome M., Fernandez-Arquero M., Arroyo R., Alvarez-Lafuente R., Cenit M.C., Urcelay E. 2011. Validation of IRF5 as multiple sclerosis risk gene: Putative role in interferon beta therapy and human herpes virus-6 infection. Genes Immun. 12, 40–45.CrossRefPubMedGoogle Scholar
  66. 66.
    Lopez-Gomez C., Pino-Angeles A., Orpez-Zafra T., Pinto-Medel M.J., Oliver-Martos B., Ortega-Pinazo J., Arnaiz C., Guijarro-Castro C., Varade J., Alvarez-Lafuente R., Urcelay E., Sanchez-Jimenez F., Fernandez O., Leyva L. 2013. Candidate gene study of TRAIL and TRAIL receptors: Association with response to interferon beta therapy in multiple sclerosis patients. PLoS One. 8, e62540.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Kulakova O.G., Tsareva E.Y., Boyko A.N., Shchur S.G., Gusev E.I., Lvovs D., Favorov A.V., Vandenbroeck K., Favorova O.O. 2012. Allelic combinations of immune-response genes as possible composite markers of IFN-β efficacy in multiple sclerosis patients. Pharmacogenomics. 13, 1689–1700.CrossRefPubMedGoogle Scholar
  68. 68.
    Mazdeh M., Taheri M., Sayad A., Bahram S., Omrani M.D., Movafagh A., Inoko H., Akbari M.T., Noroozi R., Hajilooi M., Solgi G. 2016. HLA genes as modifiers of response to IFN-β-1a therapy in relapsing-remitting multiple sclerosis. Pharmacogenomics. 17, 489–498.CrossRefPubMedGoogle Scholar
  69. 69.
    Karam R.A., Rezk N.A., Amer M.M., Fathy H.A. 2016. Immune response genes receptors expression and polymorphisms in relation to multiple sclerosis susceptibility and response to INF-β therapy. IUBMB Life. 68, 727–734.CrossRefPubMedGoogle Scholar
  70. 70.
    Cenit M.D., Blanco-Kelly F., De Las Heras V., Bartolome M., De La Concha E.G., Urcelay E., Arroyo R., Martinez A. 2009. Glypican 5 is an interferon-beta response gene: A replication study. Mult. Scler. 15, 913–917.CrossRefPubMedGoogle Scholar
  71. 71.
    Alvarez-Lafuente R., Blanco-Kelly F., Garcia-Montojo M., Martinez A., De Las Heras V., Dominguez-Mozo M.I., Bartolome M., Garcia-Martinez A., De La Concha E.G., Urcelay E., Arroyo R. 2011. CD46 in a Spanish cohort of multiple sclerosis patients: Genetics, mRNA expression and response to interferon-beta treatment. Mult. Scler. 17, 513–520.CrossRefPubMedGoogle Scholar
  72. 72.
    Cunningham S., Graham C., Hutchinson M., Droogan A., O’rourke K., Patterson C., Mcdonnell G., Hawkins S., Vandenbroeck K. 2005. Pharmacogenomics of responsiveness to interferon IFN-β treatment in multiple sclerosis: A genetic screen of 100 type I interferon-inducible genes. Clin. Pharmacol. Ther. 78, 635–646.CrossRefPubMedGoogle Scholar
  73. 73.
    Torbati S., Karami F., Ghaffarpour M., Zamani M. 2015. Association of CD58 polymorphism with multiple sclerosis and response to interferon ss therapy in a subset of Iranian population. Cell J. 16, 506–513.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Martinez A., De Las Heras V., Mas Fontao A., Bartolome M., De La Concha E.G., Urcelay E., Arroyo R. 2006. An IFNG polymorphism is associated with interferon-beta response in Spanish MS patients. J. Neuroimmunol. 173, 196–199.CrossRefPubMedGoogle Scholar
  75. 75.
    Ristic S., Starcevic Cizmarevic N., Lavtar P., Lovrecic L., Perkovic O., Sepcic J., Sega Jazbec S., Kapovic M., Peterlin B. 2017. Angiotensin-converting enzyme insertion/deletion gene polymorphism and interferon-beta treatment response in multiple sclerosis patients: A preliminary report. Pharmacogenet. Genomics. 27, 232–235.CrossRefPubMedGoogle Scholar
  76. 76.
    Sayad A., Ghafouri-Fard S., Omrani M.D., Noroozi R., Taheri M. 2017. Myxovirus resistance protein A (MxA) polymorphism is associated with IFNβ response in Iranian multiple sclerosis patients. Neurol. Sci. 38, 1093–1099.CrossRefPubMedGoogle Scholar
  77. 77.
    Sriram U., Barcellos L.F., Villoslada P., Rio J., Baranzini S.E., Caillier S., Stillman A., Hauser S.L., Montalban X., Oksenberg J.R. 2003. Pharmacogenomic analysis of interferon receptor polymorphisms in multiple sclerosis. Genes Immun. 4, 147–152.CrossRefPubMedGoogle Scholar
  78. 78.
    Malhotra S., Morcillo-Suarez C., Nurtdinov R., Rio J., Sarro E., Moreno M., Castillo J., Navarro A., Montalban X., Comabella M. 2013. Roles of the ubiquitin peptidase USP18 in multiple sclerosis and the response to interferon-beta treatment. Eur. J. Neurol. 20, 1390–1397.CrossRefPubMedGoogle Scholar
  79. 79.
    Villoslada P., Barcellos L.F., Rio J., Begovich A.B., Tintore M., Sastre-Garriga J., Baranzini S.E., Casquero P., Hauser S.L., Montalban X., Oksenberg J.R. 2002. The HLA locus and multiple sclerosis in Spain. Role in disease susceptibility, clinical course and response to interferon-beta. J. Neuroimmunol. 130, 194–201.CrossRefPubMedGoogle Scholar
  80. 80.
    Fernandez O., Fernandez V., Mayorga C., Guerrero M., Leon A., Tamayo J.A., Alonso A., Romero F., Leyva L., Alonso A., Luque G., De Ramon E. 2005. HLA class II and response to interferon-beta in multiple sclerosis. Acta Neurol. Scand. 112, 391–394.CrossRefPubMedGoogle Scholar
  81. 81.
    Comabella M., Fernandez-Arquero M., Rio J., Guinea A., Fernandez M., Cenit M.C., De La Concha E.G., Montalban X. 2009. HLA class I and II alleles and response to treatment with interferon-beta in relapsing-remitting multiple sclerosis. J. Neuroimmunol. 210, 116–119.CrossRefPubMedGoogle Scholar
  82. 82.
    Comabella M., Craig D.W., Morcillo-Suarez C., Rio J., Navarro A., Fernandez M., Martin R., Montalban X. 2009. Genome-wide scan of 500,000 single-nucleotide polymorphisms among responders and nonresponders to interferon beta therapy in multiple sclerosis. Arch. Neurol. 66, 972–978.CrossRefPubMedGoogle Scholar
  83. 83.
    O’Doherty C., Favorov A., Heggarty S., Graham C., Favorova O., Ochs M., Hawkins S., Hutchinson M., O’Rourke K., Vandenbroeck K. 2009. Genetic polymorphisms, their allele combinations and IFN-beta treatment response in Irish multiple sclerosis patients. Pharmacogenomics. 10, 1177–1186.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Platanias L.C. 2005. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5, 375–386.CrossRefPubMedGoogle Scholar
  85. 85.
    Weinstock-Guttman B., Tamano-Blanco M., Bhasi K., Zivadinov R., Ramanathan M. 2007. Pharmacogenetics of MXA SNPs in interferon-beta treated multiple sclerosis patients. J. Neuroimmunol. 182, 236–239.CrossRefPubMedGoogle Scholar
  86. 86.
    Tamura T., Yanai H., Savitsky D., Taniguchi T. 2008. The IRF family transcription factors in immunity and oncogenesis. Annu. Rev. Immunol. 26, 535–584.CrossRefPubMedGoogle Scholar
  87. 87.
    Shusta E.V., Zhu C., Boado R.J., Pardridge W.M. 2002. Subtractive expression cloning reveals high expression of CD46 at the blood-brain barrier. J. Neuropathol. Exp. Neurol. 61, 597–604.CrossRefPubMedGoogle Scholar
  88. 88.
    Astier A.L., Meiffren G., Freeman S., Hafler D.A. 2006. Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis. J. Clin. Invest. 116, 3252–3257.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Falschlehner C., Schaefer U. Walczak H. 2009. Following TRAIL’s path in the immune system. Immunology. 127, 145–154.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Hoffmann O., Zipp F., Weber J.R. 2009. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in central nervous system inflammation. J. Mol. Med. (Berlin). 87, 753–763.CrossRefPubMedGoogle Scholar
  91. 91.
    Stegbauer J., Lee D.H., Seubert S., Ellrichmann G., Manzel A., Kvakan H., Muller D.N., Gaupp S., Rump L.C., Gold R., Linker R.A. 2009. Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system. Proc. Natl. Acad. Sci. U. S. A. 106, 14942–14947.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Platten M., Youssef S., Hur E.M., Ho P.P., Han M.H., Lanz T.V., Phillips L.K., Goldstein M.J., Bhat R., Raine C.S., Sobel R.A., Steinman L. 2009. Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity. Proc. Natl. Acad. Sci. U. S. A. 106, 14948–14953.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Constantinescu C.S., Goodman D.B., Grossman R.I., Mannon L.J., Cohen J.A. 1997. Serum angiotensin-converting enzyme in multiple sclerosis. Arch. Neurol. 54, 1012–1015.CrossRefPubMedGoogle Scholar
  94. 94.
    Kawajiri M., Mogi M., Higaki N., Matsuoka T., Ohyagi Y., Tsukuda K., Kohara K., Horiuchi M., Miki T., Kira J.I. 2009. Angiotensin-converting enzyme (ACE) and ACE2 levels in the cerebrospinal fluid of patients with multiple sclerosis. Mult. Scler. 15, 262–265.CrossRefPubMedGoogle Scholar
  95. 95.
    Leyva L., Fernandez O., Fedetz M., Blanco E., Fernandez V.E., Oliver B., Leon A., Pinto-Medel M.J., Mayorga C., Guerrero M., Luque G., Alcina A., Matesanz F. 2005. IFNAR1 and IFNAR2 polymorphisms confer susceptibility to multiple sclerosis but not to interferon-beta treatment response. J. Neuroimmunol. 163, 165–171.CrossRefPubMedGoogle Scholar
  96. 96.
    Malhotra S., Morcillo-Suarez C., Brassat D., Goertsches R., Lechner-Scott J., Urcelay E., Fernandez O., Drulovic J., Garcia-Merino A., Martinelli Boneschi F., Chan A., Vandenbroeck K., Navarro A., Bustamante M.F., Rio J., et al. 2011. IL28B polymorphisms are not associated with the response to interferon-beta in multiple sclerosis. J. Neuroimmunol. 239, 101–104.CrossRefPubMedGoogle Scholar
  97. 97.
    Malhotra S., Rio J., Urcelay E., Nurtdinov R., Bustamante M.F., Fernandez O., Oliver B., Zettl U., Brassat D., Killestein J., Lechner-Scott J., Drulovic J., Chan A., Martinelli-Boneschi F., Garcia-Merino A., et al. 2015. NLRP3 inflammasome is associated with the response to IFN-β in patients with multiple sclerosis. Brain. 138, 644–652.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Malhotra S., Sorosina M., Rio J., Peroni S., Midaglia L., Villar L.M., Alvarez-Cermeno J.C., Schroeder I., Esposito F., Clarelli F., Zettl U.K., Lechner-Scott J., Spataro N., Navarro A., Comi G., et al. 2018. NLRP3 polymorphisms and response to interferon-beta in multiple sclerosis patients. Mult. Scler. 24, 1507–1510.CrossRefPubMedGoogle Scholar
  99. 99.
    Favorov A.V., Andreewski T.V., Sudomoina M.A., Favorova O.O., Parmigiani G., Ochs M.F. 2005. A Markov chain Monte Carlo technique for identification of combinations of allelic variants underlying complex diseases in humans. Genetics. 171, 2113–2121.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Lvovs D., Favorova O.O., Favorov A.V. 2012. A polygenic approach to treatment of polygenic diseases. Acta Naturae. 4, 62–75.CrossRefGoogle Scholar
  101. 101.
    Byun E., Caillier S.J., Montalban X., Villoslada P., Fernandez O., Brassat D., Comabella M., Wang J., Barcellos L.F., Baranzini S.E., Oksenberg J.R. 2008. Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis. Arch. Neurol. 65, 337–344.CrossRefPubMedGoogle Scholar
  102. 102.
    Mahurkar S., Moldovan M., Suppiah V., Sorosina M., Clarelli F., Liberatore G., Malhotra S., Montalban X., Antiguedad A., Krupa M., Jokubaitis V.G., Mckay F.C., Gatt P.N., Fabis-Pedrini M.J., Martinelli V., et al. 2017. Response to interferon-beta treatment in multiple sclerosis patients: A genome-wide association study. Pharmacogenomics J. 17, 312–318.CrossRefPubMedGoogle Scholar
  103. 103.
    Esposito F., Sorosina M., Ottoboni L., Lim E.T., Replogle J.M., Raj T., Brambilla P., Liberatore G., Guaschino C., Romeo M., Pertel T., Stankiewicz J.M., Martinelli V., Rodegher M., Weiner H.L., et al. 2015. A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity. Ann. Neurol. 78, 115–127.CrossRefPubMedGoogle Scholar
  104. 104.
    Clarelli F., Liberatore G., Sorosina M., Osiceanu A.M., Esposito F., Mascia E., Santoro S., Pavan G., Colombo B., Moiola L., Martinelli V., Comi G., Martinelli-Boneschi F. 2017. Pharmacogenetic study of long-term response to interferon-beta treatment in multiple sclerosis. Pharmacogenomics J. 17, 84–91.CrossRefPubMedGoogle Scholar
  105. 105.
    Ross C.J., Towfic F., Shankar J., Laifenfeld D., Thoma M., Davis M., Weiner B., Kusko R., Zeskind B., Knappertz V., Grossman I., Hayden M.R. 2017. A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis. Genome Med. 9, 50.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Favorova O.O., Bashinskaya V.V., Kulakova O.G., Favorov A.V., Boiko A.N. 2014. Genome-wide association study as a method to analyze the genome architecture in polygenic diseases, with the example of multiple sclerosis. Mol. Biol. (Moscow). 48 (4), 496–507.CrossRefGoogle Scholar
  107. 107.
    Ohgaki R., Van I.S.C., Matsushita M., Hoekstra D., Kanazawa H. 2011. Organellar Na+/H+ exchangers: Novel players in organelle pH regulation and their emerging functions. Biochemistry. 50, 443–450.CrossRefPubMedGoogle Scholar
  108. 108.
    Beydoun R., Hamood M.A., Gomez Zubieta D.M., Kondapalli K.C. 2017. Na(+)/H(+) exchanger 9 regulates iron mobilization at the blood-brain barrier in response to iron starvation. J. Biol. Chem. 292, 4293–4301.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Liu G., Zhang F., Hu Y., Jiang Y., Gong Z., Liu S., Chen X., Jiang Q. Hao J. 2017. Genetic variants and multiple sclerosis risk gene SLC9A9 expression in distinct human brain regions. Mol. Neurobiol. 54, 6820–6826.CrossRefPubMedGoogle Scholar
  110. 110.
    Australia and New Zealand Multiple Sclerosis Genetics C. 2009. Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat. Genet. 41, 824–828.Google Scholar
  111. 111.
    International Multiple Sclerosis Genetics C., Wellcome Trust Case Control C., Sawcer S., Hellenthal G., Pirinen M., Spencer C.C., Patsopoulos N.A., Moutsianas L., Dilthey A., Su Z., Freeman C., Hunt S.E., Edkins S., Gray E., Booth D.R., et al. 2011. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 476, 214–219.Google Scholar
  112. 112.
    Dhib-Jalbut S., Valenzuela R.M., Ito K., Kaufman M., Ann Picone M., Buyske S. 2013. HLA DR and DQ alleles and haplotypes associated with clinical response to glatiramer acetate in multiple sclerosis. Mult. Scler. Relat. Disord. 2, 340–348.CrossRefPubMedGoogle Scholar
  113. 113.
    Alifirova V.M., Orlova Yu.Yu., Babenko S.A., Rudko A.A., Puzyrev V.P. 2006. IL12B gene polymorphism 1188 A/C in patients with multiple sclerosis in Tomsk oblast and possibilities for assessing the efficacy of immunomodulatory therapy. Zh. Nevrol. Psikhiatr. im. S.S. Korsakova. 3, 130–135.Google Scholar
  114. 114.
    Tsareva E., Kulakova O.G., Makarycheva O., Boiko A.N., Shchur S.G., Lashch N., Popova N.F., Gusev E.I., Bashinskaia V.V., L’vov D V., Favorov A.V., Ochs M.F., Favorova O.O. 2011. Pharmacogenomics of multiple sclerosis: Association of immune response genes polymorphism with copaxone treatment efficacy. Mol. Biol. (Moscow). 45, 886–893.CrossRefGoogle Scholar
  115. 115.
    Kulakova O., Bashinskaya V., Kiselev I., Baulina N., Tsareva E., Nikolaev R., Kozin M., Shchur S., Favo-rov A., Boyko A., Favorova O. 2017. Pharmacogenetics of glatiramer acetate therapy for multiple sclerosis: the impact of genome-wide association studies identified disease risk loci. Pharmacogenomics. 18, 1563–1574.CrossRefPubMedGoogle Scholar
  116. 116.
    Tsareva E.Y., Kulakova O.G., Boyko A.N., Shchur S.G., Lvovs D., Favorov A.V., Gusev E.I., Vandenbroeck K., Favorova O.O. 2012. Allelic combinations of immune-response genes associated with glatiramer acetate treatment response in Russian multiple sclerosis patients. Pharmacogenomics. 13, 43–53.CrossRefPubMedGoogle Scholar
  117. 117.
    Barsova R.M., Lvovs D., Titov B.V., Matveeva N.A., Shakhnovich R.M., Sukhinina T.S., Kukava N.G., Ruda M.Y., Karamova I.M., Nasibullin T.R., Mustafina O.E., Osmak G.J., Tsareva E.Y., Kulakova O.G., Favorov A.V., Favorova O.O. 2015. Variants of the coagulation and inflammation genes are replicably associated with myocardial infarction and epistatically interact in Russians. PLoS One. 10, e0144190.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Kulakova O.G., Tsareva E.Y., Lvovs D., Favorov A.V., Boyko A.N., Favorova O.O. 2014. Comparative pharmacogenetics of multiple sclerosis: IFN-β versus glatiramer acetate. Pharmacogenomics. 15, 679–685.CrossRefPubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2019

Authors and Affiliations

  • E. Yu. Tsareva
    • 1
  • O. O. Favorova
    • 1
  • A. N. Boyko
    • 1
  • O. G. Kulakova
    • 1
    Email author
  1. 1.Pirogov Russian National Research Medical University, Ministry of Health of the Russian FederationMoscowRussia

Personalised recommendations