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Polymorphisms of dopamine receptor genes and risk of visual hallucinations in Parkinson’s patients

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

Visual hallucinations (VHs) are frequent non-motor complication of Parkinson’s disease (PD), associated to a negative prognosis. Previous studies showed an association between dopamine receptor (DR) gene (DR) variants and psychosis in Alzheimer’s disease, addictions, schizophrenia, and bipolar disorder. However, there are only a few studies on DR variants and VHs in PD, which did not provide conclusive results.

Objectives

The present study aimed to determine whether genetic differences of DR are associated with visual hallucinations (VHs) in a cohort of Parkinson’s disease (PD) patients.

Methods

A case-control study of 84 PD subjects, 42 with and 42 without VHs,that were matched for age, gender, disease duration, and dopaminergic medication was conducted. Polymerase chain reaction for SNPs in both D1-like (DRD1A-48G [rs4532] and C62T [rs686], DRD5T798C [rs6283]) and D2-like DR (DRD2G2137A [rs1800497] and C957T [rs6277], DRD3G25A [rs6280] and G712C [rs1800828], DRD4C616G [rs747302] and nR VNTR 48bp) analyzed genomic DNA.

Results

Patients carrying allele T at DRD1C62T had an increased risk of VHs, expressed as OR (95 % CI, p value), of 10.7 (2.9–40, p = 0.0001). Moreover, patients with DRD1-48 GG and 62TT genotype displayed shorter time to VHs, whereas a longer time to VHs was found in subjects carrying the DRD4 CG alleles.

Conclusions

PD patients with VHs display higher frequency of DR SNPs associated with increased D1-like activity and decreased D2-like activity. Our data are in line with associations reported in other neurodegenerative and psychiatric conditions. Results likely provide valuable information for personalizing pharmacological therapy in PD patients.

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References

  1. Fénelon G, Mahieux F, Huon R, Ziégler M (2000) Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 123(Pt 4):733–745

    Article  PubMed  Google Scholar 

  2. Ravina, B.; Marder, K.; Fernandez, HH., et al. Diagnostic criteria for psychosis in Parkinson’s disease: report of an NINDS/NIMH work group

  3. Levin J, Hasan A, Höglinger GU (2016) Psychosis in Parkinson’s disease: identification, prevention and treatment. J Neural Transm (Vienna) 123(1):45–50

    Article  CAS  Google Scholar 

  4. Zahodne LB, Fernandez HH (2008) Pathophysiology and treatment of psychosis in Parkinson’s disease: a review. Drugs Aging 25(8):665–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Holroyd S, Currie L, Wooten GF (2001) Prospective study of hallucinations and delusions in Parkinson’s disease. J Neurol Neurosurg Psychiatry 70:734–738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Williams-Gray CH, Mason SL, Evans JR, et al. (2013) The CamPaIGN study of Parkinson’s disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry 84(11):1258–1264

    Article  PubMed  Google Scholar 

  7. Williams-Gray CH, Hampshire A, Barker RA, Owen AM (2008) Attentional control in Parkinson’s disease is dependent on COMT val 158 met genotype. Brain 131(Pt 2):397–408

    Article  PubMed  Google Scholar 

  8. De Marchi F, Carecchio M, Cantello R, Comi C (2014) Predicting cognitive decline in Parkinson’s disease: can we ask the genes? Front Neurol 5:224

    Article  PubMed  PubMed Central  Google Scholar 

  9. Weintraub D, Chen P, Ignacio RV, Mamikonyan E (2011) Kales HC patterns and trends in antipsychotic prescribing for Parkinson disease psychosis. Arch Neurol 68(7):899–904

    Article  PubMed  PubMed Central  Google Scholar 

  10. Arbouw ME, Guchelaar HJ, Egberts TC (2010) Novel insights in pharmacogenetics of drug response in Parkinson’s disease. Pharmacogenomics 11(2):127–129

    Article  CAS  PubMed  Google Scholar 

  11. Baker WL, Silver D, White CM, Kluger J, Aberle J, Patel AA, Coleman CI (2009) Dopamine agonists in the treatment of early Parkinson’s disease: a meta-analysis. Parkinsonism Relat Disord 15(4):287–294

    Article  PubMed  Google Scholar 

  12. Stowe RL, Ives NJ, Clarke C, van Hilten J, Ferreira J, Hawker RJ, et al. (2008) Dopamine agonist therapy in early Parkinson’s disease. Cochrane Database Syst Rev 2:CD006564

    PubMed  Google Scholar 

  13. Sweet RA, Nimgaonkar VL, Kamboh MI, Lopez OL, Zhang F, DeKosky ST (1998) Dopamine receptor genetic variation, psychosis, and aggression in Alzheimer disease. Arch Neurol 55(10):1335–1340

    Article  CAS  PubMed  Google Scholar 

  14. Wong AH, Buckle CE, Van Tol HH (2000) Polymorphisms in dopamine receptors: what do they tell us? Eur J Pharmacol 410(2–3):183–203

    Article  CAS  PubMed  Google Scholar 

  15. McAllister TW, Summerall L (2003) Genetic polymorphisms in the expression and treatment of neuropsychiatric disorders. Curr Psychiatry Rep 5(5):400–409

    Article  PubMed  Google Scholar 

  16. Le Foll B, Gallo A, Le Strat Y, Lu L, Gorwood P (2009) Genetics of dopamine receptors and drug addiction: a comprehensive review. Behav Pharmacol 20(1):1–17

    Article  CAS  PubMed  Google Scholar 

  17. Goetz CG, Burke PF, Leurgans S, et al. (2001) Genetic variation analysis in parkinson disease patients with and without hallucinations: case-control study. Arch Neurol 58(2):209–213

    Article  CAS  PubMed  Google Scholar 

  18. Makoff AJ, Graham JM, Arranz MJ, et al. (2000) Association study of dopamine receptor gene polymorphisms with drug-induced hallucinations in patients with idiopathic Parkinson’s disease. Pharmacogenetics 10(1):43–48

    Article  CAS  PubMed  Google Scholar 

  19. Ferrari M, Bolla E, Bortolaso P, et al. (2012) Association between CYP1A2 polymorphisms and clozapine-induced adverse reactions in patients with schizophrenia. Psychiatry Res 200(2–3):1014–1017

    Article  CAS  PubMed  Google Scholar 

  20. Ferrari M, Guasti L, Maresca A, et al. (2014) Association between statin-induced creatine kinase elevation and genetic polymorphisms in SLCO1B1, ABCB1 and ABCG2. Eur J Clin Pharmacol 70(5):539–547

    Article  CAS  PubMed  Google Scholar 

  21. Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE (2010) Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 25(15):2649–2653

    Article  PubMed  Google Scholar 

  22. Cosentino M, Ferrari M, Kustrimovic N, Rasini E, Marino F (2015) Influence of dopamine receptor gene polymorphisms on circulating T lymphocytes: a pilot study in healthy subjects. Hum Immunol 76(10):747–752

    Article  CAS  PubMed  Google Scholar 

  23. Pappert E, Goetz C, Niederman F, Raman R, Leurgans S (1999) Hallucinations, sleep fragmentation, and altered dream phenomena in Parkinson’s disease. Mov Disord 14(1):117–121

    Article  CAS  PubMed  Google Scholar 

  24. Goetz CG, Stebbins GT (1995) Mortality and hallucinations in nursing home patients with advanced Parkinson’s disease. Neurology 45(4):669–671

    Article  CAS  PubMed  Google Scholar 

  25. Holmes C, Smith H, Ganderton R, Arranz M, Collier D, Powell J, Lovestone S (2001) Psychosis and aggression in Alzheimer’s disease: the effect of dopamine receptor gene variation. J Neurol Neurosurg Psychiatry 71(6):777–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kaiser R, Hofer A, Grapengiesser A, Gasser T, Kupsch A, Roots I, Brockmöller J (2003) L -dopa-induced adverse effects in PD and dopamine transporter gene polymorphism. Neurology 60(11):1750–1755

    Article  CAS  PubMed  Google Scholar 

  27. Ortega VE (2014) Meyers DA2. Pharmacogenetics: implications of race and ethnicity on defining genetic profiles for personalized medicine. J Allergy Clin Immunol 133(1):16–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ibarretxe-Bilbao N, Junque C, Marti MJ, Tolosa E (2011) Cerebral basis of visual hallucinations in Parkinson’s disease: structural and functional MRI studies. J Neurol Sci 310(1–2):79–81

    Article  PubMed  Google Scholar 

  29. Edwards IR, Biriell C (1994) Harmonisation in pharmacovigilance. Drug Saf 10(2):93–102

    Article  CAS  PubMed  Google Scholar 

  30. Janssens AC, Moonesinghe R, Yang Q, Steyerberg EW, van Duijn CM, Khoury MJ (2007) The impact of genotype frequencies on the clinical validity of genomic profiling for predicting common chronic diseases. Genet Med 9(8):528–535

    Article  PubMed  Google Scholar 

  31. Lenka A et al. (2016 May 15) Genetic substrates of psychosis in patients with Parkinson’s disease: a critical review. J Neurol Sci 364:33–41

    Article  PubMed  Google Scholar 

  32. Huang W, Ma JZ, Payne TJ, Beuten J, Dupont RT, Li MD (2008) Significant association of DRD1 with nicotine dependence. Hum Genet 123(2):133–140

    Article  CAS  PubMed  Google Scholar 

  33. Duan J, Wainwright MS, Comeron JM, et al. (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 12(3):205–216

    Article  CAS  PubMed  Google Scholar 

  34. Hirvonen MM, Laakso A, Någren K, Rinne JO, Pohjalainen T, Hietala J (2009) C957T polymorphism of dopamine D2 receptor gene affects striatal DRD2 in vivo availability by changing the receptor affinity. Synapse 63(10):907–912

    Article  CAS  PubMed  Google Scholar 

  35. Novak G, LeBlanc M, Zai C, et al. (2010) Association of polymorphisms in the BDNF, DRD1 and DRD3 genes with tobacco smoking in schizophrenia. Ann Hum Genet 74(4):291–298

    Article  CAS  PubMed  Google Scholar 

  36. Batel P, Houchi H, Daoust M, Ramoz N, Naassila M, Gorwood P (2008) A haplotype of the DRD1 gene is associated with alcohol dependence. Alcohol Clin Exp Res 32(4):567–572

    Article  CAS  PubMed  Google Scholar 

  37. Ota VK, Spíndola LN, Gadelha A, dos Santos Filho AF, Santoro ML, Christofolini DM, Bellucco FT, Ribeiro-dos-Santos ÂK, Santos S, Mari Jde J, Melaragno MI, Bressan RA, Smith MA, Belangero SI (2012) DRD1 rs4532 polymorphism: a potential pharmacogenomic marker for treatment response to antipsychotic drugs. Schizophr Res 142(1–3):206–208

    Article  PubMed  Google Scholar 

  38. Johnson AD, Zhang Y, Papp AC, et al. (2008) Polymorphisms affecting gene transcription and mRNA processing in pharmacogenetic candidate genes: detection through allelic expression imbalance in human target tissues. Pharmacogenet Genomics 18(9):781–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lundstrom K, Turpin MP (1996) Proposed schizophrenia-related gene polymorphism: expression of the Ser9Gly mutant human dopamine D3 receptor with the Semliki Forest virus system. Biochem Biophys Res Commun 225(3):1068–1072

    Article  CAS  PubMed  Google Scholar 

  40. Kang SG, Lee BH, Lee JS, et al. (2014) DRD3 gene rs6280 polymorphism may be associated with alcohol dependence overall and with Lesch type I alcohol dependence in Koreans. Neuropsychobiology 69(3):140–146

    Article  CAS  PubMed  Google Scholar 

  41. Kuo SC, Yeh YW, Chen CY, et al. (2014) DRD3 variation associates with early-onset heroin dependence, but not specific personality traits. Prog Neuro-Psychopharmacol Biol Psychiatry 51:1–8

    Article  CAS  Google Scholar 

  42. Simpson J, Vetuz G, Wilson M, Brookes KJ, Kent L (2010) The DRD4 receptor Exon 3 VNTR and 5′ SNP variants and mRNA expression in human post-mortem brain tissue. Am J Med Genet B Neuropsychiatr Genet 153B(6):1228–1233

    CAS  PubMed  Google Scholar 

  43. Vereczkei A, Demetrovics Z, Szekely A, et al. (2013) Multivariate analysis of dopaminergic gene variants as risk factors of heroin dependence. PLoS One 8(6):e66592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ptácek R, Kuzelová H, Stefano GB (2011) Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders. Med Sci Monit 17(9):RA215–RA220

    Article  PubMed  PubMed Central  Google Scholar 

  45. Evans AH, Lawrence AD, Potts J, MacGregor L, Katzenschlager R, Shaw K, Zijlmans J, Lees AJ (2006) Relationship between impulsive sensation seeking traits, smoking, alcohol and caffeine intake, and Parkinson’s disease. J Neurol Neurosurg Psychiatry 77(3):317–321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Center of Research in Medical Pharmacology, University of Insubria, Via Ottorino Rossi n. 9, 21100, Varese, Italy

    M Ferrari, F Marino & M Cosentino

  2. Movement Disorders Centre, Neurology Unit, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy

    C Comi, L Magistrelli, F De Marchi & R Cantello

  3. Departments of Biotechnology and Life Science, University of Insubria, Varese, Italy

    G Riboldazzi & G Bono

Authors
  1. M Ferrari
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  2. C Comi
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  3. F Marino
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  4. L Magistrelli
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  5. F De Marchi
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  9. M Cosentino
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Corresponding author

Correspondence to M Ferrari.

Ethics declarations

The study was approved by the local Ethics Committee (Novara, protocol number 9606), and patients were enrolled after having read and signed an informed consent form.

Conflict of interest

The authors declare that they have no conflict of interest.

Author contribution

Study conception and design: Ferrari F; Comi C. Marino F; Bono G; Cosentino M.

Acquisition of data: Ferrari F; Comi C. Magistrelli L., De Marchi F., Cantello R., Riboldazzi G.

Analysis and interpretation of data: Ferrari F; Comi C. Marino F; Bono G; Cosentino M.

All authors were involved in drafting the article and/or revising it critically for important intellectual content, and all authors approved the final version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved, and declare to have confidence in the integrity of the contributions of their co-authors.

Additional information

Ferrari M. and Comi C. contributed equally to the manuscript

Electronic supplementary material

Figure S1

ROC curve of SNPs in DR as predictors of VHs in PD patients. (GIF 14 kb)

High resolution image (TIFF 268 kb)

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(DOCX 12 kb)

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Ferrari, M., Comi, C., Marino, F. et al. Polymorphisms of dopamine receptor genes and risk of visual hallucinations in Parkinson’s patients. Eur J Clin Pharmacol 72, 1335–1341 (2016). https://doi.org/10.1007/s00228-016-2111-4

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  • DOI: https://doi.org/10.1007/s00228-016-2111-4

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