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.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
- SNP :
- CB2 :
cannabinoid receptor type 2
- ITP :
- JIA :
juvenile idiopathic arthritis
- IBD :
inflammatory bowel disease
- RA :
- MS :
- OR :
- CI :
- HWE :
- RRMS :
- SPMS :
- PPMS :
- AIC :
Akaike information criterion
- CNS :
central nerve system
- EC :
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
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
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
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
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
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
Chiurchiu V (2016) Endocannabinoids and immunity. Cannabis Cannabinoid Res 1:59–66
Ehsan M, Xixis KL (2018) Sclerosis, multiple. StatPearls [internet]. StatPearls publishing
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
Howard J, Trevick S, Younger DS (2016) Epidemiology of multiple sclerosis. Neurol Clin 34:919–939
Huang WJ, Chen WW, Zhang X (2017) Multiple sclerosis: pathology, diagnosis and treatments. Experimental and therapeutic medicine 13:3163–3166
Ismail M, Khawaja G (2018) Study of cannabinoid receptor 2 Q63R gene polymorphism in Lebanese patients with rheumatoid arthritis 37: 2933-2938
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
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
Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M (2009) Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 1:1333–1349
Peterson LK, Fujinami RS (2007) Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis. J Neuroimmunol 184:37–44
Reggio PH (2010) Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem 17:1468–1486
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
Rom S, Persidsky Y (2013) Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. J NeuroImmune Pharmacol 8:608–620
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
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
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
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
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
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
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
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
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
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
Witkamp R, Meijerink J (2014) The endocannabinoid system: an emerging key player in inflammation. Curr Opin Clin Nutr Metab Care 17:130–138
Wu GF, Alvarez E (2011) The immunopathophysiology of multiple sclerosis. Neurol Clin 29:257–278
Yamout BI, Alroughani R (2018) Multiple sclerosis. Semin Neurol 38:212–225
Yao B, Mackie K (2009) Endocannabinoid receptor pharmacology. Curr Top Behav Neurosci 1:37–63
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
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).
Conflict of Interest
The authors declare that they have no conflict of interest.
The current human study was approved by the science and bioethics committee of Golestan University of Medical Sciences (IR.GOUMS.REC.1397.045).
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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). https://doi.org/10.1007/s12031-019-01395-9
- Cannabinoid receptor type 2
- Multiple sclerosis
- Single-nucleotide polymorphism