The association between polymorphisms in the cytochrome P-450 2D6 gene and Parkinson's disease: a case-control study and meta-analysis
Introduction
The risk of developing Parkinson's disease (PD) is increased in people who have lived in rural areas, ingested well water, had exposure to pesticides or have relatives with PD (Tanner, 1992). This suggests that PD is caused by environmental neurotoxins to which some people have a genetic susceptibility. Part of this genetic susceptibility may be conferred by polymorphisms within the gene for cytochrome P450 2D6 (CYP2D6, debrisoquine hydroxylase) (Barbeau et al., 1985).
CYP2D6 metabolises many xenobiotics including, possibly, neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Coleman et al., 1996). The activity of CYP2D6 is genetically determined and two distinct subgroups are recognised. The term poor metaboliser is used to describe those people who have undetectable CYP2D6 activity. This phenotype is inherited as autosomal recessive trait. Over 95% of the poor metaboliser phenotypes in Caucasians are secondary to three polymorphisms: G to A transition at the intron 3/exon 4 junction (CYP2D6B), base pair deletion in exon 5 (CYP2D6A) and, rarely, deletion of the entire gene (CYP2D6D) (Spurr et al., 1991). Individuals with any two defective alleles are classified as having the poor metaboliser genotype.
Barbeau et al. (1985)first suggested that poor metabolisers may have an increased susceptibility to Parkinson's disease because of impaired detoxification of neurotoxins. This hypothesis was supported initially by pharmacokinetic studies of CYP2D6 activity (Barbeau et al., 1985). However, the results were flawed by the confounding effects of antiparkinsonian drug therapy, and not supported by subsequent studies (Kallio et al., 1991, Steiger et al., 1992). Investigations using analysis of CYP2D6 genotype are not influenced by such confounding effects. Nevertheless, the results of genotypic studies have similarly been inconsistent (Armstrong et al., 1992, Smith et al., 1992, Kondo and Kanazawa, 1993, Kurth and Kurth, 1993, Tsuneoka et al., 1993, Plante-Bordeneuve et al., 1994, Agundez et al., 1995, Akhmedova et al., 1995, Diederich et al., 1996, Bordet et al., 1996, Sandy et al., 1996, Gasser et al., 1996, Lucotte et al., 1996). Most of these studies have had limited statistical power and used different techniques (restriction fragment length polymorphisms vs polymerase chain reaction) and diagnostic criteria. Thus, the association of the poor metaboliser genotype with PD remains an important but unresolved issue. We report a large study of the association of the poor metaboliser genotype with PD. We also combined our results with previous reports using meta-analysis.
Section snippets
Methods
Patients and controls were collected from community groups, hospitals, and outpatient clinics in South-East Queensland and Central-West New South Wales. They were matched for age, gender and site of collection. All patients and controls were Caucasian. The diagnosis of Parkinson's disease was made according to the criteria of Calne et al. (1992). Human genomic DNA was extracted from peripheral blood leukocyte nuclei and amplified using polymerase chain reaction with allele-specific primers (
Results
There were no significant differences in age or gender between the PD patients (n=112, age 69±9 years, M:F 69:43) and controls (n=206, age 69±11 years, M:F 129:77). The average age of onset of symptoms in the patients was 61±9 years. The poor metaboliser genotype was more common in the patients (12.5% vs 7.8%, odds ratio 1.7, 95% CI: 0.94–2.45) as was the frequency of the B allele (21.0% vs 18.4.0%, odds ratio 1.17, 95% CI: 0.77–1.58) but these results did not reach statistical significance.
Discussion
There have been many reports on the association of the poor metaboliser phenotype and genotype of CYP2D6 with Parkinson's disease. The results have been inconsistent. The major problem with most studies is that the sample size has been small which has limited the statistical power and increased the likelihood of a type II error. This can be overcome by the use of larger population samples and meta-analysis. However, it must be recognised that such an approach cannot overcome other potential
Acknowledgements
We acknowledge the support of the Queensland Geriatric Medical Foundation, Australian Federation of University Women, Charles and Sylvia Viertel Foundation, Princess Alexandra Hospital Research Foundation and the National Health and Medical Research Council. We would like to thank Dr Daniel Chan, Dr Chen Yi, Dr Richard Boyle and Prof. Michael McManus for their assistance and advice.
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