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Genetic predisposition and risk factors for neurodegenerative diseases
Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
2004 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

The inter-individual variability in biotransformation, may lead to differences in activation and detoxification of both endogenous and exogenous compounds. Polymorphism studies in such genes were applied for Parkinson's disease (PD) and Chronic toxic encephalopathy (CTE), two diseases influenced by both genetic and enviromnental factors.

An elevated median age for the onset of PD was found among GS1M1 gene carriers compared to PD patients being GS1M1 null genotypes (68 years versus 57 years). No similar difference was found for GSTT1. mEPHX (113HH) isoform, which has been suggested as a low activity variant, is over represented in PD patients (OR=3.8, CI 95%, 1.2-11.8).

Monoamine oxidases (MAO-A and -B) are important in the dopamine metabolism and in the detoxification of neurotoxins and genetic variants in these genes have earlier been assigned to PD. However, no difference was revealed between any of the polymorphisms studied in the MAO-A and -B genes and PD. Smoking displayed an enviromnental exposure with a strong decreased risk for PD in this study (OR=0.40 for men and OR=0.48 for women) but no obvious interaction with the MAO genotypes could be observed.

Mitochondrial dysfunction and oxidative stress have been hypothesized to contribute to the pathogenesis of PD. The superoxide dismutases (SOD) potentially play an important role in PD by detoxifying superoxide radicals in mitochondria. Polymorphisms neither in superoxide dismutase 2 (SOD2) nor mitochondrial complex I subunit, NDUFV2, were associated with PD.

An increased risk ratio for CTE was found in smokers with the GSTM1 null genotype (RR=2.5, Cl 95%, 1.4-4.2) or the GSTT1 null genotype (RR=1.4, Ci 95%, 1.02-2.0). In non-smokers GS1M1 null genotype did not confer any risk for CTE. Polymorphisms in mEPHX were not associated with an increased risk for CTE.

Thus, various genetic and enviromnental factors most likely influence both PD and solvent-induced CTE. Detoxification pathways may represent important protective mechanisms against reactive intermediates, thus genetic predisposition in these pathways could modify the susceptibility and onset of PD and solvent-induced CTE.

sted, utgiver, år, opplag, sider
Linköping: Linköpings universitet , 2004. , s. 63
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 844
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-24042Lokal ID: 3598ISBN: 91-7373-817-4 (tryckt)OAI: oai:DiVA.org:liu-24042DiVA, id: diva2:244358
Disputas
2004-04-16, Elsa Brändström-Salen, Hälsouniversitetet, Linköping, 09:00 (svensk)
Opponent
Tilgjengelig fra: 2009-10-07 Laget: 2009-10-07 Sist oppdatert: 2012-10-22bibliografisk kontrollert
Delarbeid
1. GSTM1 and mEPHX polymorphisms in Parkinson's disease and age of onset
Åpne denne publikasjonen i ny fane eller vindu >>GSTM1 and mEPHX polymorphisms in Parkinson's disease and age of onset
Vise andre…
2000 (engelsk)Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 269, nr 3, s. 676-680Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Both environmental and genetic factors are involved in the development of PD and biotransformation of exogenous and endogenous compounds and may play a role in inter-individual susceptibility. Therefore, we investigated the presence of null genotypes of GSTM1, GSTT1, and two polymorphisms of mEPHX in subjects with Parkinson's disease and in a reference population. The study included 35 male PD patients and a male control group including 283 subjects. Homozygosity of the histidine (H) 113 isoform of mEPHX was significantly increased in PD patients (odds ratio = 3.8 CI 95% 1.2–11.8) and analysis of allele frequencies displayed an increased frequency of the H-allele among PD patients (odds ratio = 1.9 CI 95% 1.1–3.3). However, a significantly elevated median age for the onset of PD was found among GSTM1 gene carriers (median age = 68 years) compared to PD patients being GSTM1 null genotypes (median age = 57 years). Our observations suggest that (H) 113 isoform of mEPHX, which has been suggested as a low activity isoform, is overrepresented in PD patients and that inherited carriers of the GSTM1 gene postpone the onset of PD. These detoxification pathways may represent important protective mechanisms against reactive intermediates modifying the susceptibility and onset of PD.

HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-24837 (URN)10.1006/bbrc.2000.2338 (DOI)9235 (Lokal ID)9235 (Arkivnummer)9235 (OAI)
Tilgjengelig fra: 2009-10-07 Laget: 2009-10-07 Sist oppdatert: 2017-12-13bibliografisk kontrollert
2. Monoamine oxidase A and B genes polymorphisms in Parkinson's disease
Åpne denne publikasjonen i ny fane eller vindu >>Monoamine oxidase A and B genes polymorphisms in Parkinson's disease
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Abstract [en]

Parkinson's disease (PD) is a common progressive neurodegenerative disorder characterized by degeneration of nig:rostriatal dopaminergic neurons including the loss of cell bodies in the pars compacta of substantia nigra (SN). The mechanism for neurodegeneration is unknown, but the pathogenesis is considered to be multifactorial involving exposure for toxins, genetic inheritance, age, oxidative stress and mitochondrial electron transport chain defects. This study has been focused on polymorphisms in the genes for the enzymes monoamine oxidase A and B (MAO-A, MAO-B) and relation to smoking for the development of idiopathic Parkinson's disease. MAO enzymes are important in the dopamine metabolism and in the detoxification of neurotoxins. During metabolism of dopamine, MAO generates large amounts of free radicals and hydrogen peroxide, and may damage the neurons in substantia nigra, which has been suggested as a pathologic mechanism for PD.

Blood samples were collected from 256 PD patients, age 30-80 years, and 582 unrelated control individuals, age 31 - 78 years, from southeastern Sweden.

Two polymorphisms (exon 8 and exon 14) located in the MAO-A gene and one polymorphism located in the MA O-B gene were examined, with denatming HPLC, PCR-RFLP or DNA sequencing. Genotype and allele frequencies were determined for patients and controls. No statistical significant difference was revealed between any of the polymorphisms in the MAO-A and MAO-B genes and Parkinson's disease. Smoking displayed an enviromnental exposure with a strong decreased risk for both male (OR=0.40, 95% CI 0.25 - 0.63) and female (OR=0.48, 95% CI 0.25-0.89) PD without any interaction with MAO genotype.

The polymorphisms in MAO genes might therefore not be acting as modifiers of risk for developing of PD either by itself or by interacting with smoking. With respect to the size of the study (256 PD patients and 582 controls) MAO polymorphisms do not represent any predisposing factor or a weak PD susceptibility factor.

HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-84799 (URN)
Tilgjengelig fra: 2012-10-22 Laget: 2012-10-22 Sist oppdatert: 2012-10-22bibliografisk kontrollert
3. Manganese superoxide dismutase and NDUFV2 polymorphisms and susceptibility to Parkinson's disease
Åpne denne publikasjonen i ny fane eller vindu >>Manganese superoxide dismutase and NDUFV2 polymorphisms and susceptibility to Parkinson's disease
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
Abstract [en]

Mitochondrial dysfunction has been hypothesized to contribute to the pathogenesis of Parkinson's disease (PD). Oxidative stress and production of oxygen radicals is produced in mitochondria. The superoxide dismutases (SOD) potentially play an important role in PD by detoxifying superoxide radicals. Oxidative stress has also an important role to decrease Complex I activity in the mitochondria. In addition, Complex I contains several subunits, where one, NDUFV2, plays a major role in the electron transport pathway of Complex I in substantia nigra.

The aim of this project was to study polymorphisms in MTS-SOD2 and the Complex I subunit, NDUFV2 as predisposing factors for the development of idiopathic PD.

Blood samples from 200 PD and 404 population controls were collected from the Southeastern part of Sweden. DNA was isolated and the polymorphisms were analyzed by pyrosequencing and direct dideoxy termination sequencing.

Genotypes and allele frequencies were compared for the patient and control groups with Χ2 statistics. No statistical significant difference was evident for any of the polymorphisms neither in MTS-SOD2 (OR=0<85, 95% CI, 0<52-1.38) nor NDUFV2 (OR=0.64, 95% CI, 0.24-1.64) genes and PD.

These results indicate that the MTS-SOD2 and NDUFV2 gene variants do not contribute to PD pathogenesis.

Emneord
SOD2, NDUFV2, polymorphisms, Parkinson's disease
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-84800 (URN)
Tilgjengelig fra: 2012-10-22 Laget: 2012-10-22 Sist oppdatert: 2012-10-22bibliografisk kontrollert
4. Glutathione S-transferase M1 null genotype as a risk modifier for solvent-induced chronic toxic encephalopathy
Åpne denne publikasjonen i ny fane eller vindu >>Glutathione S-transferase M1 null genotype as a risk modifier for solvent-induced chronic toxic encephalopathy
Vise andre…
1996 (engelsk)Inngår i: Scandinavian Journal of Work, Environment and Health, ISSN 0355-3140, E-ISSN 1795-990X, Vol. 22, nr 5, s. 360-363Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Objectives Exposure to organic solvents increases the risk of neuropsychiatric disability or chronic toxic encephalopathy (CTE). Polymorphisms in the biotransformation of xenobiotics and solvents may influence individual susceptibility to develop toxic effects. In this study the problem of whether there could be any association between the glutathione S-transferase M1 (GSTM1) null genotype and the risk for CTE, with regard to solvent exposure, was investigated.

Methods Sixty patients referred to a clinic because of some degree of some degrees of psychiatric or neurological symptoms, as well as exposure to solvents, were examined by means of a validated questionnaire and psychometric testing. The degree of exposure to solvents was assessed by a thorough interview. According to clinical findings, the patients were classified into three categories as those with solvent-induced CTE, those with incipient CTE, and those who were non-CTE patients. Afterwards, leukocyte DNA (deoxyribonucleic acid) was isolated and the GSTM1 null genotype was determined by an assay based on polymerase chain reaction, blindly with regard to both exposure and disease status.

Results The relative proportion (RP) of GSTM1 null genotypes was significantly increased for patients with a diagnosed CTE when they were compared with non-CTE patients (RP 2.55, 95% confidence interval 1.0--6.2). Dichotomizing the patients by high and low exposure revealed an increased risk for both GSTM1 gene carriers and the GSTM1 null genotype in the high-exposure group, the relative risks (RR) being 4.5 and 7.9, respectively. The chi-square for the Mantel extension for trend was 6.2 (P=0.025).

Conclusion The GSTM1 null genotype acts as a risk modifier for CTE among patients occupationally exposed to solvents. The risk seems to increase in a dose-dependent fashion.

HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-84801 (URN)10.5271/sjweh.154 (DOI)
Tilgjengelig fra: 2012-10-22 Laget: 2012-10-22 Sist oppdatert: 2017-12-07bibliografisk kontrollert
5. Interaction between smoking and glutathione S-transferase polymorphisms in solvent-induced chronic toxic encephalopathy
Åpne denne publikasjonen i ny fane eller vindu >>Interaction between smoking and glutathione S-transferase polymorphisms in solvent-induced chronic toxic encephalopathy
2002 (engelsk)Inngår i: Toxicology and industrial health, ISSN 0748-2337, E-ISSN 1477-0393, Vol. 18, nr 6, s. 289-296Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Exposure to organic solvents is still common in industrial and other work environments, and increases the risk of chronic toxic encephalopathy (CTE). Genetic variation in metabolic enzymes for solvents and other xenobiotics may modify the risk of developing toxic effects. Therefore, we investigated the presence of null genotypes for glutathione S-transferases M1 and T1 (GSTM1, GSTT1) and two genetic polymorphisms of microsomal epoxide hydrolase (mEPHX) in relation to the risk for chronic toxic encephalopathy (CTE) when exposed to solvents and smoking. We genotyped 115 patients who were classified into three categories: CTE (n = 56), incipient CTE (n = 27) and non-CTE (n = 32) patients. DNA was isolated from leucocytes and the GSTM 1 and GSTT1 null genotypes were determined by multiplex-polymerase chain reaction. The two polymorphisms of mEPHX were analysed by PCR-RFLP (restriction fragment length polymorphism) based assays. All analyses were performed blindly with regard to both exposure and disease status. An increased binomial regression risk ratio = 2.5, 95% confidence interval (CI) 1.5-4.2, of the GSTM1 null genotype for CTE was found in smokers and for the GSTT1 null genotype (binomial regression risk ratio 1.5, 95% CI 1.0-2.0). In nonsmokers, the GSTM1 null genotype did not confer any risk for CTE. None of the studied mEPHX polymorphisms were associated with an increased risk for CTE. We suggest that the GSTM1 null genotype in smokers is a possible risk for solvent-induced CTE.

Emneord
chronic toxic encephalopathy, molecular epidemiology, polymorphism, smoking, solvent exposure
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-46280 (URN)10.1191/0748233702th152oa (DOI)
Tilgjengelig fra: 2009-10-11 Laget: 2009-10-11 Sist oppdatert: 2017-12-13bibliografisk kontrollert

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