Skip to main content
Article thumbnail
Location of Repository

Case-only study of interactions between specific genetic polymorphisms and cigarette smoking in the aetiology of Parkinson's disease

By Yifu Deng

Abstract

The aetiology of Parkinson's disease (PD) is still unclear. Research findings suggest that both environmental and genetic factors may contribute to its development. The interactions between genes and the environment might exist and play a key role. Cigarette smoking was found to be one of the few factors exhibiting a protective effect. If chemical compounds found in cigarette smoke influence PD risk, the difference in the ability of certain individuals in metabolising these substances might alter their susceptibility to the risk of developing PD. Many metabolic enzyme genes exhibit polymorphic traits with alteration of gene function. These might be associated with an altered susceptibility of individuals to PD. Few studies have examined the hypothesis that metabolic enzyme gene polymorphisms might modulate the effect of smoking on PD risk. However, it is crucial to consider these potential interactions when we try to elucidate the aetiology of PD. Even if each factor only contributes a slight variation and influences a small portion of the whole population, non-linear and unpredictable interactions may account for a high proportion of the aetiological fraction. Previous studies have not been strictly designed to examine the interactions between smoking and metabolic enzyme genetic polymorphisms. These studies have not been able to elucidate the extent of the interaction. Therefore, this PhD project attempted to examine whether genetic factors, operating in the phase one and phase two metabolic pathways, interact with smoking to influence the development of PD. This is the first genetic epidemiological study of PD specifically addressing this issue. The research aids in further understanding the aetiology of PD and may be useful for identifying people at higher risk. A case-only design was chosen for this project for two reasons: first, PD is a relatively rare disease and the case-only design is much more efficient at detecting gene-environment interactions; second, the PD cases for the project were recruited over the past few years and represent a prevalence series, for which an appropriate comparison group for the cases is difficult to identify and recruit. In a case-only study, only cases are used to investigate the multiplicative effects of the exposures and susceptible genotypes of interest, while non-case subjects (traditionally controls) are solely used to test the independence between the exposure and the susceptible genotype. Therefore, this approach avoids the challenges of control selection, a major limitation inherent in the case-control approach. This thesis comprised of three independent studies: the first study investigated the interactions between genetic polymorphisms of GSTM1, P1, T1 and Z1 and smoking in PD; the second study examined the interactions between genetic polymorphisms of CYP2E1 and smoking in PD; and the third study examined the interactions between genetic polymorphisms of CYP2D6 and smoking in PD. The first two studies recruited 400 white Caucasian PD cases from both hospital wards and private neurology clinics (230 men and 170 women). The third study further included 142 white Caucasian PD cases newly recruited from the same sources (542 in total, 321 men, and 221 women). The mean age of cases was 67 years with the average onset age at 60 years. GSTM1, GSTP1, GSTT1, GSTZ1 AND CYP2E1 genotyping processes were performed using protocols previously published with minor modification, whereas CYP2D6 genotyping methods were mainly developed by me with assistance from associate supervisor Dr. George Mellick. Reliability and validity of the PCR and RFLP methods were assessed through re-conducting the genotype assays using at least a 10% sample of our DNA samples. The results for all re-assessments were 100% concordant. Crude bivariate analyses were adjusted for potential confounding effects of the variables, including age at onset, gender, family history of PD and pesticide exposures. Among our unaffected, aged subjects (mean age: 63.9 years, sd: 11.4 years), the genotype frequencies at each locus were similar to those reported in other Caucasian populations. The first study showed that the proportion of carriers of the GSTP1-114Val allele (mutant) increased with increasing smoking dose from 0 to > 30 pack-years. Homozygotes of the 114Ala allele (wild-type) decreased with increasing smoking dose (trend test: p=0.02). This trend existed both in male and female cases. This dose-effect relationship was most significant in the group of cases with late-onset PD (i.e., age at onset > 55 years) with the ORicase-only values of 1.88 (95%CI: 0.65-5.48) and 2.63 (95%CI: 1.07-6.49) for > 0-10 and > 10 pack-years, respectively. No similar trend was found among our unaffected, aged subjects (p=0.42). Haplotype analyses revealed significant differences for GSTP1 haplotypes between smoking and non-smoking PD cases (ORicase-only for *C haplotype=2.00 (95%CI: 1.11-3.60), p=0.03). In this case, smoking-exposed PD cases were more likely to posses the *C haplotype defined by A to G base-pair transition at nucleotide +313 and C to T base-pair transition at nucleotide +341 (at amino acid level, valine at both positions 105 and 114). The second study found no difference in CYP2E1 genotype frequencies between PD cases who ever smoked compared to those who never smoked (odds ratio for interaction (ORi) = 1.00 (95% CI: 0.39-2.51, p=0.99)). No CYP2E1 gene-smoking interactions were detected in relation to age at onset of PD. The third study found that among cases without regular pesticide exposures, CYP2D6 PMs who smoked more than 5 pack-years had a later mean age at disease onset (68.6 years) than those with extensive metaboliser phenotypes (EMs) (61.1 years, p=0.02) and non-smokers (60.5 years, p=0.01). Analysis of aged subjects without PD confirmed that neither smoking status nor CYP2D6 PM status was associated with age itself. Our data suggest: 1. smoking exposure is independent of GSTM1, P1, T1, Z1 and CYP2E1 genotypes; 2. smoking may be, to some extent, associated with CYP2D6 genotypes; 3. there are no multiplicative interactive effects linking smoking and GSTM1, T1, Z1 or CYP2E1 genotypes with the risk for PD; 4. there is a multiplicative interactive effect between smoking and GSTP1 haplotype - particularly for genotypes carrying the 114Val allele; and 5. there is a multiplicative interactive effect between smoking and CYP2D6 PMs - particularly for people who ever smoked cigarettes more than 5 pack-years. In general, this thesis provides a model for exploring the gene-smoking interactions in PD. Further studies need to consider the recruitment of a large number of population-based and randomly-selected samples and to pay more attention to measurement of environmental exposures. Further studies also need to examine simultaneously the impact of smoking, pesticide exposures and other potential risk factors on PD. These studies will build evidence for interactions contributing to this common neurological movement disorder

Topics: Parkinson’s disease, smoking, GSTM1, GSTP1, GSTT1, GSTZ1, CYP2D6, CYP2E1, gene-environment interaction
Publisher: Queensland University of Technology
Year: 2005
OAI identifier: oai:eprints.qut.edu.au:16211

Suggested articles

Citations

  1. (1986). (+)-4-Propyl-9-hydroxynaphthoxazine in Parkinson's disease. Lancet,
  2. (1998). [Association between the debrisoquine hydroxylase gene polymorphism and the genetic susceptibility of Parkinson's disease]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi,
  3. [New clues to the etiology of Parkinson disease: parkinsonism induced by the neurotoxin MPTP].
  4. (1999). [Parkin gene and its function; a key to understand nigral degeneration]. Rinsho Shinkeigaku,
  5. (1991). [Parkinson's disease and environmental factors]. Rev Epidemiol Sante Publique,
  6. (1986). 1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3-MPTP) is a more potent dopaminergic neurotoxin than MPTP in mice.
  7. (1991). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity: partial protection against striatonigral dopamine depletion in C57BL/6J mice by cigarette smoke exposure and by beta-naphthoflavone-pretreatment. Neurosci Lett,
  8. (1986). 1-methyl-4-phenylpyridine is neurotoxic to the nigrostriatal dopamine pathway. Nature,
  9. (1987). 1,2,3,6-tetrahydro-1-methyl-4-(methylpyrrol-2-yl)pyridine: studies on the mechanism of action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
  10. (1987). 4-Phenylpyridine (4PP) and MPTP: the relationship between striatal MPP+ concentrations and neurotoxicity. Life Sci,
  11. (1986). A case-control study of twin pairs discordant for Parkinson's disease: a search for environmental risk factors. Neurology,
  12. (1998). A genetic polymorphism of MAO-B modifies the association of cigarette smoking and Parkinson's disease. Neurology,
  13. (1999). A genome-wide search for loci contributing to smoking and alcoholism. Genet Epidemiol,
  14. (2002). A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease. Ann Neurol,
  15. (1996). A multiplex PCR procedure for polymorphic analysis of GSTM1 and GSTT1 genes in population studies. Cancer Lett,
  16. (2004). A Novel Screen for Nuclear Mitochondrial Gene Associations with Parkinson's Disease.
  17. (1991). A pilot study of occupational and environmental risk factors for Parkinson's disease. Neurotoxicology,
  18. (2002). A population-based, case-control study of polymorphisms in carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk.
  19. (1968). A retrospective study of smoking in Parkinson's disease.
  20. (1999). A study of five candidate genes in Parkinson's disease and related neurodegenerative disorders.
  21. (1999). Absence of effect of seven functional mutations in the CYP2D6 gene in Parkinson's disease. Mov Disord,
  22. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases.
  23. Aetiology of Parkinson's disease.
  24. (2002). Age at onset of Parkinson disease and apolipoprotein E genotypes.
  25. (2002). Age-environment and gene-environment interactions in the pathogenesis of Parkinson's disease. Rev Environ Health,
  26. Alzheimer's disease, Parkinson's disease, and motoneurone disease: abiotrophic interaction between ageing and environment?
  27. An association between idiopathic Parkinson's disease and polymorphisms of phase II detoxification enzymes: glutathione S-transferase M1 and quinone oxidoreductase 1 and 2. Biochem Biophys Res Commun,
  28. (1995). An E-M algorithm and testing strategy for multiple-locus haplotypes.
  29. and CYP2E1 polymorphisms and trihalomethanes in drinking water: effect on childhood leukemia. Environ Health Perspect,
  30. (2003). Association between Parkinson's disease and polymorphisms in the nNOS and iNOS genes in a community-based casecontrol study. Hum Mol Genet,
  31. (1994). Association between restriction fragment length polymorphism of the human cytochrome P450IIE1 gene and susceptibility to alcoholic liver cirrhosis.
  32. (1995). Association between the oxidative polymorphism and early onset of Parkinson's disease. Clin Pharmacol Ther,
  33. (2001). Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease. Jama,
  34. (1997). Association of slow acetylator genotype for Nacetyltransferase 2 with familial Parkinson's disease. Lancet,
  35. BamHI and EcoRI restriction fragment length polymorphisms at the glutathione S-transferase 3 locus.
  36. (2000). Case-control study of debrisoquine 4-hydroxylase, N-acetyltransferase 2, and apolipoprotein E gene polymorphisms in Parkinson's disease. Mov Disord,
  37. (1998). Case-control study of interactions between genetic and environmental factors in Parkinson's disease.
  38. (2004). Case-only study of interactions between genetic polymorphisms of GSTM1, P1, T1 and Z1 and smoking in Parkinson's disease. Neurosci Lett,
  39. (1986). Characterization of ethanol-inducible human liver Nnitrosodimethylamine demethylase. Biochemistry,
  40. (1994). Chronic nicotine treatment counteracts dopamine D2 receptor upregulation induced by a partial meso-diencephalic hemitransection in the rat. Brain Res,
  41. (1993). Chronic nicotine treatment counteracts nigral cell loss induced by a partial mesodiencephalic hemitransection: an analysis of the total number and mean volume of neurons and glia in substantia nigra of the male rat. Neuroscience,
  42. (1980). Cigarette smoking and Parkinson disease: 1. Comparison of cases with matched neighbors. Neurology,
  43. (1992). Cigarette smoking and Parkinson disease: the illusion of a neuroprotective effect. Clin Neuropharmacol,
  44. (2004). Cigarette smoking and Parkinson's disease: A casecontrol study in a population characterized by a high prevalence of pesticide exposure. Mov Disord,
  45. (1986). Cigarette smoking and Parkinson's disease. Neurology,
  46. (1999). Cigarette smoking.
  47. (1985). Comparative behavioral, biochemical and pigmentary effects of MPTP, MPP+ and paraquat in Rana pipiens. Life Sci,
  48. (1998). Conjugates of catecholamines with cysteine and GSH in Parkinson's disease: possible mechanisms of formation involving reactive oxygen species.
  49. (1992). Criteria for diagnosing Parkinson's disease. Ann Neurol,
  50. (1996). CYP2D6 allelic frequencies in young-onset Parkinson's disease. Neurology,
  51. (1997). CYP2D6 genotype and smoking behaviour in cigarette smokers. Pharmacogenetics,
  52. (1996). CYP2D6 genotypes in cigarette smokers and non-tobacco users. Pharmacogenetics,
  53. CYP2D6 is associated with Parkinson's disease but not with dementia with Lewy Bodies or Alzheimer's disease.
  54. (1999). CYP2D6 polymorphism and Parkinson's disease susceptibility. Mov Disord,
  55. (2001). CYP2D6 polymorphism in Parkinson's disease: the Rotterdam Study. Mov Disord,
  56. (2004). CYP2D6 polymorphism, pesticide exposure, and Parkinson's disease. Ann Neurol,
  57. (2000). CYP2D6 ultrarapid metabolizer genotype as a potential modifier of smoking behaviour. Pharmacogenetics,
  58. (2001). CYP2D6*4 polymorphism is not associated with Parkinson's disease and has no protective role against Alzheimer's disease in the Korean population. Psychiatry Clin Neurosci,
  59. (1997). Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev,
  60. (1997). Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences.
  61. (2001). Cytochrome p450 and parkinsonism: protective role of CYP2E1. Funct Neurol,
  62. (1998). Cytochrome P4502E1 inducibility and hydroxyethyl radical formation among alcoholics.
  63. (1992). Cytochrome P450IIE1 genetic polymorphisms, racial variation, and lung cancer risk. Cancer Res,
  64. (1990). Cytochrome P450IIE1: roles in nitrosamine metabolism and mechanisms of regulation. Drug Metab Rev,
  65. (1995). Debrisoquine hydroxylase gene polymorphism in Parkinson's disease and amyotrophic lateral sclerosis.
  66. (1998). Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson's disease. Hum Genet,
  67. (1997). Detection of DNA damage in transcriptionally active genes by RT-PCR and assessment of repair of cisplatin-induced damage in the glutathione S-transferase-pi gene in human glioblastoma cells. Toxicol Appl Pharmacol,
  68. (1999). Detection of gene-environment interaction by case-only studies.
  69. (1991). Determinants of disease and disability in the elderly: the Rotterdam Elderly Study.
  70. (1999). Determination of glutathione Stransferase mu and theta polymorphisms in neurological disease. Hum Exp Toxicol,
  71. (1994). Different regulation and expression of the human CYP2E1 gene due to the RsaI polymorphism in the 5'-flanking region.
  72. (1992). Differential effects of acute and chronic nicotine treatment on MPTP-(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced degeneration of nigrostriatal dopamine neurons in the black mouse. Clin Investig,
  73. (2003). Dose-dependent protective effect of coffee, tea, and smoking in Parkinson's disease: a study in ethnic Chinese.
  74. (2001). Dose-related neuroprotective effects of chronic nicotine in 6-hydroxydopamine treated rats, and loss of neuroprotection in alpha4 nicotinic receptor subunit knockout mice.
  75. (1994). Effect of ethanol on cytochrome P450 in the rat brain.
  76. (1990). Effect of normal aging on the activity of human hepatic cytochrome P450IIE1. Biochem Pharmacol,
  77. (1995). Effects of cigarette smoking on performance in a simulated driving task. Neuropsychobiology,
  78. (1993). Effects of smoking in patients with early-onset Parkinson's disease.
  79. (2001). Elucidation of CYP2E1 5' regulatory RsaI/Pstl allelic variants and their role in risk for oral cancer. Oral Oncol,
  80. (1997). Enhancing effects of captafol on the development of GST-Ppositive liver cell foci in a medium-term bioassay, and protection by Lcysteine of the enhancement in rats. Cancer Lett,
  81. (1987). Environmental factors in the etiology of Parkinson's disease.
  82. (1987). Environmental risk factors for Parkinson's disease: the epidemiologic evidence.
  83. (1972). Epidemiologic studies of Parkinson's disease. 3. A communitybased survey.
  84. (1971). Epidemiologic studies of Parkinson's disease. I. Smoking and Parkinson's disease: a survey and explanatory hypothesis.
  85. (1997). Epidemiology of Parkinson's Disease: The Rotterman Study.
  86. (1998). Epidemiology versus genetics in Parkinson's disease: progress in resolving an age-old debate. Ann Neurol,
  87. (1995). Ethanol increases cytochrome P4502E1 and induces oxidative stress in astrocytes.
  88. (1994). Ethnic variation in the CYP2E1 gene: polymorphism analysis
  89. (1984). Etiology of Parkinson's disease: A research strategy.
  90. (1986). Etiology of Parkinson's disease: current concepts. Clin Neuropharmacol,
  91. (1995). Evidence for genetic influences on smoking in adult women twins. Clin Genet,
  92. (1990). Evidence that the blockade of mitochondrial respiration by the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) involves binding at the same site as the respiratory inhibitor, rotenone. Biochem Biophys Res Commun,
  93. (1986). Experimental model of Parkinson disease induced by Nmethyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)]. Neuropatol Pol,
  94. (1992). Exposure to well water and pesticides in Parkinson's disease: a case-control study in the Madrid area. Mov Disord,
  95. (1996). Expression, catalytic activity, and inducibility of cytochrome P450 2E1 (CYP2E1) in the rat central nervous system.
  96. (2001). Failure of the ubiquitin-proteasome system in Parkinson's disease. Nat Rev Neurosci,
  97. (2002). Faster haplotype frequency estimation using unrelated subjects. Hum Hered,
  98. (1995). Frequency of a specific cytochrome P4502D6B (CYP2D6B) mutant allele in clinically differentiated groups of patients with Parkinson disease. Biochem Mol Med,
  99. (2000). Functional Cyp2e1 is required for substantial in vivo formation of 2,5-hexanedione from n-hexane in the mouse. Arch Toxicol,
  100. (2004). Further evidence that interactions between CYP2D6 and pesticide exposure increase risk for Parkinson's disease. Ann Neurol,
  101. (1996). Gene-environment interaction in parkinson's disease. The case of CYP2D6 gene polymorphism. Adv Neurol,
  102. (2002). GENECOUNTING: haplotype analysis with missing genotypes.
  103. (1998). Genetic analysis of the CYP2D6 gene in patients with Parkinson's disease. Metabolism,
  104. (1995). Genetic and environmental aspects of the role of nicotinic receptors in neurodegenerative disorders: emphasis on Alzheimer's disease and Parkinson's disease. Behav Genet,
  105. (1997). Genetic and environmental contributions to smoking. Addiction,
  106. (1999). Genetic and environmental factors in Parkinson's disease. Adv Neurol,
  107. (1999). Genetic and environmental factors in the pathogenesis of Parkinson's disease. Adv Neurol,
  108. (1998). Genetic and environmental risk factors for Parkinson's disease in a Chinese population.
  109. (1998). Genetic and environmental risk factors in Parkinson's disease. Clin Neurol Neurosurg,
  110. (1998). Genetic aspects of Parkinson's disease. Mov Disord,
  111. (1992). Genetic influence on smoking--a study of male twins.
  112. (1991). Genetic linkage of lung cancer-associated MspI polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P450IA1 gene.
  113. (1998). Genetic polymorphism and Parkinson's disease in Taiwan: study of debrisoquine 4-hydroxylase (CYP2D6). J Neurol Sci,
  114. (1994). Genetic polymorphism of cytochrome
  115. (1993). Genetic polymorphism of cytochrome P4502E1 in a Swedish population. Relationship to incidence of lung cancer.
  116. (1997). Genetic polymorphism of human CYP2E1: characterization of two variant alleles. Mol Pharmacol,
  117. (1991). Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene.
  118. (1998). Genetic risk factors in Parkinson's disease. Ann Neurol,
  119. (1997). Genetics of Parkinson's disease. Hum Mol Genet,
  120. (2001). Genetics of Parkinsonism: a review. Ann Hum Genet,
  121. (1997). Genomic cloning of hGSTP1*C, an allelic human Pi class glutathione S-transferase gene variant and functional characterization of its retinoic acid response elements.
  122. (2000). Genotyping of CYP2D6 in Parkinson's disease. Clin Chem Lab Med,
  123. (2001). Glial cells and abnormal protein handling in the pathogenesis of Parkinson's disease. Adv Neurol,
  124. (1990). Glutathione S-transferase in human brain.
  125. (2003). Glutathione S-transferase M1 and T1 genotypes and endometriosis risk: a case-controlled study.
  126. (2000). Glutathione S-transferase polymorphism in Parkinson's disease.
  127. (2000). Glutathione transferase M2-2 catalyzes conjugation of dopamine and dopa o-quinones.
  128. (1997). Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes. Biochem J,
  129. (2000). GSTM1 and mEPHX polymorphisms in Parkinson's disease and age of onset.
  130. (1994). Hepatic messenger RNA contents of cytochrome P4502E1 in patients with different P4502E1 genotypes. Alcohol Alcohol,
  131. (1997). Human class Mu glutathione transferases, in particular isoenzyme M2-2, catalyze detoxication of the dopamine metabolite aminochrome.
  132. (1998). Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis,
  133. (1999). Identification of 167 polymorphisms in 88 genes from candidate neurodegeneration pathways. Gene,
  134. Identification of a glutathione-S-transferase effector domain for inhibition of jun kinase, by molecular dynamics.
  135. (1998). Impaired clearance of oxidised proteins in neurodegenerative diseases.
  136. (1989). Incidence and risk factors of Parkinson's disease in The Netherlands. Neuroepidemiology,
  137. (1998). Increased bioactivation of dihaloalkanes in rat liver due to induction of class theta glutathione S-transferase T1-1. Biochem J,
  138. (2002). Increased dopamine peroxidation in postmortem Parkinsonian brain. Biochim Biophys Acta,
  139. (1995). Increased risk of Parkinson's disease in relatives of patients. Ann Neurol,
  140. Induction of cytochrome P450 2E1 expression in rat and gerbil astrocytes by inflammatory factors and ischemic injury.
  141. (1992). Inhibition of [3H]dopamine uptake into rat striatal slices by quaternary N-methylated nicotine metabolites. Life Sci,
  142. (1996). Inhibition of monoamine oxidase B in the brains of smokers. Nature,
  143. (2004). Interaction between GSTM1-null and CYP2D6-deficient alleles in the pathogenesis of Parkinson's disease.
  144. (1997). Is there a genetic susceptibility locus for Parkinson's disease on chromosome 22q13? Ann Neurol,
  145. (1989). Isolation of a cDNA clone and localization of the human glutathione S-transferase 3 genes to chromosome bands 11q13 and 12q13-14. Ann Hum Genet,
  146. (2000). Lack of association between cytochrome P450 2E1 gene polymorphisms and Parkinson's disease in a Chinese population. Mov Disord,
  147. (2001). Limitations of the case-only design for identifying geneenvironment interactions.
  148. (1986). Lipid peroxidation as cause of nigral cell death in Parkinson's disease. Lancet,
  149. (1984). Manganese and extrapyramidal disorders (a critical review and tribute to Dr.
  150. (1958). Manganese in health and disease. Physiol Rev,
  151. (1995). Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. Mol Biol Evol,
  152. (1990). Mechanism of the neurotoxicity of MPTP. An update. FEBS Lett,
  153. (1998). Meta-analysis of studies of the CYP2D6 polymorphism in relation to lung cancer and Parkinson's disease. Pharmacogenetics,
  154. (2001). Metabolic susceptibility genes as cancer risk factors: time for a reassessment? Cancer Epidemiol Biomarkers Prev,
  155. (1997). Metabolism of MPTP by cytochrome P4502D6 and the demonstration of 2D6 mRNA in human foetal and adult brain by in situ hybridization. Xenobiotica,
  156. (1984). Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun,
  157. (1998). Mitochondrial dysfunction in Parkinson's disease.
  158. (1997). Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S- 260 transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins.
  159. (1998). Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals. Ann Neurol,
  160. Monoamine oxidase B polymorphism, cigarette smoking and risk of Parkinson's disease: a study in an Asian population.
  161. (1986). Monoamine oxidase B, smoking, and Parkinson's disease.
  162. (1986). MPP+ can disrupt the nigrostriatal dopamine system by acting in the terminal area. Neuropharmacology,
  163. (1992). Mutant debrisoquine hydroxylation genes in Parkinson's disease.
  164. (1996). Mutation frequencies of the cytochrome CYP2D6 gene in Parkinson disease patients and in families.
  165. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science,
  166. (1998). Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature,
  167. (1986). N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the monkey: neurochemical pathology and regional brain metabolism. J Neural Transm Suppl,
  168. (1994). Naturally occurring human glutathione S-transferase GSTP1-1 isoforms with isoleucine and valine in position 104 differ in enzymic properties.
  169. Navajas, Smoking and Parkinson's disease: explanatory hypothesis.
  170. (1986). Neural mechanisms mediating 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced parkinsonism in the monkey: relative 245 contributions of the striatopallidal and striatonigral pathways as suggested by 2-deoxyglucose uptake. Neurosci Lett,
  171. (1999). Neurogenetic correlates of Parkinson's disease: apolipoprotein-E and cytochrome P450 2D6 genetic polymorphism. Neurosci Lett,
  172. (1985). New amphibian models for the study of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP). Life Sci,
  173. (1995). Nicotine consumption and Parkinson's disease--does the smoke clear up? Mov Disord,
  174. (2000). Nicotine dependence and its familial aggregation in Chinese.
  175. (1991). Nicotine dependence: diagnosis, pharmacology and treatment.
  176. (1997). No linkage of the cytochrome P-450IIE1 (CYP2E1) C1/C2 polymorphism to schizophrenia. Hum Exp Toxicol,
  177. (1994). Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies. Stat Med,
  178. (1996). Nontraditional epidemiologic approaches in the analysis of gene-environment interaction: case-control studies with no controls!
  179. (1999). Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease. Neurotoxicology,
  180. (1999). Occupational metal exposures and the risk of Parkinson's disease. Neuroepidemiology,
  181. (1998). Oxidative mechanisms in nigral cell death in Parkinson's disease. Mov Disord,
  182. (1997). Oxidative reactions and schizophrenia: a review-discussion. Schizophr Res,
  183. (1994). Oxidative stress: free radical production in neural degeneration. Pharmacol Ther,
  184. (1998). P450 enzymes and Parkinson's disease: the story so far. Mov Disord,
  185. (2000). Paraoxonase polymorphisms, pesticide exposure and Parkinson's disease in a Caucasian population.
  186. Parkinson disease in twins: an etiologic study.
  187. (2001). Parkinson disease: etiology, pathogenesis and future of gene therapy. Neurosci Res,
  188. (1983). Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.
  189. (1990). Parkinson's disease in Aberdeen: survival after 3.5 years. Acta Neurol Scand,
  190. (1999). Parkinson's disease--a multifactorial neurodegenerative disorder.
  191. Parkinson's disease, but not Alzheimer's disease, Lewy body variant associated with mutant alleles at cytochrome P450 gene.
  192. (2001). Parkinson's disease, CYP2D6 polymorphism, and age. Neurology,
  193. (1998). Parkinson's disease, pesticides, and glutathione transferase polymorphisms. Lancet,
  194. (1993). Parkinson's disease: a test of the multifactorial etiologic hypothesis. Neurology,
  195. Parkinsonism-dementia complex, an endemic disease on the island of Guam. II. Pathological features.
  196. (1961). Parkinsonism-dementia complex, en endemic disease on the island of Guam. Clinical, pathological, genetic and epidemiological features. Trans Am Neurol Assoc,
  197. (1985). Personality traits and platelet monoamine oxidase in tobacco smokers. Psychol Med,
  198. (2001). Pilot study of prevalence of Parkinson's disease in Australia. Neuroepidemiology,
  199. (2001). Platelet monoamine oxidase in healthy 9- and 15-years old children: the effect of gender, smoking and puberty. Prog Neuropsychopharmacol Biol Psychiatry,
  200. (1999). Polymorphic cytochromes P450 and drugs used in psychiatry. Cell Mol Neurobiol,
  201. (1992). Premorbid smoking, alcohol consumption, and coffee drinking habits in Parkinson's disease: a case-control study. Mov Disord,
  202. (1992). Premorbid" personality of patients with Parkinson's disease.
  203. (1996). Prevalence of parkinsonian signs and associated mortality in a community population of older people.
  204. (1994). Prospective study of cigarette smoking and the risk of developing idiopathic Parkinson's disease.
  205. (2001). Proteasomal function is impaired in substantia nigra in Parkinson's disease. Neurosci Lett,
  206. (1989). Protective effects of chronic nicotine treatment on lesioned nigrostriatal dopamine neurons in the male rat. Prog Brain Res,
  207. (2000). Regioselectivity and reversibility of the glutathione conjugation of quercetin quinone methide. Chem Res Toxicol,
  208. (1999). Regulation of JNK signaling by GSTp. Embo J,
  209. (2002). Reliability of reporting on life-style and agricultural factors by a sample of participants in the Agricultural Health Study from Iowa. Epidemiology,
  210. (1999). Risk of childhood leukemia associated with exposure to pesticides and with gene polymorphisms. Epidemiology,
  211. (1996). Risk of Parkinson's disease among first-degree relatives: A community-based study. Neurology,
  212. (1991). Role of human cytochrome P450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol,
  213. (1990). Roles of cytochrome P450IIE1 in the dealkylation and denitrosation of N-nitrosodimethylamine and Nnitrosodiethylamine in rat liver microsomes. Carcinogenesis,
  214. (1990). Roles of pituitary hormones in the regulation of hepatic cytochrome P450IIE1 in rats and mice. Arch Biochem Biophys,
  215. (1996). Rsa I polymorphism at the cytochrome P4502E1 locus is not related to the risk of alcohol-related severe liver disease. Liver,
  216. (1997). Sample size requirements in caseonly designs to detect gene-environment interaction.
  217. (1985). Selective accumulation of MPP+ in the substantia nigra: a key to neurotoxicity? Life Sci,
  218. Selective localisation of P450 enzymes and NADPH-P450 oxidoreductase in rat basal ganglia using anti-peptide antisera. Brain Res,
  219. (1998). Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations.
  220. (1994). Several closely related glutathione S-transferase isozymes catalyzing conjugation of 4-hydroxynonenal are differentially expressed in human tissues. Arch Biochem Biophys,
  221. (1999). Sib-pair linkage analyses of alcoholism: dichotomous and quantitative measures. Genet Epidemiol,
  222. (1991). Smoking and mortality among older men and women in three communities.
  223. Smoking and neurogenerative diseases.
  224. (2000). Smoking and Parkinson's and Alzheimer's disease: review of the epidemiological studies. Behav Brain Res,
  225. (1991). Smoking and Parkinson's disease--a new perspective. Rev Environ Health,
  226. (1997). Smoking and Parkinson's disease: a case-control study in Germany.
  227. (1999). Smoking and Parkinson's disease: a dose-response relationship. Neurology,
  228. (2004). Smoking and Parkinson's disease: systematic review of prospective studies. Mov Disord,
  229. (1997). Smoking and Parkinson's disease. An age-dependent risk effect?
  230. (1990). Smoking and Parkinson's disease. Epidemiology,
  231. (1994). Smoking and Parkinson's disease. Mov Disord,
  232. (1999). Smoking and Parkinson's disease. Neurology,
  233. (1975). Smoking as a cause of erythrocytosis. Ann Intern Med,
  234. (2002). Smoking only explains part of the associations between platelet monoamine oxidase activity and personality.
  235. (2000). Smoking, alcohol, and coffee consumption preceding Parkinson's disease: a case-control study. Neurology,
  236. (1994). Structure and function of glutathione Stransferases. Biochim Biophys Acta,
  237. Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions
  238. (2004). Tau promoter haplotypes regulate transcription and are associated with Parkinson's disease. Ann Neurol,
  239. (2000). Test-retest reliability of an epidemiological instrument for Parkinson's disease.
  240. (2005). Test-retest repeatability of self-reported environmental exposures in Parkinson's disease cases and healthy controls. Parkinsonism Relat Disord,
  241. (1996). The "protective" influence of cigarette smoking on Alzheimer's and Parkinson's diseases. Quagmire or opportunity for neuroepidemiology? Neurol Clin,
  242. (1986). The actions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in animals as a model of Parkinson's disease.
  243. (1997). The association between polymorphisms in the cytochrome P-450 2D6 gene and Parkinson's disease: a case-control study and meta-analysis.
  244. (2002). The biochemical basis of Parkinson's disease: the role of catecholamine o-quinones: a review-discussion. Neurotox Res,
  245. (1999). The correlation between platelet MAO activity and personality--the effect of smoking and possible mechanisms behind the correlation. Neurobiology (Bp),
  246. (1996). The CYP2D6B allele is not overrepresented in a population of German patients with idiopathic Parkinson's disease.
  247. (2002). The Cys282Tyr polymorphism in the HFE gene in Australian Parkinson's disease patients. Neurosci Lett,
  248. (1986). The dopamine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces histological lesions in the hypothalamus of the common marmoset. Neurosci Lett,
  249. (1986). The effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal and limbic catecholamine neurones in white and black mice. Antagonism by monoamine oxidase inhibitors. Neuropharmacology,
  250. (1991). The epidemiology of Parkinson's disease. A case-control study of young-onset and old-onset patients. Arch Neurol,
  251. (1997). The epidemiology of Parkinson's disease. Baillieres Clin Neurol,
  252. (1993). The human CYP2E1 gene and lung cancer: DraI and RsaI restriction fragment length polymorphisms in a Finnish study population. Carcinogenesis,
  253. (1986). The neurotoxic actions of 6-hydroxydopamine infused into the rat substantia nigra. Neurosci Lett,
  254. (2001). The parkin gene S/N167 polymorphism in Australian Parkinson's disease patients and controls. Parkinsonism and Related Disorders,
  255. (1999). The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol,
  256. (1998). The sparteine/debrisoquine (CYP2D6) oxidation polymorphism and the risk of Parkinson's disease: a meta-analysis. Pharmacogenetics,
  257. (2000). The ubiquitin carboxy-terminal hydrolase-L1 gene S18Y polymorphism does not confer protection against idiopathic Parkinson's disease. Neurosci Lett,
  258. (1998). The ubiquitin pathway in Parkinson's disease.
  259. (1959). Tobacco consumption and mortality from cancer and other diseases. Public Health Rep,
  260. (1986). Uptake inhibition protects nigro-striatal dopamine neurons from the neurotoxicity of 1-methyl-4-phenylpyridine (MPP+) in mice.
  261. (2000). Variability and validity of polymorphism association studies in Parkinson's disease. Neurology,
  262. Variant cytochrome P450 CYP2D6 allelic frequencies in Parkinson's disease.
  263. (1999). Variations in the monoamine oxidase B (MAOB) gene are associated with Parkinson's disease. Mov Disord,
  264. (1992). What features improve the accuracy of clinical diagnosis in Parkinson's disease: a clinicopathologic study. Neurology,
  265. (1993). Worldwide occurrence of Parkinson's disease: an updated review. Neuroepidemiology,

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.