Cannabinoid CB2 Receptor Functional Variation (Q63R) Is Associated with Multiple Sclerosis in Iranian Subjects


The cannabinoid system has been identified as a critical endogenous regulator of immune homeostasis through immunomodulatory actions. This system is one of the main regulatory systems of the central nervous system (CNS). Variations in the cannabinoid CB2 receptor gene (CNR2) could affect intracellular signaling and reduce system function, which has been associated with an unbalanced immune response and increased risk of a variety of autoimmune inflammatory disorders. The present study investigated the relationship between CNR2 rs35761398 (Q63R) functional variation and multiple sclerosis (MS). A total of 100 Iranian MS patients and 100 healthy controls were enrolled in the study and genotyped through TaqMan assay. The co-dominant, dominant, recessive, over-dominant, and additive inheritance models were analyzed using SNPStats software. A significant genetic association was observed between Q63R polymorphism and MS. The dominant model was accepted as the best inheritance model to fit the data (OR 2.70, 95% CI 1.47–4.97, p = 0.001). The data implied the involvement of the CNR2 gene in susceptibility to MS in Iranian patients.

This is a preview of subscription content, log in to check access.



single-nucleotide polymorphism

CB2 :

cannabinoid receptor type 2


thrombocytopenic purpura


juvenile idiopathic arthritis


inflammatory bowel disease

RA :

rheumatoid arteritis

MS :

multiple sclerosis

OR :

odds ratio

CI :

confidence interval


Hardy–Weinberg equilibrium


relapsing-remitting MS


secondary-progressive MS


primary-progressive MS


Akaike information criterion


central nerve system

EC :



  1. Bellini G, Olivieri AN, Grandone A, Alessio M, Gicchino MF, Nobili B, Perrone L, Maione S, del Giudice EM, Rossi F (2015a) Association between cannabinoid receptor type 2 Q63R variant and oligo/polyarticular juvenile idiopathic arthritis. Scand J Rheumatol 44:284–287

    CAS  Article  Google Scholar 

  2. Bellini G, Grandone A, Torella M, Miraglia del Giudice E, Nobili B, Perrone L, Maione S, Rossi F2 (2015b) The cannabinoid receptor 2 Q63R variant modulates the relationship between childhood obesity and age at menarche. PLoS One 10:e0140142

    Article  Google Scholar 

  3. Browne P, Chandraratna D, Angood C, Tremlett H, Baker C, Taylor BV, Thompson AJ (2014) Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity. Neurology 83:1022–1024

    Article  Google Scholar 

  4. Carrasquer A, Nebane NM, Williams WM, Song ZH (2010) Functional consequences of nonsynonymous single nucleotide polymorphisms in the CB2 cannabinoid receptor. Pharmacogenet Genomics 20:157–166

    CAS  Article  Google Scholar 

  5. Coppola N, Zampino R, Bellini G, Macera M, Marrone A, Pisaturo M, Boemio A, Nobili B, Pasquale G, Maione S, Adinolfi LE, Perrone L, Sagnelli E, Miraglia Del Giudice E, Rossi F (2014) Association between a polymorphism in cannabinoid receptor 2 and severe necroinflammation in patients with chroni hepatitis C. Clin Gastroenterol Hepatol 12:334–340

    CAS  Article  Google Scholar 

  6. Coppola N, Zampino R, Bellini G, Stanzione M, Capoluongo N, Marrone A, Macera M, Adinolfi LE2, Giudice EM, Gentile I, Sagnelli E, Rossi F (2016) CB2-63 polymorphism and immune-mediated diseases associated with HCV chronic infection. Dig Liver Dis 48:1364–1369

  7. Chiurchiu V (2016) Endocannabinoids and immunity. Cannabis Cannabinoid Res 1:59–66

    CAS  Article  Google Scholar 

  8. Ehsan M, Xixis KL (2018) Sclerosis, multiple. StatPearls [internet]. StatPearls publishing

  9. Gibbons GH, Liew CC, Goodarzi MO, Rotter JI, Hsueh WA, Siragy HM, Pratt R, Dzau VJ (2004) Genetic markers: progress and potential for cardiovascular disease. Circulation 109: IV-47-IV-58

  10. Howard J, Trevick S, Younger DS (2016) Epidemiology of multiple sclerosis. Neurol Clin 34:919–939

    Article  Google Scholar 

  11. Huang WJ, Chen WW, Zhang X (2017) Multiple sclerosis: pathology, diagnosis and treatments. Experimental and therapeutic medicine 13:3163–3166

    Article  Google Scholar 

  12. Ismail M, Khawaja G (2018) Study of cannabinoid receptor 2 Q63R gene polymorphism in Lebanese patients with rheumatoid arthritis 37: 2933-2938

  13. Mahmoud Gouda H, Mohamed Kamel NR (2013) Cannabinoid CB2 receptor gene (CNR2) polymorphism is associated with chronic childhood immune thrombocytopenia in Egypt. Blood Coagul Fibrinolysis 24:247–251

    CAS  Article  Google Scholar 

  14. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127

    CAS  Article  Google Scholar 

  15. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M (2009) Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 1:1333–1349

    CAS  Article  Google Scholar 

  16. Peterson LK, Fujinami RS (2007) Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. J Neuroimmunol 184:37–44

    CAS  Article  Google Scholar 

  17. Reggio PH (2010) Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem 17:1468–1486

    CAS  Article  Google Scholar 

  18. Rivas Alonso V, Flores Rivera JJ, Rito García Y, Corona T (2017) The genetics of multiple sclerosis in Latin America. Mult Scler J Exp Transl Clin 3:2055217317727295

    PubMed  PubMed Central  Google Scholar 

  19. Rom S, Persidsky Y (2013) Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. J NeuroImmune Pharmacol 8:608–620

    Article  Google Scholar 

  20. Rossi F, Bellini G, Tolone C, Luongo L, Mancusi S, Papparella A, Sturgeon C, Fasano A, Nobili B, Perrone L, Maione S, del Giudice EM (2012a) The cannabinoid receptor type 2 Q63R variant increases the risk of celiac disease: implication for a novel molecular biomarker and future therapeutic intervention. Pharmacol Re 66:88–94

    CAS  Article  Google Scholar 

  21. Rossi F, Bellini G, Alisi A, Alterio A, Maione S, Perrone L, Locatelli F, Miraglia del Giudice E, Nobili V (2012b) Cannabinoid receptor type 2 functional variant influences liver damage in children with non-alcoholic fatty liver disease. PLoS One 7:e42259

    CAS  Article  Google Scholar 

  22. Rossi F, Mancusi S, Bellini G, Roberti D, Punzo F, Vetrella S, Matarese SM, Nobili B, Maione S, Perrotta S (2011) CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura. Haematologica 96:1883–1885

    CAS  Article  Google Scholar 

  23. Sahraian MA, Khorramnia S, Ebrahim MM, Moinfar Z, Lotfi J, Pakdaman H (2010) Multiple sclerosis in Iran: a demographic study of 8,000 patients and changes over time. Eur Neurol 64:331–336

    Article  Google Scholar 

  24. Sipe JC1, Arbour N, Gerber A, Beutler E (2005) Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders. J Leukoc Biol 78:231–238

    CAS  Article  Google Scholar 

  25. Solé X, Guinó E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22:1928–1929

    Article  Google Scholar 

  26. Strisciuglio C, Bellini G, Miele E, Martinelli M, Cenni S, Tortora C, Tolone C, Miraglia Del Giudice E, Rossi F (2018) Cannabinoid receptor 2 functional variant contributes to the risk for pediatric inflammatory bowel disease. J Clin Gastroenterol 52:e37–e43

    CAS  Article  Google Scholar 

  27. Tahamtan A, Askari FS, Bont L, Salimi V (2019) Disease severity in respiratory syncytial virus infection: role of host genetic variation. Rev Med Virol 29:e2026

    Article  Google Scholar 

  28. Tahamtan A, Samieipoor Y, Nayeri FS, Rahbarimanesh AA, Izadi A, Rashidi-Nezhad A, Tavakoli-Yaraki M, Farahmand M, Bont L, Shokri F, Mokhatri-Azad T, Salimi V (2018) Effects of cannabinoid receptor type 2 in respiratory syncytial virus infection in human subjects and mice. Virulence 9:217–230

    CAS  Article  Google Scholar 

  29. Wang J, Xu J, Liu J, Zhu H, Peng Y, Ding ZM, Hua H (2018) Genetic variant Q63R of cannabinoid receptor 2 causes differential ERK phosphorylation in human immune cells. Genet Test Mol Biomarkers 22:320–326

    CAS  Article  Google Scholar 

  30. Witkamp R, Meijerink J (2014) The endocannabinoid system: an emerging key player in inflammation. Curr Opin Clin Nutr Metab Care 17:130–138

    CAS  Article  Google Scholar 

  31. Wu GF, Alvarez E (2011) The immunopathophysiology of multiple sclerosis. Neurol Clin 29:257–278

    Article  Google Scholar 

  32. Yamout BI, Alroughani R (2018) Multiple sclerosis. Semin Neurol 38:212–225

    Article  Google Scholar 

  33. Yao B, Mackie K (2009) Endocannabinoid receptor pharmacology. Curr Top Behav Neurosci 1:37–63

    CAS  Article  Google Scholar 

  34. Yonal O, Eren F, Yılmaz Y, Atuğ Ö, Över HH (2014) No association between the functional cannabinoid receptor type 2 Q63R variants and inflammatory bowel disease in Turkish subjects. Turk J Gastroenterol 25:639–643

    PubMed  Google Scholar 

Download references


The authors would like to thank all the participants in the current study.


This work was financially supported by Golestan University of Medical Sciences (No. 231195).

Author information



Corresponding author

Correspondence to Alireza Tahamtan.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

The current human study was approved by the science and bioethics committee of Golestan University of Medical Sciences (IR.GOUMS.REC.1397.045).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tahamtan, A., Rezaiy, S., Samadizadeh, S. et al. Cannabinoid CB2 Receptor Functional Variation (Q63R) Is Associated with Multiple Sclerosis in Iranian Subjects. J Mol Neurosci 70, 26–31 (2020).

Download citation


  • Cannabinoid receptor type 2
  • Multiple sclerosis
  • Single-nucleotide polymorphism
  • CNR2
  • Q63R
  • Iran