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Glutathione transferase genes (GST) are candidate genes for Parkinson's disease because they are involved with the metabolism of pesticides, dopamine, and glutathione. Recent reports have suggested an association between Parkinson's disease and polymorphisms of GSTP1 1 orGSTM1 andGSTT1.2
Recently we discovered a new polymorphic site in the zeta class G→T (GSTZ1) gene.3 This consists of a C6T transition at nucleotide 245 in exon 5 that results in an amino acid change at position 82 from methionine to threonine. The T substitution occurs in 14% of white people. We have previously reported two other polymorphic sites at nucleotides 94 and 124 in exon 3.4 There are now thought to be four alleles of GSTZ1:Z1*A(A94A124C245),Z1*B(A94G124C245),Z1*C(G94G124C245,) andZ1*D(G94G124T245). Here we investigated the association of Parkinson's disease, pesticide exposure, and theseGSTZ1 polymorphisms.
DNA was extracted from blood samples collected from patients with Parkinson's disease and matched controls as described previously.1 This study was approved by the Princess Alexandra Hospital ethics committee. Polymorphisms at nucleotide 94 and 124 were detected by polymerase chain reaction/RFLP analysis as described previously.4 To detect the nucleotide 245 polymorphism, PCR was performed with the following primers: 5′AAGAGGTGTAGTG ATGGTGC3′ and 5′GGTGCAAGTGTAC AAGTGCC3′. The PCR was carried out in a 20 μl reaction volume containing reaction buffer IV (Advanced Biotechnologies, Epsom UK; 20 mM (NH4)2SO4, 75 mM Tris/HCl pH 9.0, 0.1% Tween 20), dNTPs (0.2 mM), MgCl2 (1.5 mM), primers (0.3 μM each), thermostable DNA polymerase (Advanced Biotechnologies, 0.5 U), and DNA (25 ng). No DNA was added to control reactions. Thermal cycling was carried out using a Corbett capillary thermal cycler under the following conditions: initial denaturation at 94°C for 2 minutes; subsequently 35 cycles of 94°C for 20 seconds, 60°C for 20 seconds, 72°C for 30 seconds; and a final extension of 72°C for 2 minutes. Products of PCR were digested overnight with restriction enzymeBsh 1236I (MBI fermentas) at 37°C and fragments were separated by 8% polyacrylamide gel electrophoresis and stained with ethidium bromide. The restriction enzymeBsh 1236I cleaves the C245 fragment generating 12, 108, and 142 bp fragments and the T245 fragment generating 108 and 154 bp fragments.
We tested 307 Parkinson's disease and 105 control samples. The population samples were in Hardy-Weinberg equilibrium. There were no associations between the nucleotide 245, 94, or 124 polymorphisms and Parkinson's disease (table). A total of 87 patients and 53 controls reported a history of regular pesticide exposure. In this group there was a weak association between the nucleotide 245 genotype and Parkinson's disease (p=0.05) (table). Furthermore, in this group, theZ1*C genotype (G94G124C245) was less common in the patients with Parkinson's disease than in the controls (39%v 52%, OR=0.58, 95% confidence interval (95%CI) 0.36–0.95, p=0.03, not corrected for multiple comparisons).
There was no overall association between theGSTZ polymorphisms and Parkinson's disease. However, we found a difference when only those who reported pesticide exposure were analysed. We also combined the data for the three polymorphic sites to determine the frequency of the fourGSTZ1 alleles. TheZ1*C allele is the most common variant in white control populations. We found that this allele was less common in patients with Parkinson's disease than controls when stratified for pesticide exposure.
Studies of this nature have limitations related to selection bias, case ascertainment, recall bias, difficulty in assessing extent of exposure, and multiple comparisons. Accordingly, our conclusion that there is a potential association between GSTZ, pesticide exposure, and Parkinson's disease must be considered preliminary. Nevertheless, it is interesting that there have now been several reports suggesting an association between the risk of Parkinson's disease, polymorphic variability in detoxification genes, and exposure to environmental toxins. These include CYP2D6 and solvent exposure,5 GSTP and pesticide exposure1 and CYP2D6, pesticide exposure, and Parkinson's disease with dementia.6 Thus, it has been recognised that studies examining the association of polymorphic variation in xenobiotic metabolism genes and Parkinson's disease should take into account the effect of exposure to toxins.7
This study was funded by the National Health and Medical Research Council of Australia and the Geriatric Medical Foundation of Queensland.
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