Skip to main content
SpringerLink
Log in

Nonsynonymous Polymorphisms of Histamine-Metabolising Enzymes in Patients with Parkinson’s Disease

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

Objective    To analyze genetically based impairment in histamine-metabolising enzymes in patients with Parkinson’s disease (PD). Methods    Leukocytary DNA from 214 PD patients and a control group of 295 unrelated healthy individuals was studied for nonsynonymous histamine N-methyltransferase (HNMT) and diamine oxidase (ABP1) polymorphisms by using amplification–restriction analyses. Results    An association of the HNMT Thr105Ile polymorphism, but not of the ABP1 His645Asp polymorphism, with PD was observed. Patients with PD showed a higher frequency of homozygous HNMT genotypes leading to high activity with a gene-dose effect (P < 0.001), as compared to healthy subjects. These findings were independent of gender, but the association with the HNMT polymorphism is higher among patients with late-onset PD (P < 0.0001). Conclusion    These results, combined with previous findings indicating alterations in histamine levels in patients with PD, suggest that alterations of histamine homeostasis in the SNC are associated with the risk for PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abbas, N., Lucking, C. B., Ricard, S., Durr, A., Bonifati, V., De Michele, G., Bouley, S., Vaughan, J. R., Gasser, T., Marconi, R., Broussolle, E., Brefel-Courbon, C., Harhangi, B. S., Oostra, B. A., Fabrizio, E., Bohme, G. A., Pradier, L., Wood, N. W., Filla, A., Meco, G., Denefle, P., Agid, Y., & Brice, A. (1999). A wide variety of mutations in the parkin gene are responsible for autosomal recessive Parkinsonism in Europe. French Parkinson’s Disease Genetics Study Group and the European Consortium on Genetic Susceptibility in Parkinson’s Disease. Human Molecular Genetics, 8, 567–574.

    Article  PubMed  CAS  Google Scholar 

  • Abeliovich, A., & Flint Beal, M. (2006). Parkinsonism genes: Culprits and clues. Journal of Neurochemistry, 99, 1062–1072.

    Article  PubMed  CAS  Google Scholar 

  • Agundez, J. A., Jimenez-Jimenez, F. J., Luengo, A., Bernal, M. L., Molina, J. A., Ayuso, L., Vazquez, A., Parra, J., Duarte, J., Coria F., et al. (1995). Association between the oxidative polymorphism and early onset of Parkinson’s disease. Clinical Pharmacology and Therapeutics, 57, 291–298.

    PubMed  CAS  Google Scholar 

  • Agundez, J. A., Jimenez-Jimenez F. J., Luengo A., Molina J. A., Orti-Pareja M., Vazquez A., Ramos F., Duarte J., Coria F., Ladero J. M., Alvarez-Cermeno J. C., & Benitez J. (1998). Slow allotypic variants of the NAT2 gene and susceptibility to early-onset Parkinson’s disease. Neurology, 51, 1587–1592.

    PubMed  CAS  Google Scholar 

  • Agundez, J. A., Rodriguez I., Olivera M., Ladero J. M., Garcia M. A., Ribera J. M., & Benitez J. (1997). CYP2D6, NAT2 and CYP2E1 genetic polymorphisms in nonagenarians. Age Ageing, 26, 147–151.

    Article  PubMed  CAS  Google Scholar 

  • Anichtchik, O. V., Rinne, J. O., Kalimo, H., & Panula, P. (2000). An altered histaminergic innervation of the substantia nigra in Parkinson’s disease. Experimental Neurology, 163, 20–30.

    Article  PubMed  CAS  Google Scholar 

  • Ayuso, P., Garcia-Martin, E., Martinez, C., & Agundez, J. A. (2007). Genetic variability of human diamine oxidase: occurrence of three nonsynonymous polymorphisms and study of their effect on serum enzyme activity. Pharmacogenet Genomics, 17, 687–693.

    PubMed  CAS  Google Scholar 

  • Bonifati, V., Fabrizio, E., Vanacore, N., De Mari, M., & Meco, G. (1995). Familial Parkinson’s disease: A clinical genetic analysis. The Canadian Journal of Neurological Sciences, 22, 272–279.

    PubMed  CAS  Google Scholar 

  • Bonifati, V., Rizzu, P., van Baren, M. J., Schaap, O., Breedveld, G. J., Krieger, E., Dekker, M. C., Squitieri, F., Ibanez, P., Joosse, M., van Dongen, J. W., Vanacore, N., van Swieten, J. C., Brice, A., Meco, G., van Duijn, C. M., Oostra, B. A., & Heutink, P. (2003). Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science, 299, 256–259.

    Article  PubMed  CAS  Google Scholar 

  • Brennan, P. (2002). Gene–environment interaction and aetiology of cancer: What does it mean and how can we measure it? Carcinogenesis, 23, 381–387.

    Article  PubMed  CAS  Google Scholar 

  • Chade, A. R., Kasten, M., & Tanner, C. M. (2006). Nongenetic causes of Parkinson’s disease. Journal of Neural Transmission, Suppl, 147–151.

  • Chan, D. K., Lam, M. K., Wong, R., Hung, W. T., & Wilcken, D. E. (2003). Strong association between N-acetyltransferase 2 genotype and PD in Hong Kong Chinese. Neurology, 60, 1002–1005.

    PubMed  CAS  Google Scholar 

  • Clarimon, J., Scholz, S., Fung, H. C., Hardy, J., Eerola, J., Hellstrom, O., Chen, C. M., Wu, Y. R., Tienari, P. J., & Singleton, A. (2006). Conflicting results regarding the semaphorin gene (SEMA5A) and the risk for Parkinson disease. American Journal of Human Genetics, 78, 1082–1084; author reply 1092–1094.

    Google Scholar 

  • Coelho, M. H., Silva, I. J., Azevedo, M. S., & Manso, C. F. (1991). Decrease in blood histamine in drug-treated parkinsonian patients. Molecular and Chemical Neuropathology, 14, 77–85.

    Article  PubMed  CAS  Google Scholar 

  • Daly, A. K., & Day, C. P. (2001). Candidate gene case–control association studies: Advantages and potential pitfalls. British Journal of Clinical Pharmacology, 52, 489–499.

    Article  PubMed  CAS  Google Scholar 

  • de Rijk, M. C., Tzourio, C., Breteler, M. M., Dartigues, J. F., Amaducci, L., Lopez-Pousa, S., Manubens-Bertran, J. M., Alperovitch, A., & Rocca, W. A. (1997). Prevalence of Parkinsonism and Parkinson’s disease in Europe: The EUROPARKINSON Collaborative Study. European community concerted action on the epidemiology of Parkinson’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 62, 10–15.

    Article  PubMed  Google Scholar 

  • Dekker, M. C., Bonifati, V., & van Duijn C. M. (2003). Parkinson’s disease: Piecing together a genetic jigsaw. Brain, 126, 1722–1733.

    Article  PubMed  CAS  Google Scholar 

  • Elbaz, A., Grigoletto, F., Baldereschi, M., Breteler, M. M., Manubens-Bertran, J. M., Lopez-Pousa, S., Dartigues, J. F., Alperovitch, A., Tzourio, C., & Rocca, W. A. (1999). Familial aggregation of Parkinson’s disease: A population-based case-control study in Europe. EUROPARKINSON Study Group. Neurology, 52, 1876–1882.

    PubMed  CAS  Google Scholar 

  • Elbaz, A., Nelson, L. M., Payami, H., Ioannidis, J. P., Fiske, B. K., Annesi, G., Carmine Belin, A., Factor, S. A., Ferrarese, C., Hadjigeorgiou, G. M., Higgins, D. S., Kawakami, H., Kruger, R., Marder, K. S., Mayeux, R. P., Mellick, G. D., Nutt, J. G., Ritz, B., Samii, A., Tanner, C. M., Van Broeckhoven, C., Van Den Eeden S. K., Wirdefeldt, K., Zabetian, C. P., Dehem, M., Montimurro, J. S., Southwick, A., Myers, R. M., & Trikalinos, T. A. (2006). Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson’s disease: A large-scale international study. Lancet Neurology, 5, 917–923.

    Article  PubMed  CAS  Google Scholar 

  • Farrer, M. J., Haugarvoll, K., Ross, O. A., Stone, J. T., Milkovic, N. M., Cobb, S. A., Whittle, A. J., Lincoln, S. J., Hulihan, M. M., Heckman, M. G., White, L. R., Aasly, J. O., Gibson, J. M., Gosal, D., Lynch, T., Wszolek, Z. K., Uitti, R. J., & Toft, M. (2006). Genomewide association, Parkinson disease, and PARK10. American Journal of Human Genetics, 78, 1084–1088; author reply 1092–1094.

    Google Scholar 

  • Fearnley, J. M., & Lees, A. J. (1991). Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain, 114(Pt 5), 2283–2301.

    Google Scholar 

  • Funayama, M., Hasegawa K., Kowa, H., Saito, M., Tsuji, S., & Obata, F. (2002). A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Annals of Neurology, 51, 296–301.

    Article  PubMed  CAS  Google Scholar 

  • Gasser, T., Muller-Myhsok, B., Wszolek, Z. K., Oehlmann, R., Calne, D. B., Bonifati, V., Bereznai, B., Fabrizio, E., Vieregge, P., & Horstmann, R. D. (1998). A susceptibility locus for Parkinson’s disease maps to chromosome 2p13. Nature Genetics, 18, 262–265.

    Article  PubMed  CAS  Google Scholar 

  • Gibb, W. R., & Lees, A. J. (1989). Prevalence of Lewy bodies in Alzheimer’s disease. Annals of Neurology, 26, 691–693.

    Article  PubMed  CAS  Google Scholar 

  • Goris, A., Williams-Gray, C. H., Foltynie, T., Compston, D. A., Barker, R. A., & Sawcer, S. J. (2006). No evidence for association with Parkinson disease for 13 single-nucleotide polymorphisms identified by whole-genome association screening. American Journal of Human Genetics, 78, 1088–1090; author reply 1092–1094.

    Google Scholar 

  • Hampshire, D. J., Roberts, E., Crow, Y., Bond, J., Mubaidin, A., Wriekat, A. L., Al-Din, A., & Woods, C. G. (2001). Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36. Journal of Medical Genetics, 38, 680–682.

    Article  PubMed  CAS  Google Scholar 

  • Hardy, J., Cai, H., Cookson, M. R., Gwinn-Hardy, K., & Singleton, A. (2006). Genetics of Parkinson’s disease and parkinsonism. Annals of Neurology, 60, 389–398.

    Article  PubMed  CAS  Google Scholar 

  • Hicks, A. A., Petursson, H., Jonsson, T., Stefansson, H., Johannsdottir, H. S., Sainz, J., Frigge, M. L., Kong, A., Gulcher, J. R., Stefansson, K., & Sveinbjornsdottir, S. (2002). A susceptibility gene for late-onset idiopathic Parkinson’s disease. Annals of Neurology, 52, 549–555.

    Article  PubMed  CAS  Google Scholar 

  • Hughes, A. J., Daniel, S. E., Kilford, L., & Lees, A. J. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. Journal of Neurology, Neurosurgery, and Psychiatry, 55, 181–184.

    PubMed  CAS  Google Scholar 

  • Jimenez-Jimenez, F. J., Tabernero, C., Mena, M. A., Garcia de Yebenes, J., Garcia de Yebenes, M. J., Casarejos, M. J., Pardo, B., Garcia-Agundez, J. A., Benitez, J., Martinez, A., et al. (1991). Acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in a model of rat designated a poor metabolizer of debrisoquine. Journal Neurochemistry, 57, 81–87.

    Article  CAS  Google Scholar 

  • Kim, S. H., Krapfenbauer, K., Cheon, M. S., Fountoulakis, M., Cairns, N. J., & Lubec, G. (2002). Human brain cytosolic histamine-N-methyltransferase is decreased in Down syndrome and increased in Pick’s disease. Neuroscience Letters, 321, 169–172.

    Article  PubMed  CAS  Google Scholar 

  • Langlais, P. J., Zhang, S. X., Weilersbacher, G., Hough, L. B., & Barke, K. E. (1994). Histamine-mediated neuronal death in a rat model of Wernicke’s encephalopathy. Journal of Neuroscience Research, 38, 565–574.

    Article  PubMed  CAS  Google Scholar 

  • Leroy, E., Boyer, R., Auburger, G., Leube, B., Ulm, G., Mezey, E., Harta, G., Brownstein, M. J., Jonnalagada, S., Chernova, T., Dehejia, A., Lavedan, C., Gasser, T., Steinbach, P. J., Wilkinson, K. D., & Polymeropoulos, M. H. (1998). The ubiquitin pathway in Parkinson’s disease. Nature, 395, 451–452.

    Article  PubMed  CAS  Google Scholar 

  • Li, Y., Rowland, C., Schrodi, S., Laird, W., Tacey, K., Ross, D., Leong, D., Catanese, J., Sninsky, J., & Grupe, A. (2006). A case-control association study of the 12 single-nucleotide polymorphisms implicated in Parkinson disease by a recent genome scan. American Journal of Human Genetics, 78, 1090–1092; author reply 1092–1094.

    Google Scholar 

  • Maraganore, D. M., de Andrade, M., Lesnick, T. G., Strain, K. J., Farrer, M. J., Rocca, W. A., Pant, P. V., Frazer, K. A., Cox, D. R., & Ballinger, D. G. (2005). High-resolution whole-genome association study of Parkinson disease. American Journal of Human Genetics, 77, 685–693.

    Article  PubMed  CAS  Google Scholar 

  • Marder, K., Tang, M. X., Mejia, H., Alfaro, B., Cote, L., Louis, E., Groves, J., & Mayeux, R. (1996). Risk of Parkinson’s disease among first-degree relatives: A community-based study. Neurology, 47, 155–160.

    PubMed  CAS  Google Scholar 

  • Matsumine, H., Saito, M., Shimoda-Matsubayashi, S., Tanaka, H., Ishikawa, A., Nakagawa-Hattori, Y., Yokochi, M., Kobayashi, T., Igarashi, S., Takano, H., Sanpei, K., Koike, R., Mori, H., Kondo, T., Mizutani, Y., Schaffer, A. A., Yamamura, Y., Nakamura, S., Kuzuhara, S., Tsuji, S., & Mizuno, Y. (1997). Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2–27. American Journal of Human Genetics, 60, 588–596.

    PubMed  CAS  Google Scholar 

  • Obata, T. (2002). Semicarbazide-sensitive amine oxidase (SSAO) in the brain. Neurochemical Research, 27, 263–268.

    Article  PubMed  CAS  Google Scholar 

  • Pankratz, N., Nichols, W. C., Uniacke, S. K., Halter, C., Rudolph, A., Shults, C., Conneally, P. M., & Foroud, T. (2003). Significant linkage of Parkinson disease to chromosome 2q36–37. American Journal of Human Genetics, 72, 1053–1057.

    Article  PubMed  CAS  Google Scholar 

  • Panula, P., Yang, H. Y., & Costa, E. (1984). Histamine-containing neurons in the rat hypothalamus. Proceedings of the National Academy of Sciences of the United States of America, 81, 2572–2576.

    Article  PubMed  CAS  Google Scholar 

  • Pértegas Díazs, S., & Pita Fernández, S. (2003). Cálculo del poder estadístico de un estudio. Cad Aten Prim, 10, 59–63.

    Google Scholar 

  • Piccini, P., Burn, D. J., Ceravolo, R., Maraganore, D., & Brooks, D. J. (1999). The role of inheritance in sporadic Parkinson’s disease: evidence from a longitudinal study of dopaminergic function in twins. Annals of Neurology, 45, 577–582.

    Article  PubMed  CAS  Google Scholar 

  • Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., Stenroos, E. S., Chandrasekharappa, S., Athanassiadou, A., Papapetropoulos, T., Johnson, W. G., Lazzarini, A. M., Duvoisin, R. C., Di, Iorio, G., Golbe, L. I., & Nussbaum, R. L. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 276, 2045–2047.

    Article  PubMed  CAS  Google Scholar 

  • Prell, G. D., & Green, J. P. (1991). Histamine metabolites and pros-methylimidazoleacetic acid in human cerebrospinal fluid. Agents Actions Supplement, 33, 343–363.

    CAS  Google Scholar 

  • Preuss, C. V., Wood, T. C., Szumlanski, C. L., Raftogianis, R. B., Otterness, D. M., Girard, B., Scott, M. C., & Weinshilboum, R. M. (1998). Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity. Molecular Pharmacology, 53, 708–717.

    PubMed  CAS  Google Scholar 

  • Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., Lincoln, S., Crawley, A., Hanson, M., Maraganore, D., Adler, C., Cookson, M. R., Muenter, M., Baptista, M., Miller, D., Blancato, J., Hardy, J., & Gwinn-Hardy, K. (2003). Alpha-Synuclein locus triplication causes Parkinson’s disease. Science, 302, 841.

    Article  PubMed  CAS  Google Scholar 

  • Tan, E. K., Chan, D. K., Ng, P. W., Woo, J., Teo, Y. Y., Tang, K., Wong, L. P., Chong, S. S., Tan, C., Shen, H., Zhao, Y., & Lee, C. G. (2005). Effect of MDR1 haplotype on risk of Parkinson disease. Archives of Neurology, 62, 460–464.

    Article  PubMed  Google Scholar 

  • Tanner, C. M., Ottman, R., Goldman, S. M., Ellenberg, J., Chan, P., Mayeux, R., & Langston, J. W. (1999). Parkinson disease in twins: an etiologic study. The Journal of American Medical Association, 281, 341–346.

    Article  CAS  Google Scholar 

  • Thoburn, K. K., Hough, L. B., Nalwalk, J. W., & Mischler, S. A. (1994). Histamine-induced modulation of nociceptive responses. Pain, 58, 29–37.

    Article  PubMed  CAS  Google Scholar 

  • Thomas, B., & Prell, G. D. (1995). Imidazoleacetic acid, a gamma-aminobutyric acid receptor agonist, can be formed in rat brain by oxidation of histamine. Journal of Neurochemisry, 65, 818–826.

    Article  CAS  Google Scholar 

  • Valente, E. M., Salvi, S., Ialongo, T., Marongiu, R., Elia, A. E., Caputo, V., Romito, L., Albanese, A., Dallapiccola, B., & Bentivoglio, A. R. (2004). PINK1 mutations are associated with sporadic early-onset parkinsonism. Annals of Neurology, 56, 336–341.

    Article  PubMed  CAS  Google Scholar 

  • van Duijn, C. M., Dekker, M. C., Bonifati, V., Galjaard, R. J., Houwing-Duistermaat, J. J., Snijders, P. J., Testers, L., Breedveld, G. J., Horstink, M., Sandkuijl, L. A., van Swieten, J. C., Oostra, B. A., & Heutink, P. (2001). Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. American Journal of Human Genetics, 69 , 629–634.

    Article  PubMed  Google Scholar 

  • Vizuete, M. L., Merino, M., Venero, J. L., Santiago, M., Cano, J., & Machado, A. (2000). Histamine infusion induces a selective dopaminergic neuronal death along with an inflammatory reaction in rat substantia nigra. Journal of Neurochemistry, 75, 540–552.

    Article  PubMed  CAS  Google Scholar 

  • Watanabe, T., Taguchi, Y., Shiosaka, S., Tanaka, J., Kubota, H., Terano, Y., Tohyama, M., & Wada, H. (1984). Distribution of the histaminergic neuron system in the central nervous system of rats; a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker. Brain Research, 295, 13–25.

    Article  PubMed  CAS  Google Scholar 

  • Wilk, J. B., Tobin, J. E., Suchowersky, O., Shill, H. A., Klein, C., Wooten, G. F., Lew, M. F., Mark, M. H., Guttman, M., Watts, R. L., Singer, C., Growdon, J. H., Latourelle, J. C., Saint-Hilaire, M. H., DeStefano, A. L., Prakash, R., Williamson, S., Berg, C. J., Sun, M., Goldwurm, S., Pezzoli, G., Racette, B. A., Perlmutter, J. S., Parsian, A., Baker, K. B., Giroux, M. L., Litvan, I., Pramstaller, P. P., Nicholson, G., Burn, D. J., Chinnery, P. F., Vieregge, P., Slevin, J. T., Cambi, F., MacDonald, M. E., Gusella, J. F., Myers, R. H., & Golbe, L. I. (2006). Herbicide exposure modifies GSTP1 haplotype association to Parkinson onset age: the GenePD Study. Neurology, 67, 2206–2210.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Grants SAF 2003–00967 from Ministerio de Ciencia y Tecnología, FIS 05/1056 and 06/1252 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III.

Author information

Authors and Affiliations

  1. Department of Pharmacology & Psychiatry, Medical School, University of Extremadura, Badajoz, Spain

    José A. G. Agúndez, Oscar Herráez & Carmen Martínez

  2. Service of Neurology, University Hospital La Princesa, Madrid, Spain

    Antonio Luengo

  3. Department of Medicine—Neurology, Príncipe de Asturias Hospital, University of Alcalá de Henares, Madrid, Spain

    Hortensia Alonso-Navarro & Félix Javier Jiménez-Jiménez

  4. Department of Biochemistry and Molecular Biology, School of Biological Sciences, University of Extremadura, Avda. de Elvas s/n, 06071, Badajoz, Spain

    Elena García-Martín

Authors
  1. José A. G. Agúndez
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Luengo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oscar Herráez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carmen Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hortensia Alonso-Navarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Félix Javier Jiménez-Jiménez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elena García-Martín
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elena García-Martín.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Agúndez, J.A.G., Luengo, A., Herráez, O. et al. Nonsynonymous Polymorphisms of Histamine-Metabolising Enzymes in Patients with Parkinson’s Disease. Neuromol Med 10, 10–16 (2008). https://doi.org/10.1007/s12017-007-8017-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-007-8017-7

Keywords

Search

Navigation