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A genetic basis for the variable effect of smoking/nicotine on Parkinson’s disease

Abstract

Prior studies have established an inverse association between cigarette smoking and the risk of developing Parkinson’s disease (PD), and currently, the disease-modifying potential of the nicotine patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nicotine, we conducted genome-wide interaction studies in humans and in Drosophila. We identified SV2C, which encodes a synaptic-vesicle protein in PD-vulnerable substantia nigra (P=1 × 10−7 for gene–smoking interaction on PD risk), and CG14691, which is predicted to encode a synaptic-vesicle protein in Drosophila (P=2 × 10−11 for nicotine–paraquat interaction on gene expression). SV2C is biologically plausible because nicotine enhances the release of dopamine through synaptic vesicles, and PD is caused by the depletion of dopamine. Effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful (P=5 × 10−10). Taken together, cross-validating evidence from humans and Drosophila suggests SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine.

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GenBank/EMBL/DDBJ

Gene Expression Omnibus

References

  1. Hernan MA, Takkouche B, Caamano-Isorna F, Gestal-Otero JJ . A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease. Ann Neurol 2002; 52: 276–284.

    Article  PubMed  Google Scholar 

  2. Powers K, Kay D, Factor S, Zabetian C, Higgins D, Samii A et al. Combined effects of smoking, coffee and NSAIDs on Parkinson's disease risk. Mov Disord 2008; 23: 88–95.

    Article  PubMed  Google Scholar 

  3. Quik M, Parameswaran N, McCallum SE, Bordia T, Bao S, McCormack A et al. Chronic oral nicotine treatment protects against striatal degeneration in MPTP-treated primates. J Neurochem 2006; 98: 1866–1875.

    CAS  Article  PubMed  Google Scholar 

  4. Chen JF, Xu K, Petzer JP, Staal R, Xu YH, Beilstein M et al. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J Neurosci 2001; 21: RC143.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Evans AH, Lawrence AD, Potts J, MacGregor L, Katzenschlager R, Shaw K et al. Relationship between impulsive sensation seeking traits, smoking, alcohol and caffeine intake, and Parkinson's disease. J Neurol Neurosurg Psychiatry 2006; 77: 317–321.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Hamza TH, Chen H, Hill-Burns EM, Rhodes SL, Montimurro J, Kay DM et al. Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. PLoS Genet 2011; 7: e1002237.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Costello S, Cockburn M, Bronstein J, Zhang X, Ritz B . Parkinson's disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am J Epidemiol 2009; 169: 919–926.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wang A, Costello S, Cockburn M, Zhang X, Bronstein J, Ritz B . Parkinson's disease risk from ambient exposure to pesticides. Eur J Epidemiol 2011; 26: 547–555.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M et al. Rotenone, paraquat, and Parkinson's disease. Environ Health Perspect 2011; 119: 866–872.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Chaudhuri A, Bowling K, Funderburk C, Lawal H, Inamdar A, Wang Z et al. Interaction of genetic and environmental factors in a Drosophila parkinsonism model. J Neurosci 2007; 27: 2457–2467.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet 2010; 42: 781–785.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ . The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002; 125 (Pt 4): 861–870.

    Article  PubMed  Google Scholar 

  13. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    CAS  Article  PubMed  Google Scholar 

  15. Payami H, Joe S, Farid NR, Stenszki V, Chan SH, Thomson G . Relative predispositional effects (RPE's) of marker alleles with disease: HLA-DR and autoimmune thyroid disease. Am J Hum Genet 1989; 45: 541–546.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Hill-Burns EM, Factor SA, Zabetian CP, Thomson G, Payami H . Evidence for more than one Parkinson's disease-associated variant within the HLA region. PLoS One 2011; 6: e27109.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Wang K, Li M, Hadley D, Liu R, Glessner J, Grant SF et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res 2007; 17: 1665–1674.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Kaplan E, Meier EL . Nonparametric estimation from incomplete observations. J Am Statist Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  19. Gentleman R, Carey V, Bates D, Bolstad B, Dettling M, Dudoit S et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004; 5: R80.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wu Z, Irizarry RA . Preprocessing of oligonucleotide array data. Nat Biotechnol 2004; 22: 656–658.

    CAS  Article  PubMed  Google Scholar 

  21. Smyth G . limma: Linear models for microarray data. In: Gentleman R, Carey VJ, Huber W, Irizarry RA, Dudoit S, (eds) Bioinformatics and Computational Biology Solutions Using R and Bioconductor. Springer: New York, 2005 pp 397–420.

    Chapter  Google Scholar 

  22. Benjamini Y, Hochberg Y . Controlling the false discovery rate: A practical and powerful approach to multiple testing. J Roy Statist Soc Ser B 1995; 57: 289–300.

    Google Scholar 

  23. Hu Y, Flockhart I, Vinayagam A, Bergwitz C, Berger B, Perrimon N et al. An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC Bioinformatics 2011; 12: 357.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Thomas D . Gene—environment-wide association studies: emerging approaches. Nat Rev Genet 2010; 11: 259–272.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Turner TJ . Nicotine enhancement of dopamine release by a calcium-dependent increase in the size of the readily releasable pool of synaptic vesicles. J Neurosci 2004; 24: 11328–11336.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Esposito G, Ana Clara F, Verstreken P . Synaptic vesicle trafficking and Parkinson's disease. Dev Neurobiol 2012; 72: 134–144.

    CAS  Article  PubMed  Google Scholar 

  27. Feany MB, Lee S, Edwards RH, Buckley KM . The synaptic vesicle protein SV2 is a novel type of transmembrane transporter. Cell 1992; 70: 861–867.

    CAS  Article  PubMed  Google Scholar 

  28. Dardou D, Dassesse D, Cuvelier L, Deprez T, De Ryck M, Schiffmann SN . Distribution of SV2C mRNA and protein expression in the mouse brain with a particular emphasis on the basal ganglia system. Brain Res 2011; 1367: 130–145.

    CAS  Article  PubMed  Google Scholar 

  29. Nowack A, Malarkey EB, Yao J, Bleckert A, Hill J, Bajjalieh SM . Levetiracetam reverses synaptic deficits produced by overexpression of SV2A. PLoS One 2011; 6: e29560.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Janz R, Sudhof TC . SV2C is a synaptic vesicle protein with an unusually restricted localization: anatomy of a synaptic vesicle protein family. Neuroscience 1999; 94: 1279–1290.

    CAS  Article  PubMed  Google Scholar 

  31. Quik M, O’Leary K, Tanner CM . Nicotine and Parkinson’s disease: implications for therapy. Mov Disord 2008; 23: 1641–1652.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Itti E, Villafane G, Malek Z, Brugieres P, Capacchione D, Itti L et al. Dopamine transporter imaging under high-dose transdermal nicotine therapy in Parkinson's disease: an observational study. Nucl Med Commun 2009; 30: 513–518.

    Article  PubMed  Google Scholar 

  33. Villafane G, Cesaro P, Rialland A, Baloul S, Azimi S, Bourdet C et al. Chronic high dose transdermal nicotine in Parkinson's disease: an open trial. Eur J Neurol 2007; 14: 1313–1316.

    CAS  Article  PubMed  Google Scholar 

  34. Lemay S, Chouinard S, Blanchet P, Masson H, Soland V, Beuter A et al. Lack of efficacy of a nicotine transdermal treatment on motor and cognitive deficits in Parkinson's disease. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 31–39.

    CAS  Article  PubMed  Google Scholar 

  35. Vieregge A, Sieberer M, Jacobs H, Hagenah JM, Vieregge P . Transdermal nicotine in PD: a randomized, double-blind, placebo-controlled study. Neurology 2001; 57: 1032–1035.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank the persons with Parkinson's disease and volunteers who participated in the study. We also thank Dr John Nutt for his continued support for this project and Dr Sridar Chittur (Center for Functional Genomics at State University of New York at Albany) for processing the expression arrays. The project was funded by grants from the National Institute of Neurological Disorders and Stroke (R01NS36960 and R01NS067469). Additional support was provided by a Merit Review Award from the Department of Veterans Affairs (1I01BX000531), National Institute of Aging (P30AG08017), Office of Research & Development, Clinical Sciences Research & Development Service, Department of Veteran Affairs, and the Close to the Cure Foundation. Genotyping services were provided by the Center for Inherited Disease Research, which is funded by the National Institutes of Health (HHSN268200782096C).

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Correspondence to H Payami.

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Hill-Burns, E., Singh, N., Ganguly, P. et al. A genetic basis for the variable effect of smoking/nicotine on Parkinson’s disease. Pharmacogenomics J 13, 530–537 (2013). https://doi.org/10.1038/tpj.2012.38

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Keywords

  • SV2C
  • nicotine
  • Parkinson’s disease

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