| 1. |
- Landtblom, Anne-Marie, 1953-, et al.
(författare)
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Multiple sclerosis and exposure to organic solvents, investigated by genetic polymorphisms of the GSTM1 and CYP2D6 enzyme systems
- 2003
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Ingår i: Neurological Sciences. - : Springer Science and Business Media LLC. - 1590-1874 .- 1590-3478. ; 24:4, s. 248-251
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Tidskriftsartikel (refereegranskat)abstract
- An association between multiple sclerosis (MS) and exposure to organic solvents has been discussed. Organic solvents are metabolised by enzyme systems like glutathione S-transferase M1 (GSTM1) and CYP2D6, which express polymorphisms in the general poulation. GSTM1 null genotype has been associated with solvent-induced chronic toxic encephalopathy. Our aim was to see if a defect in one of these enzyme systems could explain the association between MS and exposure to organic solvents. In our study, 50 patients with MS were investigated, including 24 who had been significantly exposed to organic solvents and 26 who were not exposed. Polymerase chain reaction-based methods were used for genotyping GSTM1 and CYP2D6 polymorphisms in leukocyte DNA. No differences in genetic predisposition were found between MS patients exposed and those not exposed to organic solvents regarding GSTM1 null or CYP2D6 poor metaboliser genotypes. The possible association between multiple sclerosis and solvents may not, as for chronic toxic encephalopathy, be explained by defects in these systems.
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| 2. |
- Lindqvist Appell, Malin, 1976-, et al.
(författare)
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Identification of two novel sequence variants affecting thiopurine methyltransferase enzyme activity
- 2004
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Ingår i: Pharmacogenetics. - : Ovid Technologies (Wolters Kluwer Health). - 0960-314X .- 1473-561X. ; 14:4, s. 261-265
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Tidskriftsartikel (refereegranskat)abstract
- The polymorphic enzyme thiopurine methyltransferase (TPMT) is involved in the methylation of thiopurines. On comparing the phenotype with the genotype in Swedish patients with inflammatory bowel disease and healthy individuals, we found two discordant cases with low TPMT enzyme activity (0.3 and 0.4 U/ml packed red blood cells (pRBC). Genotyping by pyrosequencing revealed that they carried the nucleotide substitutions 460G>A and 719A>G, giving two possible genotypes (TPMT*1/*3A or TPMT*3B/ *3C). DNA sequencing of exon III to X was performed in the patients and their parents. We identified an A>G transition in the start codon (exon III, 1A>G, Met>Val, TPMT*14) in one of the patients and her father (6.3 U/ml pRBC). The mother in this family carried the 460G>A and 719A>G nucleotide substitutions (TPMT*3A, 5.0 U/ml pRBC). In the second family, sequencing revealed a G>A transition in the acceptor splice site in intron VII/exon VIII (IVS7 - 1G>A, TPMT*15) in the patient and his mother (6.9 U/ml pRBC). His father was genotyped as TPMT*1/*3A (6.0 U/ml pRBC). Hence, we report the identification of two novel sequence variants, present in highly conserved nucleotide positions of the human TPMT gene, resulting in a loss of enzyme activity.
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| 3. |
- Lindqvist Appell, Malin, 1976-, et al.
(författare)
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Real-time RT-PCR methodology for quantification of thiopurine methyltransferase gene expression
- 2003
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 59:3, s. 207-211
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of the present study was to develop a real-time reverse-transcription polymerase chain reaction (RT-PCR) methodology for the quantification of thiopurine methyltransferase (TPMT) gene expression in whole blood and compare it with the TPMT enzyme activity measured in red blood cells. Methods: TPMT gene expression was quantified relative to the housekeeping gene cyclophilin (huCYC) and expressed as a TPMT/huCYC ratio. TPMT activity in red blood cells was determined by measuring the formation rate of 6- 14C-methylmercaptopurine from 6-MP using S-adenosyl-L-( 14C-methyl)-methlonine as methyl donor. Thirty-nine individuals were included in the study. A cut-off value of 9 U/ml pRBC was used to distinguish intermediate TPMT enzyme activity from high TPMT enzyme activity. Results: Sequencing of the real-time RT-PCR amplicon proved that the method was specific for the TPMT cDNA, without co-amplification of the highly similar TPMT processed pseudogene. The intra-assay coefficients of variation (CVs), as determined by the threshold cycle, were 0.7% for TPMT and 0.5% for huCYC. The interassay CVs were 1.5% for TPMT and 4.0% for huCYC. The intra- and interassay CVs, as determined by the TPMT/huCYC ratio, were 8.6% and 25%, respectively. There was a statistically significant correlation between TPMT enzyme activity and mRNA level in blood cells from individuals with an enzyme activity above 9 U/ml pRBC (rs = 0.66, P = 0.0001). However, we did not find any statistically significant correlation in individuals with lower enzyme activity or when analysing the whole population. Conclusion: We present a specific and robust real-time RT-PCR method for quantifying TPMT gene expression. The method may be used for studies on TPMT gene regulation.
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| 4. |
- Ahmadi, Ahmad, 1964-, et al.
(författare)
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GSTM1 and mEPHX polymorphisms in Parkinson's disease and age of onset
- 2000
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 269:3, s. 676-680
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
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| 6. |
- Eklund, Lena, 1969-, et al.
(författare)
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Regional mapping of suppressor loci for anchorage independence and tumorigenicity on human chromosome 9
- 2001
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Ingår i: Cancer Genetics and Cytogenetics. - 0165-4608 .- 1873-4456. ; 130:2, s. 118-126
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Tidskriftsartikel (refereegranskat)abstract
- By microcell-mediated chromosome transfer to the malignant Syrian hamster cell line BHK-191-5C, we previously identified two suppressor functions on human chromosome 9 (HSA9), one for anchorage independence and another for tumorigenicity. However, the precise chromosomal locations of these suppressor functions were not determined. The present study was undertaken to define the regional location of these suppressor loci using a panel of microcell hybrids containing structurally altered HSA9 with different deleted regions in the BHK-191-5C background. DNA derived from the cell hybrids was analyzed by PCR for verification of the presence of HSA9 genetic material by amplifying 62 microsatellite markers and 13 genes, covering the entire length of HSA9. Our deletion mapping data on anchorage independent and tumorigenic hybrids suggest that the suppressor function for anchorage independence is located in the region between 9q32 to 9qter. The suppressor for tumorigenicity may be located in one of three deleted regions on HSA9, the first one between the markers D9S162 and D9S1870, the second one between the markers D9S1868 and TIGRA002I21, and the third one between the markers D9S59 and D9S155.
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| 9. |
- Juliusson, Gunnar, 1954-, et al.
(författare)
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Adjusted conditioning for allogeneic transplantation in a single center setting : Mixed chimerism heralds relapse
- 2003
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 44:4, s. 669-679
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Tidskriftsartikel (refereegranskat)abstract
- The role of mixed chimerism on subsequent relapse was prospectively evaluated in an allotransplant program. Sixty-six patients with median age of 54 and mainly high-risk hematologic disease and/or solid tumors had individually adjusted non-myeloablative conditioning. Thirty-nine donors were siblings and 27 unrelated. Frequent chimerism analyses supported immune manipulation including donor lymphocyte infusions. The need for transfusions, iv fluids, and antibiotics, and weight loss was less than in a control cohort. Most patients had immediate full and consistent donor chimerism, one-third required immune manipulation. Eight of ten evaluable CML patients were BCR/ABL-negative at days 14-58 post-transplant. Mixed chimerism frequently preceded relapse, and the relapse rate was 38% in 26 patients with mixed chimerism vs. 11% among 35 with consistent full donor chimerism (p = 0.015). The current transplant- and disease-related mortality were 11 and 9%, respectively, among 35 non-high-risk patients, and 35 and 10% for 29 high-risk patients with hematologic malignancy. With a median follow-up of 15 months the 2-year overall survival is 73% for non-high-risk, and 46% for high-risk patients. Adjusted conditioning reduces early toxicity and resource requirements without impairing tumor control, probably due to a rapid establishment of the graft-versus-cancer effect. Mixed chimerism heralded relapse, and tumor-related mortality is not greater with adjusted than with conventional conditioning.
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