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Clinical Rheumatology

, Volume 37, Issue 11, pp 2933–2938 | Cite as

Study of cannabinoid receptor 2 Q63R gene polymorphism in Lebanese patients with rheumatoid arthritis

  • Morouj Ismail
  • Ghada KhawajaEmail author
Original Article

Abstract

The cannabinoid (CB) receptor 2, primarily expressed in immune cells, was shown to play important immune-regulatory functions. In particular, the CB2-R63 functional variant has been shown to alter the ability of the CB2 receptor to exert its inhibitory function on T lymphocytes. The aim of this study was to investigate the association between a common dinucleotide polymorphism, Q63R, in the cannabinoid receptor 2 gene (CNR2) and rheumatoid arthritis (RA) in the Lebanese population. One hundred five unrelated Lebanese RA patients and one hundred five controls from different Lebanese governorates were recruited in this study. Genomic DNA was extracted, polymerase chain reaction was performed, and CNR2 was genotyped in a blinded fashion. The χ2 test was used to determine the differences in genotypes and allele frequencies. CNR2 genotyping showed significantly higher frequencies of the CB2-R63 variant (allele frequencies, P < 0.00001; genotype distribution, P < 0.00001) in RA patients when compared with healthy controls. Moreover, RR carriers had more than 10-fold risk for developing RA (OR = 10.8444, 95% CI = 5.0950–23.0818; P < 0.0001), and QR carriers had more than 3-fold risk (OR = 3.8667, 95% CI = 1.7886–8.3591; P = 0.0006) as compared with QQ carriers. Our preliminary results suggest a role of CB2-Q63R gene polymorphism in the etiology of RA, thus supporting its potential use as a pharmacological target for selective agonists in clinical practice.

Keywords

Cannabinoid receptor 2 CB2-Q63R gene polymorphism Rheumatoid arthritis 

Notes

Acknowledgments

The authors are thankful to Dr. Seifedine Kadry, Department of Mathematics and Computer Science, Faculty of Science, Beirut Arab University for his assistance in the statistical analysis.

Funding

There has been no specific funding for this work; it was individually funded.

Compliance with ethical standards

Disclosures

None.

References

  1. 1.
    Scott DL, Wolfe F, Huizinga TWJ Rheumatoid arthritis. Lancet 376(9746):1094–1108CrossRefGoogle Scholar
  2. 2.
    Hazes JMW, Luime JJ (2011) The epidemiology of early inflammatory arthritis. Nat Rev Rheumatol 7:381–390CrossRefGoogle Scholar
  3. 3.
    Raslan HM, Attia HR, Salama I, Ibrahim MH, Hassan EM, El Hussieny MS et al (2016) Association of PTPN22 1858C-->T polymorphism, HLA-DRB1 shared epitope and autoantibodies with rheumatoid arthritis. Rheumatol Int 36(8):1167–1175CrossRefGoogle Scholar
  4. 4.
    Klareskog L, Padyukov L, Lorentzen J, Alfredsson L (2006) Mechanisms of disease: genetic susceptibility and environmental triggers in the development of rheumatoid arthritis. Nat Clin Pract Rheumatol 2(8):425–433CrossRefGoogle Scholar
  5. 5.
    van der Woude D, Houwing-Duistermaat JJ, Toes RE, Huizinga TW, Thomson W, Worthington J et al (2009) Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis. Arthritis Rheum 60(4):916–923CrossRefGoogle Scholar
  6. 6.
    Barton A, Worthington J (2009) Genetic susceptibility to rheumatoid arthritis: an emerging picture. Arthritis Rheum 61(10):1441–1446CrossRefGoogle Scholar
  7. 7.
    Orozco G, Eyre S, Hinks A, Ke X, Wilson AG, Bax DE et al (2010) Association of CD40 with rheumatoid arthritis confirmed in a large UK case-control study. Ann Rheum Dis 69(5):813–816CrossRefGoogle Scholar
  8. 8.
    Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP et al (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42(6):508–514CrossRefGoogle Scholar
  9. 9.
    Plenge RM (2009) Recent progress in rheumatoid arthritis genetics: one step towards improved patient care. Curr Opin Rheumatol 21(3):262–271CrossRefGoogle Scholar
  10. 10.
    van Heemst J, Huizinga TJ, van der Woude D, Toes RE (2015) Fine-mapping the human leukocyte antigen locus in rheumatoid arthritis and other rheumatic diseases: identifying causal amino acid variants? Curr Opin Rheumatol 27(3):256–261CrossRefGoogle Scholar
  11. 11.
    Terao C, Ohmura K, Kochi Y, Ikari K, Okada Y, Shimizu M et al (2015) Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: a meta-analysis of genome-wide association study in a Japanese population. Arthritis Res Ther 17:104CrossRefGoogle Scholar
  12. 12.
    Kim K, Bang SY, Lee HS, Bae SC (2017) Update on the genetic architecture of rheumatoid arthritis. Nat Rev Rheumatol 13(1):13–24CrossRefGoogle Scholar
  13. 13.
    Shahmohamadnejad S, Vaisi-Raygani A, Shakiba Y, Kiani A, Rahimi Z, Bahrehmand F et al (2015) Association between butyrylcholinesterase activity and phenotypes, paraoxonase192 rs662 gene polymorphism and their enzymatic activity with severity of rheumatoid arthritis: correlation with systemic inflammatory markers and oxidative stress, preliminary report. Clin Biochem 48(1–2):63–69CrossRefGoogle Scholar
  14. 14.
    Shakiba E, Tavilani H, Goodarzi MT, Kiani A, Pourmotabbed T, Vaisi-Raygani A (2014) The ITGAV-rs3911238 polymorphism is associated with disease activity in rheumatoid arthritis. Iran J Allergy Asthma Immunol 13(5):356–363PubMedGoogle Scholar
  15. 15.
    Barrie N, Kuruppu V, Manolios E, Ali M, Moghaddam M, Manolios N (2017) Endocannabinoids in arthritis: current views and perspective. Int J Rheum Dis 20(7):789–797CrossRefGoogle Scholar
  16. 16.
    Croxford JL, Yamamura T (2005) Cannabinoids and the immune system: potential for the treatment of inflammatory diseases? J Neuroimmunol 166(1–2):3–18CrossRefGoogle Scholar
  17. 17.
    Mackie K (2006) Cannabinoid receptors as therapeutic targets. Annu Rev Pharmacol Toxicol 46:101–122CrossRefGoogle Scholar
  18. 18.
    Pertwee RG (2006) The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond) 30(Suppl 1):S13–S18CrossRefGoogle Scholar
  19. 19.
    Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M, Zapletalova O et al (2011) A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex((R))), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol 18(9):1122–1131CrossRefGoogle Scholar
  20. 20.
    Beal JE, Olson R, Lefkowitz L, Laubenstein L, Bellman P, Yangco B et al (1997) Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manag 14(1):7–14CrossRefGoogle Scholar
  21. 21.
    Paradisi A, Oddi S, Maccarrone M (2006) The endocannabinoid system in ageing: a new target for drug development. Curr Drug Targets 7(11):1539–1552CrossRefGoogle Scholar
  22. 22.
    Ware MA, Adams H, Guy GW (2005) The medicinal use of cannabis in the UK: results of a nationwide survey. Int J Clin Pract 59(3):291–295CrossRefGoogle Scholar
  23. 23.
    Katz D, Katz I, Porat-Katz BS, Shoenfeld Y (2017) Medical cannabis: another piece in the mosaic of autoimmunity? Clin Pharmacol Ther 101(2):230–238CrossRefGoogle Scholar
  24. 24.
    Richardson D, Pearson RG, Kurian N, Latif ML, Garle MJ, Barrett DA et al (2008) Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther 10(2):R43CrossRefGoogle Scholar
  25. 25.
    Sipe JC, 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(1):231–238CrossRefGoogle Scholar
  26. 26.
    Ishiguro H, Iwasaki S, Teasenfitz L, Higuchi S, Horiuchi Y, Saito T et al (2007) Involvement of cannabinoid CB2 receptor in alcohol preference in mice and alcoholism in humans. Pharmacogenomics J 7(6):380–385CrossRefGoogle Scholar
  27. 27.
    Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U et al (2005) Cannabinoid receptor type 2 gene is associated with human osteoporosis. Hum Mol Genet 14(22):3389–3396CrossRefGoogle Scholar
  28. 28.
    Carrasquer A, Nebane NM, Williams WM, Song ZH (2010) Functional consequences of nonsynonymous single nucleotide polymorphisms in the CB2 cannabinoid receptor. Pharmacogenet Genomics 20(3):157–166CrossRefGoogle Scholar
  29. 29.
    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(3):247–251CrossRefGoogle Scholar
  30. 30.
    Bellini G, Olivieri AN, Grandone A, Alessio M, Gicchino MF, Nobili B et al (2015) Association between cannabinoid receptor type 2 Q63R variant and oligo/polyarticular juvenile idiopathic arthritis. Scand J Rheumatol 44(4):284–287CrossRefGoogle Scholar
  31. 31.
    Coppola N, Zampino R, Bellini G, Macera M, Marrone A, Pisaturo M et al (2014) Association between a polymorphism in cannabinoid receptor 2 and severe necroinflammation in patients with chronic hepatitis C. Clin Gastroenterol Hepatol 12(2):334–340CrossRefGoogle Scholar
  32. 32.
    Darwish MJ, Armenian HK (1987) A case-control study of rheumatoid arthritis in Lebanon. Int J Epidemiol 16(3):420–424CrossRefGoogle Scholar
  33. 33.
    Rossi F, Mancusi S, Bellini G, Roberti D, Punzo F, Vetrella S et al (2011) CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura. Haematologica 96(12):1883–1885CrossRefGoogle Scholar
  34. 34.
    Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L et al (2003) The cannabinoid system and immune modulation. J Leukoc Biol 74(4):486–496CrossRefGoogle Scholar
  35. 35.
    Rieder SA, Chauhan A, Singh U, Nagarkatti M, Nagarkatti P (2010) Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology 215(8):598–605CrossRefGoogle Scholar
  36. 36.
    Gui H, Liu X, Wang ZW, He DY, Su DF, Dai SM (2014) Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis. Rheumatology (Oxford, England) 53(5):802–809CrossRefGoogle Scholar
  37. 37.
    Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365(6441):61–65CrossRefGoogle Scholar
  38. 38.
    Brown SM, Wager-Miller J, Mackie K (2002) Cloning and molecular characterization of the rat CB2 cannabinoid receptor. Biochim Biophys Acta 1576(3):255–264CrossRefGoogle Scholar
  39. 39.
    Xie XQ, Chen JZ, Billings EM (2003) 3D structural model of the G-protein-coupled cannabinoid CB2 receptor. Proteins 53(2):307–319CrossRefGoogle Scholar
  40. 40.
    Veselinovic M, Barudzic N, Vuletic M, Zivkovic V, Tomic-Lucic A, Djuric D et al (2014) Oxidative stress in rheumatoid arthritis patients: relationship to diseases activity. Mol Cell Biochem 391(1–2):225–232CrossRefGoogle Scholar
  41. 41.
    Horvath B, Magid L, Mukhopadhyay P, Batkai S, Rajesh M, Park O et al (2012) A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury. Br J Pharmacol 165(8):2462–2478CrossRefGoogle Scholar
  42. 42.
    Mukhopadhyay P, Rajesh M, Pan H, Patel V, Mukhopadhyay B, Batkai S et al (2010) Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy. Free Radic Biol Med 48(3):457–467CrossRefGoogle Scholar
  43. 43.
    Javed H, Azimullah S, Haque ME, Ojha SK (2016) Cannabinoid type 2 (CB2) receptors activation protects against oxidative stress and neuroinflammation associated dopaminergic neurodegeneration in rotenone model of Parkinson’s disease. Front Neurosci 10:321CrossRefGoogle Scholar
  44. 44.
    Elshabrawy HA, Chen Z, Volin MV, Ravella S, Virupannavar S, Shahrara S (2015) The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 18(4):433–448CrossRefGoogle Scholar
  45. 45.
    Azizi G, Boghozian R, Mirshafiey A (2014) The potential role of angiogenic factors in rheumatoid arthritis. Int J Rheum Dis 17(4):369–383CrossRefGoogle Scholar
  46. 46.
    Casanova ML, Blazquez C, Martinez-Palacio J, Villanueva C, Fernandez-Acenero MJ, Huffman JW et al (2003) Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111(1):43–50CrossRefGoogle Scholar
  47. 47.
    Huang HC, Wang SS, Hsin IF, Chang CC, Lee FY, Lin HC et al (2012) Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats. Hepatology (Baltimore, MD) 56(1):248–258CrossRefGoogle Scholar
  48. 48.
    Staiano RI, Loffredo S, Borriello F, Iannotti FA, Piscitelli F, Orlando P et al (2016) Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors. J Leukoc Biol 99(4):531–540CrossRefGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  1. 1.Department of Biological Sciences, Faculty of ScienceBeirut Arab UniversityDebbiehLebanon

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