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

  • Alireza TahamtanEmail author
  • Shahrzad Rezaiy
  • Saeed Samadizadeh
  • Abdolvahab Moradi
  • Alijan Tabarraei
  • Naeme Javid
  • Morteza Oladnabi
  • Mohammad Hosein Naeimi


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.


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



single-nucleotide polymorphism


cannabinoid receptor type 2


thrombocytopenic purpura


juvenile idiopathic arthritis


inflammatory bowel disease


rheumatoid arteritis


multiple sclerosis


odds ratio


confidence interval


Hardy–Weinberg equilibrium


relapsing-remitting MS


secondary-progressive MS


primary-progressive MS


Akaike information criterion


central nerve system





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

Funding Information

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

Compliance with Ethical Standards

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).


  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 44:284–287CrossRefPubMedGoogle 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:e0140142CrossRefPubMedPubMedCentralGoogle 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 83:1022–1024CrossRefPubMedPubMedCentralGoogle 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 20:157–166CrossRefPubMedGoogle 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 12:334–340CrossRefPubMedGoogle 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 48:1364–1369Google Scholar
  7. Chiurchiu V (2016) Endocannabinoids and immunity. Cannabis Cannabinoid Res 1:59–66CrossRefPubMedPubMedCentralGoogle Scholar
  8. Ehsan M, Xixis KL (2018) Sclerosis, multiple. StatPearls [internet]. StatPearls publishingGoogle Scholar
  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-58Google Scholar
  10. Howard J, Trevick S, Younger DS (2016) Epidemiology of multiple sclerosis. Neurol Clin 34:919–939CrossRefPubMedGoogle Scholar
  11. Huang WJ, Chen WW, Zhang X (2017) Multiple sclerosis: pathology, diagnosis and treatments. Experimental and therapeutic medicine 13:3163–3166CrossRefPubMedPubMedCentralGoogle Scholar
  12. Ismail M, Khawaja G (2018) Study of cannabinoid receptor 2 Q63R gene polymorphism in Lebanese patients with rheumatoid arthritis 37: 2933-2938Google Scholar
  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 24:247–251CrossRefPubMedGoogle 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 50:121–127CrossRefPubMedGoogle Scholar
  15. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M (2009) Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 1:1333–1349CrossRefPubMedPubMedCentralGoogle Scholar
  16. Peterson LK, Fujinami RS (2007) Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. J Neuroimmunol 184:37–44CrossRefPubMedGoogle Scholar
  17. Reggio PH (2010) Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem 17:1468–1486CrossRefPubMedPubMedCentralGoogle 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 3:2055217317727295PubMedPubMedCentralGoogle Scholar
  19. Rom S, Persidsky Y (2013) Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. J NeuroImmune Pharmacol 8:608–620CrossRefPubMedPubMedCentralGoogle 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 66:88–94CrossRefGoogle 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:e42259CrossRefPubMedPubMedCentralGoogle 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 96:1883–1885CrossRefPubMedPubMedCentralGoogle 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 64:331–336CrossRefPubMedGoogle 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 78:231–238CrossRefPubMedGoogle Scholar
  25. Solé X, Guinó E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22:1928–1929CrossRefPubMedGoogle 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–e43CrossRefPubMedGoogle 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:e2026CrossRefPubMedGoogle 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 9:217–230CrossRefPubMedGoogle 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 22:320–326CrossRefPubMedGoogle Scholar
  30. Witkamp R, Meijerink J (2014) The endocannabinoid system: an emerging key player in inflammation. Curr Opin Clin Nutr Metab Care 17:130–138CrossRefPubMedGoogle Scholar
  31. Wu GF, Alvarez E (2011) The immunopathophysiology of multiple sclerosis. Neurol Clin 29:257–278CrossRefPubMedPubMedCentralGoogle Scholar
  32. Yamout BI, Alroughani R (2018) Multiple sclerosis. Semin Neurol 38:212–225CrossRefPubMedGoogle Scholar
  33. Yao B, Mackie K (2009) Endocannabinoid receptor pharmacology. Curr Top Behav Neurosci 1:37–63CrossRefPubMedGoogle 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 25:639–643PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Neuroscience Research CenterGolestan University of Medical SciencesGorganIran
  2. 2.Department of Microbiology, Faculty of MedicineGolestan University of Medical SciencesGorganIran
  3. 3.Islamic Azad University of MashhadMashhadIran
  4. 4.Ischemic Disorders Research CenterGolestan University of Medical SciencesGorganIran
  5. 5.Department of Neurology, Sayyad HospitalGolestan University of Medical SciencesGorganIran

Personalised recommendations