摘要:

To standardizeDPYDallele nomenclature and to conform with international human gene nomenclature guidelines, an alternative to the current arbitrary system is described. Based on recommendations for human genome nomenclature, we propose that each distinct allele be designed byDPYDfollowed by an asterisk and an Arabic numeral. The number specifies the key mutation and, where appropriate, a letter following the number indicates an additional mutation on the mutant allele. Criteria for classification as a distinct allele are also presented.

ISSN:0960-314X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Although some blood parameters have been suggested to modulate in-vitro induction of sister chromatid exchanges by 1,2:3,4-diepoxybutane (DEB), a metabolite of 1,3-butadiene, the increased sensitivity has largely been assigned to a homozygous deletion of glutathioneS-transferase T1 gene (GSTT1null genotype). However, some DEB-sensitive individuals have been shown to beGSTT1positive (having at least one undeletedGSTT1allele). To examine potential causes for this overlap, we evaluated the effect ofGSTMI, GSTPI, andGSTT1genotypes, together with various life-style and blood parameters, on the DEB induction of sister chromatid exchanges and cells with chromosomal aberrations (aberrant cells) in lymphocyte cultures of 115 and 62 human donors, respectively. Our results supported the important role of theGSTT1genotype in DEB sensitivity; 76% of cultures fromGSTT1null donors but only 4% of those fromGSTT1positive donors were DEB-sensitive, as defined by sister chromatid exchange measurements. TheGSTT1genotype also clearly affected DEB-induced aberrant cells, 92% ofGSTT1null and 8% ofGSTT1positive donors being sensitive to DEB. AH individuals showing a high response to DEB in both sister chromatid exchange and aberrant cell analyses wereGSTT1null. Baseline aberrant cell measurements but not sister chromatid exchange measurements were marginally higher amongGSTT1null donors compared withGSTT1positive donors.GSTM1andGSTP1genotypes had no influence on these cytogenetic end-points. Blood transaminases, gamma-glutamyl transferase, urea, creatinine and white blood cell count showed a clear negative association with DEB-induced aberrant cells, whereas wine drinkers had more aberrant cells than non-drinkers. A higher sister chromatid exchange-response to DEB was observed in lymphocytes from women and smokers than from men and non-smokers, respectively. Erythrocyte count correlated negatively with DEB-induced sister chromatid exchanges. Thus, a variety of parameters seemed to modulate the individual DEB-sensitivity together with theGSTT1genotype. Although the known contributing factors accounted for a considerable part of individual variability in sister chromatid exchanges (59.4%) and aberrant cells (46.7%) in DEB treatment, they did not, however, fully explain the overlap in cytogenetic response betweenGSTT1positive and null individuals.

ISSN:0960-314X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The association between the sparteine/debrisoquine (CYP2D6) oxidation polymorphism and the risk of Parkinson's disease was examined in a meta-analysis of case-control studies. The odds ratio was calculated for the risk of Parkinson's disease among poor metabolisers compared with extensive metabolisers. Twenty-one studies were identified of which six were excluded because they were not reported as full papers (n= 3), used incomplete genotype analysis (n= 2) or used Parkinson patients as both control individuals and cases (n= 1). The overall odds ratio was 1.48 (95% confidence interval 1.10–1.99). The odds ratio was 1.05 (95% confidence interval 0.63–1.77) in studies discriminating extensive and poor metabolisers by phenotyping (n= 8) and 1.67 (95% confidence interval 1.11–2.50) in studies using genotyping (n= 7). This difference was caused by a single large study using genotyping. We conclude that there is no convincing evidence of an association between the debrisoquine/sparteine polymorphism and Parkinson's disease. However, it could prove worthwhile to perform another large study using genotyping.

ISSN:0960-314X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Dopamine receptors are strong candidates for involvement in schizophrenia and are targeted by a wide variety of antipsychotics. We hypothesized that genetic variation in these neurotransmitter receptors may influence clinical response to clozapine, an antipsychotic which displays high affinity for dopamine D2 receptors in the limbic system. To test this hypothesis, we studied a functional polymorphism in the promoter region of the D2 receptor gene (-141CIns/Del) in a sample of 151 clozapine treated patients of British origin. In addition, the influence of this polymorphism on antipsychotic response in general was investigated on a sample of 146 Han Chinese schizophrenic patients treated with a variety of antipsychotics. No association was found between this polymorphism and clinical response in either of the two samples suggesting that genetic variation in D2 receptors does not play a major role in determining clinical response to antipsychotic treatment.

ISSN:0960-314X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Genetic susceptibility to toxic chemicals is of major importance but most studies concentrate on candidate genes and searches for unknown susceptibility genes are uncommon. Human sporadic porphyria cutanea tarda is usually precipitated by alcohol, oestrogens, hepatitis viruses, HIV or haemodialysis. The mechanism is not known but there is a role for iron metabolism and an underlying genetic predisposition is suspected. A similar porphyria in humans has also been caused by hexachlorobenzene. These human porphyrias can be modelled in iron-loaded mice exposed to hexachlorobenzene, in which C57BL/10ScSn is a prototype susceptible strain whereas DBA/2 mice are extremely resistant. A search for susceptibility genes was undertaken using complex trait analysis with DNA microsatellite markers of ‘high’ and ‘low’ responders from an F2intercross. Correlation of markers with susceptibility, defined as accumulation of uroporphyrin in the liver, was assessed by chi-squared test for the proportion of C57BL/10ScSn and DBA/2 alleles present. Susceptibility loci on chromosomes 12, 14 and 17 were identified. Further analysis of markers on chromosomes 14 and 17 by MAPMAKER/EXP and MAPMAKER/QTL gave LOD scores of 7.3 and 3.6, respectively. Typing of chromosome 12 for theAhrgene, using a restriction fragment length polymorphism distinguishing between theb-1anddalleles, gave significant but not perfect linkage. However, no strong association between alleles or expression ofCyplal/2genes, regulated byAhr, and susceptibility for porphyria was detected. The results demonstrate that the porphyria induced by hexachlorobenzene in C57BL/10ScSn mice is a complex trait determined by at least three genes, which may be of relevance to susceptibility in the development of sporadic porphyria cutanea tarda and unknown aspects of liver damage.

ISSN:0960-314X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

GlutathioneS-transferases GSTM1, GSTM3, GSTP1 and GSTT1 are involved in the detoxification of active metabolites of several carcinogens in tobacco smoke. We studied the potential role ofGSTM3andGSTP1gene polymorphisms either separately, or in combination withGSTM1andGSTT1gene polymorphisms, in susceptibility to lung cancer using peripheral blood DNA from 150 lung cancer patients and 172 control individuals, all regular smokers. The frequencies ofGSTM3, AA, ABandBBgenotypes were 70.7%, 24.0% and 5.3% in cases and 72.7%, 24.4% and 2.9% in control individuals respectively. The frequencies ofGSTP1, AA, AGandGGgenotypes were 44.7%, 44.0% and 11.3% in cases and 50.0%, 37.2% and 12.8% in control individuals respectively. When studied separately, neitherGSTM3norGSTP1genotypes contributed significantly to the risk of lung cancer. Although failing to reach statistical significance, the combinedGSTM3 AAandGSTP1(AGorGG) genotype conferred a nearly threefold risk when theGSTM1gene was concurrently lacking (odds ratio 2.9, 95% confidence interval 0.7–12.1). Significant interactions were observed between pack-years of smoking and the combinedGSTM3 AAandGSTP1(AGorGG) genotype, or the combinedGSTM3 AA, GSTP1(AGorGG) andGSTM1null genotype. The combination of these threea prioriat risk genotypes conferred an increased risk of lung cancer among smokers with a history of at least 35 pack-years (odds ratio 2.7, 95% confidence interval 1.2–6.0), but not in lighter smokers, probable because of the lower average number of pack-years of smoking found among control individuals with this genotype combination.

ISSN:0960-314X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

p53 mutation status was analysed in relation to DNA polymorphisms ofGSTM1, CYP1A1andCYP2E1from 105 surgically resected non-small cell lung cancer cases. Demographic factors, smoking, occupation, family history, tumour histology, grade and stage were taken into account. p53 mutations, detected either directly by DNA sequencing (P= 0.04, adjusted for smoking) or indirectly by immunostaining (P= 0.06), were overrepresented amongCYP1A1variants. Mutations in exon 8 and transitions at CpG sites in the p53 gene were favoured in this subset. There was no relation between the individual gene polymorphisms or p53 mutations and disease-free survival by Kaplan-Meier analysis. The finding of excessCYP1A1heterozygotes in individuals with p53 mutations after adjustment for smoking suggests thatCYP1A1activation contributes to lung Cancer via p53 inactivation.

ISSN:0960-314X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Human hepaticN-acetyltransferase (NAT2) is subject to a genetic polymorphism. Because NAT2 is an important enzyme for the detoxification and/or bioactivation of several carcinogenic arylamines, it has been postulated that the polymorphism ofNAT2gene is associated with the occurrence of colorectal and bladder carcinomas. Several mutations have been described in the humanNAT2gene that have been associated with reduced NAT2 activity. However, the majority are single base substitutions at positions 481 (NAT2*5A), 590 (NAT2*6A) and 857 (NAT2*7A) of theNAT2gene. This study was performed to evaluate the relative distribution ofNAT2alleles and genotypes in 216 colorectal carcinoma patients and 187 normal individuals. The frequencies ofNAT2alleles and genotypes in the sampled Chinese population were characterized by allele-specific polymerase chain reaction. No differences were observed in the distribution of the genotypes coding rapid acetylation (homozygous wild-type and heterozygous wild-type with any of the mutations) when comparing colorectal carcinoma patients with control individuals (P> 0.05). However, the rapid acetylation genotype was associated with cancer occurring on the right site of the colon. The frequencies of theNAT2*4,NAT2*5A,NAT2*6AandNAT2*7Aalleles of theNAT2gene (0.51, 0.07, 0.32 and 0.10, respectively) in control individuals were significantly different from those in patients (0.49, 0.06, 0.26 and 0.19, respectively,P< 0.01). There was a significant increase in the frequency of patients who were compound heterozygotes ofNAT2*7Aand a variant non-NAT2*7Aallele. TheNAT2*7Aallele was also seen more frequently in distal Cancer.

ISSN:0960-314X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The heterocyclic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a potent mutagen and is a mammary carcinogen in rodents. In man, hepatic activation is carried out by cytochrome P450 (CYP) 1A2 and the ultimate DNA-reactive species is thought to be a nitrenium ion formed via an acetoxy ester of an exocyclic amino group. Because most human breast tumours are ductal in origin, we investigated the ability of cell types present in the mammary gland (breast epithelial cells and neutrophils present in milk) to activate IQ to DNA-binding species using32P-post-labelling. Phorbol myristate acetate-stimulated neutrophils produced a similar pattern of IQ-DNA adducts to that produced by human mammary epithelial cells. Adduct formation in stimulated neutrophils was inhibited 80% by the myeloperoxidase inhibitor sodium azide (1 mM) but was not affected by proadifen (100 μM), indomethacin (100 μM), or eicosatetraynoic acid (100 μM), inhibitors of cytochrome P450, prostaglandin synthetase, and lipoxygenase, respectively. Similar experiments in human mammary epithelial cells showed no azide inhibition of IQ-DNA adduct formation. Analysis of gene expression by reverse transcription-polymerase chain reaction showed that CYP1A1 and CYP1B1, but not CYP1A2, were expressed at detectable levels in untreated mammary epithelial cells, whereas in neutrophils cytochrome P450 expression was confined to low levels of CYP1A1. In cultured epithelial cells, IQ-DNA adduct formation and CYP1A1, but not CYP1B1 expression were induced threefold by benz[a]anthracene treatment; IQ-DNA adduct formation was inhibited by α-naphthoflavone. Our results indicate possible mechanisms for the metabolic activation of dietary carcinogens in the human breast.

ISSN:0960-314X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

CYP2D6genotyping (CYP2D6*3,CYP2D6*4, CYP2D6*5, CYP2D6*13, CYP2D6*16alleles and gene duplications) was previously performed on 1053 Caucasian and African-American lung cancer cases and control individuals and no significant difference in allele frequencies between cases and control individuals detected. We have carried out additional genotyping (CYP2D6*6, CYP2D6*7, CYP2D6*8, CYP2D6*9, CYP2D6*10, CYP2D6*17alleles) and debrisoquine phenotyping on subgroups from this study to assess phenotype-genotype relationships. African-Americans showed significant differences from Caucasians with respect to frequency of defectiveCYP2D6alleles, particularlyCYP2D6*4and CYP2D6*5. TheCYP2D6*17allele occurred at a frequency of 0.26 among 87 African-Americans and appeared to explain higher average metabolic ratios among African-Americans compared with Caucasians.CFP2D6*6, CYP2D6*8, CYP2D6*9andCYP2D6*10were rare in both ethnic groups but explained approximately 40% of higher than expected metabolic ratios among extensive metabolizers. Among individuals phenotyped with debrisoquine, 32 out of 359 were in the poor metabolizer range with 24 of these (75%) also showing two defectiveCYP2D6alleles. Additional single strand conformational polymorphism analysis screening of samples showing large phenotype – genotype discrepancies resulted in the detection of three novel polymorphisms. If subjects taking potentially interfering drugs were excluded, this additional screening enabled the positive identification of 88% of phenotypic poor metabolizers by genotyping. This sensitivity was comparable with that of phenotyping, which identified 90% of those with two defective alleles as poor metabolizers.

ISSN:0960-314X    

出版商:OVID    

年代:1998

数据来源: OVID