Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxidative stress is widely thought to contribute significantly to the pathogenesis Parkinson's disease (PD). Given the role of glutathione S-transferases (GSTs) in the conjugation of electrophiles and protection against reactive oxygen species, genes encoding the GSTs have been considered candidates for association studies of PD. We tested for associations between genotypes of GSTM1(homozygous deletion vs. non-deleted), GSTT1(homozygous deletion vs. non-deleted), and GSTP1 (Ile104Val and Ala113Val) and PD in a case-control study of 214 idiopathic PD cases and 330 age- and gender-matched, unrelated controls of Caucasian ethnicity. No significant associations with any of the GST genotypes were observed. However, there was a marginally significant difference in the distribution of GSTP1 104 genotypes between cases and controls (P=0.07), with an excess of Ile104Val heterozygotes found among cases (odds ratio (OR)=1.43; 95% Confidence Interval (CI): 0.98-2.08). This difference in the genotype distribution was strongest among smokers (OR for heterozygote=1.92; 95% CI: 1.12-3.29) versus non-smokers and among males (OR for heterozygote=1.99; 95% CI: 1.24-3.19) versus females. The distribution of GSTP1 Ile104Val and Ala113Val haplotypes did not differ between cases and controls. Taken together, these results suggest a potentially minor role of GSTP1 in PD, but do not give evidence for associations with either GSTM1 or GSTT1.
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PMID:Glutathione S-transferase M1, T1, and P1 polymorphisms and Parkinson's disease. 1252 58

Current opinion contends that complex interactions between genetic and environmental factors play a role in the etiology of Parkinson's disease (PD). Cigarette smoking is thought to reduce risk of PD, and emerging evidence suggests that genetic factors may modulate smoking's effect. We used a case-only design, an approach not previously used to study gene-environment interactions in PD, specifically to study interactions between glutathione-S-transferase (GST) gene polymorphisms and smoking in relation to PD. Four-hundred PD cases (age at onset: 60.0 +/- 10.7 years) were genotyped for common polymorphisms in GSTM1, P1, T1 and Z1 using well-established methods. Smoking exposure data were collected in face-to-face interviews. The independence of the studied GST genotypes and smoking exposure was confirmed by studying 402 healthy, aged individuals. No differences were observed in the distributions of GSTM1, T1 or Z1 polymorphisms between ever-smoked and never-smoked PD cases using logistic regression (all P > 0.43). However, GSTP1 *C haplotypes were over-represented among PD cases who ever smoked (odds ratio for interaction (ORi) = 2.00 (95% CI: 1.11-3.60, P = 0.03)). Analysis revealed that ORi between smoking and the GSTP1-114Val carrier status increased with increasing smoking dose (P = 0.02 for trend). These data suggest that one or more GSTP1 polymorphisms may interact with cigarette smoking to influence the risk for PD.
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PMID:Case-only study of interactions between genetic polymorphisms of GSTM1, P1, T1 and Z1 and smoking in Parkinson's disease. 1528 44

Monogenic forms of Parkinson's disease (PD) provide an opportunity to examine mechanisms underlying phenotypic variation. Glutathione S-transferase (GST) has detoxification and antioxidative functions. To screen genetic variations in GST for an effect on the onset age (OA) of PD, we typed seven common genetic polymorphisms in five GST isoenzymes, M1, M3, P1, T1, and Z1, in 36 affected individuals of Italian or Greek origin with the alpha-synuclein A53T (PARK1) mutation. Mean OA was 45.2 years with a wide SD of 11.03 years, similar to that of idiopathic PD. Our allelic analysis showed that the subjects homozygous for the GSTP1 G-for-A nucleotide substitution at position 313 had a mean OA acceleration of 15.2 years (31.3 +/- 7.09 years, n = 3 vs. 46.5 +/- 10.50 years, n = 33, P = 0.020). The GSTP1 C341T substitution was associated with a 9.7-year acceleration of OA, but the significance was borderline (36.4 +/- 8.35 years vs. 46.7 +/- 10.85 years, P = 0.0519). After correction for the five genes examined, both results lose statistical significance. Nevertheless, our results suggest that further investigation in GSTP1 variants and PD pathogenesis is warranted in sporadic PD and that a search for toxins that accelerate PD OA should pay particular attention to GST-P1 substrates.
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PMID:Glutathione S-transferase polymorphisms and onset age in alpha-synuclein A53T mutant Parkinson's disease. 1703 8

Genetic predisposition, environmental toxins and aging contribute to Parkinson's disease (PD) multifactorial etiology. Weak environmental neurotoxic factors may accumulate over time increasing the disease risk in genetically predisposed subjects. Polymorphic genes encoding drug-metabolizing-enzymes (DMEs) are considered to account for PD susceptibility by determining individual toxic response variability. In this work, the allelic distributions and genotype associations of three major brain-expressed DMEs were characterized, in sporadic PD cases and controls. No significant association was found between CYP2D6 genotype and PD, but subjects with extensive metabolizer (EM) CYP2D6 phenotype, and the variant GSTP1*B genotype were at significantly higher PD risk than the corresponding poor or intermediary metabolizers (CYP2D6 poor metabolizer phenotype+intermediary metabolizers). A significant association was observed between the GSTP1*B allele and zygosity with PD (GSTP1*A/*B- 51.58%/34.37%, odds ratio (OR) = 2.29; 95% confidence interval (95% CI) = 1.25-4.18; *B/*B- 6.32%/1.05%, OR = 10.67; 95% CI = 1.19-94.79). This association was particularly strong in the elder patients group (> or =69 year) who showed double PD risk for GSTP1*B heterozygous, whilst GSTP1*B/*B homozygous were exclusively found amongst patients. An interaction between GSTM1 and GSTP1 was observed in this late onset PD group. The present results suggest that native GSTP1 encoding the fully active transferase variant should play a relevant role in dopaminergic neuroprotection.
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PMID:Association of A313 G polymorphism (GSTP1*B) in the glutathione-S-transferase P1 gene with sporadic Parkinson's disease. 1725 Jul 23

Attempts were made in the present case-control study to investigate the association of polymorphism in the genes encoding proteins involved in toxication-detoxication and dopaminergic pathways and susceptibility to Parkinson's disease (PD). Seventy patients suffering from PD and one hundred healthy controls belonging to the same geographical location and same ethnicity were included in the study. PCR-RFLP and allele-specific PCR-based methodology were used to identify the genotypes. Multivariate logistic regression analysis revealed that heterozygous genotypes of cytochrome P4502D6*4(CYP2D6*4), CYP2E1*5B (RsaI) polymorphism and homozygous mutant genotypes of CYP2E1*6 (Dra1) were found to be overrepresented in PD cases when compared to the controls. Risk was also found to be increased in patients carrying glutathione S-transferase T1 (GSTT1) null or homozygous variant genotypes of GSTP1. Significant association was observed for monoamine oxidase-B(MAO-B) variant allele G and PD, whereas no difference in genotype and allele frequencies was observed for manganese-superoxide dismutase (MnSOD), dopamine receptor-D2(DRD2), and dopamine transporter (DAT) genes between controls and PD cases. Genotype combinations characterized by the presence of two variant genotypes on their corresponding loci revealed that four combinations of GSTT1 null and MnSOD(-9Val) or GST null and MAOB-G or CYP2E1*5B and MAO-B-AG or CYP2E1*5B and DRD2 (Taq1A-het) genotypes in the patients exhibited severalfold higher and significant association with risk to PD. Our data suggest that polymorphism in the genes involved in detoxification and dopamine regulation may modulate the susceptibility to PD and could be important risk factors in the pathogenesis of PD.
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PMID:Polymorphism in environment responsive genes and association with Parkinson disease. 1832 68

MPTP-induced dopaminergic neurotoxicity involves major biochemical processes such as oxidative stress and impaired energy metabolism, leading to a significant reduction in the number of nigrostriatal dopaminergic neurons. Glutathione S-transferase pi (GSTpi) is a phase II detoxifying enzyme that provides protection of cells from injury by toxic chemicals and products of oxidative stress. In humans, polymorphisms of GSTP1 affect substrate selectivity and stability increasing the susceptibility to parkinsonism-inducing effects of environmental toxins. Given the ability of MPTP to increase the levels of reactive oxygen species and the link between altered redox potential and the expression and activity of GSTpi, we investigated the effect of MPTP on GSTpi cellular concentration in an in vivo model of Parkinson's disease. The present study demonstrates that GSTpi is actively expressed in both substantia nigra pars compacta and striatum of C57BL/6 mice brain, mostly in oligodendrocytes and astrocytes. After systemic administration of MPTP, GSTpi expression is significantly increased in glial cells in the vicinity of dopaminergic neurons cell bodies and fibers. The results suggest that GSTpi expression may be part of the mechanism underlying the ability of glial cells to elicit protection against the mechanisms involved in MPTP-induced neuronal death.
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PMID:GSTpi expression in MPTP-induced dopaminergic neurodegeneration of C57BL/6 mouse midbrain and striatum. 1879 12

A case-control study of genetic, environmental, and occupational risk factors for Parkinson's disease (PD) was carried out in five European countries (Italy, Malta, Romania, Scotland, and Sweden) to explore the possible contribution of interactions among host and environmental factors in sporadic PD. Whereas smoking habits confirmed its negative association with PD, a possible modulatory role of genetic polymorphisms was investigated to obtain further mechanistic insights. We recruited 767 cases of PD and 1989 age-matched and gender-matched controls. Participants completed an interviewer-administered questionnaire including the history of smoking habits. The polymorphisms of genes involved either in metabolism of compounds contained in tobacco smoke (CYP2D6, CYP1B1, GSTM1, GSTT1, GSTM3, GSTP1, NQO1, SOD2, EPHX and NAT2) or in dopaminergic neurotransmission (MAOA, MAOB, DAT1 and DRD2) were characterized by PCR based methods on genomic DNA. We found evidence of statistically significant gene-tobacco interaction for GSTM1, NAT2, and GSTP1, the negative association between tobacco smoking and PD being significantly enhanced in subjects expressing GSTM1-1 activity, in NAT2 fast acetylators, and in those with the GSTP1*B*C haplotype. Owing to the retrospective design of the study, these results require confirmation.
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PMID:A case-control study of Parkinson's disease and tobacco use: gene-tobacco interactions. 2046 8

Patients with idiopathic Parkinson's disease (PD) appear to have reduced capacity for detoxification of certain environmental compounds. The glutathione S-transferases (GSTs) are candidate genes for PD because they are involved in the metabolism of pesticides and cigarette smoke. We investigated the relationship of the seven GST polymorphisms (GSTM1 deletion, GSTT1 deletion, GSTP1 rs1695, GSTO1 rs4925, GSTO1 rs11191972, GSTO2 rs156697 and GSTO2 rs2297235) and PD risk with special reference to the interaction with pesticide use or cigarette smoking among 238 patients with PD cases and 370 controls in a Japanese population. None of the GST polymorphisms were associated with PD. GSTO1 rs4925 and GSTO2 rs2297235 were found to be in strong linkage disequilibrium (D' = 0.98). Cigarette smoking was significantly associated with decreased risk of PD. However, no interaction of smoking with any of the GST polymorphisms was observed. Self-reported pesticide use was not associated with increased risk of PD. There was no evidence of interaction between self-reported pesticide use and either GST polymorphism. Our results suggest that the tested GST polymorphisms did not play an important role in PD susceptibility in our Japanese population. Our study does not give evidence of interaction between the GST polymorphisms and smoking may although this study provided sufficient statistical power to detect modest interaction. As for interaction between GSTP polymorphisms and pesticide use, the power of this study to detect an interactive effect was low due to a small number of pesticide users. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the GST polymorphisms in PD development.
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PMID:GST polymorphisms, interaction with smoking and pesticide use, and risk for Parkinson's disease in a Japanese population. 2047 88

Parkinson's disease (PD) is one of the most common neurodegenerative disorders whose etiology is multifactorial including both hereditary and environmental factors. Currently, pathogenic mutations in at least five genes have been implicated in familial PD generally accounting for less than 10 % of all PD cases in most populations. It has been suggested that polymorphisms in other genes such as those encoding enzymes involved in oxidative metabolism and detoxification could be involved in predisposition to PD since oxidative stress in dopaminergic neurons is thought to be of central importance in the pathogenesis of the disease. The aim of our work was to study the association of genetic polymorphisms in genes involved in oxidative metabolism and detoxification mechanism, namely GSTM1, GSTT1, GSTP1, and those involved in DNA damage repair, OGG1 and XRCC1, in an Italian cohort of sporadic PD patients. We did not detect any association between GSTT1 and GTTM1 null polymorphisms and PD, whereas the 104GSTP1 polymorphism was associated with PD in male patients but not in females. Furthermore, we detected a protective effect of wild type genotype of XRCC1 in women.
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PMID:Epidemiological, clinical, and molecular study of a cohort of Italian Parkinson disease patients: association with glutathione-S-transferase and DNA repair gene polymorphisms. 2355 77

The relative role of genetic and environmental factors in the pathogenesis of Parkinson's disease (PD) has been the matter of investigation and debate, especially in the last 30 years. The possible interaction between genetic and environmental factors led to a great number of association studies between single nucleotide polymorphisms (SNPs) of many candidate genes and PD risk. In this study we summarized and critically reviewed the results of studies published on this issue, with especial reference to those reported in the last 5 years. Many studies provided conflicting findings and, when positive associations were identified, associations were weak. Polymorphisms related with activation or detoxification of drugs and xenobiotics, such as CYP1A1, CYP1A2, CYP19A1, CYP1B1, CYP2C9, CYP2C19, CYP2E1, CYP2D6, NAT2, GSTM1, GSTM3, GSTO1, GSTP1, PON1, PON2, ABCB1 and ADH genes have not been demonstrated convincingly a definitive association with the risk of developing PD. Nor did polymorphisms in genes related to dopamine or serotonin DRD, DAT, TH, DDC, DBH, MAO, COMT, SLC6A4, MTR, MTHFR, oxidative stress NOQ1, NOQ2, mEPHX, HFE, GPX, CAT, mnSOD, HFE, HO-1, HO-2, NFE2L2, KEAP1, inflammatory processes, ILs, TNF, ACT, NOS, HNMT, ABP1, HRHs, trophic and growth factors BDNF, FGF, or mitochondrial metabolism and function. In addition we analyzed other putative relations and genes associated with monogenic familial PD.Taking together the results of candidate gene association studies and genome wide association studies, only some SNPs of the MAPT, SNCA, HLA and GBA genes seem to be the most likely associated with PD risk.
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PMID:Genomic and pharmacogenomic biomarkers of Parkinson's disease. 2469 31


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