CC BY 4.0 · Glob Med Genet 2023; 10(03): 164-171
DOI: 10.1055/s-0043-1771001
Original Article

ADAR Expression and Single Nucleotide Variants in Multiple Sclerosis Patients Affect the Response to Interferon Beta Therapy

Fatemeh Fakhr
1   Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Vahid Shaygannejad
2   Department of Neurosciences Research Center, Alzahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
Mehdi Khorrami
1   Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Leila Saberi
1   Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Omid Mirmosayyeb
2   Department of Neurosciences Research Center, Alzahra Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
Erfan Sadeghi
3   Department of Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
4   Department of Biostatistics and Epidemiology, Faculty of Health, Isfahan University of Medical Sciences, Isfahan, Iran
Majid Kheirollahi
1   Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
› Author Affiliations
Funding The project was supported by deputies of research of Isfahan University of Medical Sciences. All procedures performed in studies involving human participants were in accordance with the Ethics Committee of Isfahan Neurosciences Research Center (Code of Ethics: IR.MUI.MED.REC.1398.524) and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.


Interferon (IFN)-β is the first-line disease management choice in multiple sclerosis (MS) with profound effects; however, in up to 50% of patients, clinical response does not occur. Ascertaining the responding state, need a long-term clinical follow-up, and this may lead to delay in use of other effective medications. IFN-induced cascade and its regulation is considered to play a major role in MS. Adenosine deaminase, RNA-specific (ADAR) dysregulation is important to IFN signaling pathway as an activity suppressor. Hence, we investigated the expression of ADAR and its single nucleotide variants of rs2229857 association with response to IFN-β in relapsing-remitting MS patients. mRNA levels and genotyping of rs2229857 in 167 MS patients were investigated via SYBR Green real-time (RT)-quantitative polymerase chain reaction and high-resolution melting RT PCR, respectively. The allele-A in rs2229857 and higher expression of ADAR were associated with poor response to IFN-β. Two response groups were significantly different in terms of annualized relapse rate, first symptoms, first extended disability status scale (EDSS), current EDSS, and the MS severity score. According to this study's findings, assessment of transcript levels and also variants in ADAR may be useful in identifying patients' response to IFN-β before starting treatment. Further investigations are needed to determine the potency of ADAR to be a predictive biomarker in drug responsiveness.

Publication History

Article published online:
10 July 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Vandenbroeck K, Urcelay E, Comabella M. IFN-β pharmacogenomics in multiple sclerosis. Pharmacogenomics 2010; 11 (08) 1137-1148
  • 2 Leray E, Moreau T, Fromont A, Edan G. Epidemiology of multiple sclerosis. Rev Neurol (Paris) 2016; 172 (01) 3-13
  • 3 Kulakova OG, Tsareva EY, Lvovs D, Favorov AV, Boyko AN, Favorova OO. Comparative pharmacogenetics of multiple sclerosis: IFN-β versus glatiramer acetate. Pharmacogenomics 2014; 15 (05) 679-685
  • 4 Hočevar K, Ristić S, Peterlin B. Pharmacogenomics of multiple sclerosis: a systematic review. Front Neurol 2019; 10: 134
  • 5 Vandenbroeck K, Comabella M. Single-nucleotide polymorphisms in response to interferon-beta therapy in multiple sclerosis. J Interferon Cytokine Res 2010; 30 (10) 727-732
  • 6 Van Baarsen LG, Vosslamber S, Tijssen M. et al. Pharmacogenomics of interferon-β therapy in multiple sclerosis: baseline IFN signature determines pharmacological differences between patients. PloS One 2008; 3 (04) e1927
  • 7 Pravica V, Popadic D, Savic E, Markovic M, Drulovic J, Mostarica-Stojkovic M. Single nucleotide polymorphisms in multiple sclerosis: disease susceptibility and treatment response biomarkers. Immunol Res 2012; 52 (1-2): 42-52
  • 8 Sospedra M, Martin R. Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23 (01) 683-747
  • 9 Gross R, Healy BC, Cepok S. et al. Population structure and HLA DRB1 1501 in the response of subjects with multiple sclerosis to first-line treatments. J Neuroimmunol 2011; 233 (1-2): 168-174
  • 10 Hojati Z, Kay M, Dehghanian F. Mechanism of action of interferon beta in treatment of multiple sclerosis. In: Multiple Sclerosis. Academic Press: Elsevier; 2016: 365-392
  • 11 Reder AT, Feng X. How type I interferons work in multiple sclerosis and other diseases: some unexpected mechanisms. J Interferon Cytokine Res 2014; 34 (08) 589-599
  • 12 Feng X, Petraglia AL, Chen M, Byskosh PV, Boos MD, Reder AT. Low expression of interferon-stimulated genes in active multiple sclerosis is linked to subnormal phosphorylation of STAT1. J Neuroimmunol 2002; 129 (1-2): 205-215
  • 13 van Baarsen LG, van der Pouw Kraan TC, Kragt JJ. et al. A subtype of multiple sclerosis defined by an activated immune defense program. Genes Immun 2006; 7 (06) 522-531
  • 14 Comabella M, Lünemann JD, Río J. et al. A type I interferon signature in monocytes is associated with poor response to interferon-β in multiple sclerosis. Brain 2009; 132 (Pt 12): 3353-3365
  • 15 Mannion N, Arieti F, Gallo A, Keegan LP, O'Connell MA. New insights into the biological role of mammalian ADARs; the RNA editing proteins. Biomolecules 2015; 5 (04) 2338-2362
  • 16 Vitali P, Scadden AD. Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis. Nat Struct Mol Biol 2010; 17 (09) 1043-1050
  • 17 Tossberg JT, Heinrich RM, Farley VM, Crooke III PS, Aune TM. Adenosine-to-inosine RNA editing of Alu double-stranded (ds) RNAs is markedly decreased in multiple sclerosis and unedited Alu dsRNAs are potent activators of proinflammatory transcriptional responses. J Immunol 2020; 205 (10) 2606-2617
  • 18 Ji S, Takitani M, Miyoshi J. Kino Y. RNA-Seq data analysis identifies the comprehensive profile of in vivo interferon-β-stimulated genes in multiple sclerosis. Clin Exp Neuroimmunol 2016; 7 (01) 39-51
  • 19 Gurevich M, Miron G, Falb RZ. et al. Transcriptional response to interferon beta-1a treatment in patients with secondary progressive multiple sclerosis. BMC Neurol 2015; 15 (01) 240
  • 20 Gallo A, Locatelli F. ADARs: allies or enemies? The importance of A-to-I RNA editing in human disease: from cancer to HIV-1. Biol Rev Camb Philos Soc 2012; 87 (01) 95-110
  • 21 Niino M, Kikuchi S. Pharmacogenomics of multiple sclerosis: current status and potential applications. Curr Pharmacogenomics Person Med 2010; 8 (04) 273-279
  • 22 Comabella M, Craig DW, Morcillo-Suárez C. et al. Genome-wide scan of 500,000 single-nucleotide polymorphisms among responders and nonresponders to interferon beta therapy in multiple sclerosis. Arch Neurol 2009; 66 (08) 972-978
  • 23 Byun E, Caillier SJ, Montalban X. et al. Genome-wide pharmacogenomic analysis of the response to interferon beta therapy in multiple sclerosis. Arch Neurol 2008; 65 (03) 337-344
  • 24 Sørensen PS, Deisenhammer F, Duda P. et al; EFNS Task Force on Anti-IFN-beta Antibodies in Multiple Sclerosis. Guidelines on use of anti-IFN-β antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-β antibodies in multiple sclerosis. Eur J Neurol 2005; 12 (11) 817-827
  • 25 Río J, Castilló J, Rovira A. et al. Measures in the first year of therapy predict the response to interferon β in MS. Mult Scler 2009; 15 (07) 848-853
  • 26 Tsareva E, Kulakova O, Boyko A, Favorova O. Pharmacogenetics of multiple sclerosis: personalized therapy with immunomodulatory drugs. Pharmacogenet Genomics 2016; 26 (03) 103-115
  • 27 Bush WS, Moore JH. Chapter 11: genome-wide association studies. PLOS Comput Biol 2012; 8 (12) e1002822
  • 28 Roskell NS, Zimovetz EA, Rycroft CE, Eckert BJ, Tyas DA. Annualized relapse rate of first-line treatments for multiple sclerosis: a meta-analysis, including indirect comparisons versus fingolimod. Curr Med Res Opin 2012; 28 (05) 767-780
  • 29 Inusah S, Sormani MP, Cofield SS. et al. Assessing changes in relapse rates in multiple sclerosis. Mult Scler 2010; 16 (12) 1414-1421