摘要:

The current number of 9422 symbols for human gene names (http://www.gene.ucl.ac.uk/nomenclature/) is expected to increase 7- to 15-fold over the next 2 years. In and around each gene, a tremendous degree of single-nucleotide polymorphism (SNP) heterogeneity is now realized to exist. This review is intended to be visionary, to point out some of the enormously complex nomenclature issues that we face, and to offer some reasonable solutions to these issues. For example, I believe that a 'gene' should be defined as that region from the furthest 5′-ward enhancer to at least 150 bases downstream of the last exon. Just as established rules are critically important for the systematic naming of all new genes, standardized nomenclature rules for the naming of allelic variants are also desperately needed. The evolving consensus for naming the alleles of all human genes (ideally based on evolutionarily diverging haplotype patterns) is described herein. Because of the anticipated explosion in finding new genes and allelic variants due to high-throughput resequencing and DNA-chip technologies, this excess of new knowledge will undoubtedly overwhelm their publication by scientific journals alone. I suggest that the best approach to this staggering 'information overload' is to place the data on appropriate web sites - with numerous links between sites, and frequent updates of all information - so that colleagues in all fields of medical and genetic research can remain knowledgeable. Examples of successful web sites to date include those for the cytochrome P450 (CYP) genes and humanCYPalleles, UDP glycosyltransferase (UGT) genes and human alleles, humanN-acetylaminotransferase (NAT2, NAT1) alleles, and aldehyde dehydrogenase (ALDH) genes and human alleles. Many more web sites will be necessary. For each site, the webmaster will need to be responsible, accurate, energetic, highly organized, and keen to keep the site current. I believe that interactive discussions on these sites should be encouraged, and advisory committees must be willing to check frequently to ensure that all new information is accurate. Lastly, for the field of molecular epidemiology, the importance of correlating an informative genotype with an unequivocal phenotype is emphasized, and the emerging realization that racial and ethnic groups are highly admixed is summarized and updated.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

One major interest to analyse the extent ofN-acetyltransferase 1 (NAT1*) allelic variation in the human population stems to a great extent from the possible association of interindividual differences in the metabolism of aromatic amines with certain chemically induced diseases, including cancer. Considering the increasing number of mutations in theNAT1gene that are detected,NAT1* genotyping using conventional polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) or allele-specific amplification assays has become complicated. We developed a rapid and powerful strategy allowing the full characterization ofNAT1* alleles. This method, based on single-strand conformation polymorphism analysis of a unique PCR product encompassing the entire intronlessNAT1* coding region along with additional flanking segments in the 5′ and 3′ untranslated regions, was then applied to DNA samples from 270 individuals. NineNAT1* allelic variants, including two novel (NAT1*28andNAT1*29), and 15 different genotypes were identified. This approach could be advantageously used in epidemiological studies to provide more definite data on suspected associations betweenNAT1* genotype and certain pathological processes.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

To evaluate the potential association betweenGSTM1andGSTT1genotypes and development of breast cancer, a hospital based case-control study was conducted in a South Korean study population consisting of 189 histologically confirmed incident breast cancer cases and their 189 age-matched control subjects with no present or previous history of cancer. A multiplex polymerase chain reaction method was used for the genotyping analyses and statistical evaluations were performed by unconditional logistic regression model. TheGSTM1null genotype was significantly associated with breast cancer risk in premenopausal women [odds ratio (OR) = 2.0, 95% confidence interval (CI) = 1−3.7], but not in the postmenopausal women (OR = 0.9, 95% CI = 0.5−1.9), nor in all women grouped together (OR = 1.3, 95% CI = 0.8−1.1). TheGSTT1null genotype posed a similar risk of breast cancer with an OR of 1.6 (95% CI = 1.0−2.5) for the total breast cancer group, OR of 1.7 (95% CI = 0.9−3.2) for pre-menopausal women, and OR of 1.3 (95% CI = 0.6−2.8) for post-menopausal women. The breast cancer risk associated with concurrent lack of bothGSTM1andGSTT1genes was 2.2 (95% CI = 1.1−4.5), and the risk increased as the number of null genotype increased (Pfor trend = 0.03). When the data were stratified by the known risk factors of breast cancer, a significant interaction was observed between theGSTM1genotypes and alcohol consumption (Pfor interaction = 0.03). An especially remarkable risk of breast cancer was observed for alcohol-consuming premenopausal women lacking both theGSTM1andGSTT1genes (OR = 5.3, 95% CI = 1.0−27.8) compared to those with both of the genes. Our findings thus suggest a novel gene-environment interaction which plays an important role in the individual susceptibility to breast cancer.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Cancer susceptibility differences may be attributed in part to genetic variation in genes involved in metabolism of environmental procarcinogens. Increased risks for some cancers have been linked to polymorphisms in certain phase I and II genes, and have been associated with genomic instability and chromosomal aberrations. Aberration frequencies in general, and stable aberration frequencies (translocations and insertions) in particular, are used as biomarkers for disease. Thus, knowledge of the genetic factors that influence the frequency of stable aberrations in a normal population is important for cancer risk determination. In this work, genotypes for a number of xenobiotic enzymes (CYP1A1, CYP2D6, GSTM1, GSTT1, GSTP1, NAT1, NAT2and epoxide hydrolase) and stable aberration frequencies were determined for 65 normal individuals aged 19-77 years. The population was divided at age 60 years for analysis because there was a significant difference in stable aberration frequencies between these groups. Subjects with low levels (0-66th percentile) of stable aberrations were compared to those with high levels (67th percentile and above). Of all the genotypes studied, onlyNAT2showed a notable difference between the high and the low stable aberration groups in the percentage of polymorphisms observed, and this was seen only in the older subjects group. All individuals in the older-high stable aberration group wereNAT2rapid acetylator smokers.NAT2slow acetylator smokers had significantly lower stable aberration frequencies compared to theNAT2rapid acetylator smokers. Following previous work showing an increased risk of cancer associated with high levels of aberrations (above the 66th percentile), we hypothesize that smokers with theNAT2rapid acetylator genotype may be at an increased risk for cancer.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Peroxisome proliferator-activated receptor (PPAR)α-null mice have a defect in fatty acid metabolism but reproduce normally. The lack of a detrimental effect of the null phenotype in development and reproduction opens up the possibility for null or variant PPARα gene (PPARA) alleles in humans. To search the coding region and splice junctions for mutant and variant PPARα alleles, the human PPARα gene was cloned and characterized, and sequencing by polymerase chain reaction was carried out. Two point mutations in the human gene were found in the DNA binding domain at codons for amino acids 131 and 162. The allele containing the mutation in codon 162 (CTT to GTT, L162V) designatedPPARA*3,was found at a high frequency in a Northern Indian population. Transfection assays of this mutant showed that the non-ligand dependent transactivation activity was less than one-half as active as the wild-type receptor.PPARA*3was also unresponsive to low concentrations of ligand as compared to the wild-typePPARA*1receptor. However, the difference is ligand concentration-dependent; at concentrations of the peroxisome proliferator Wy-14 643 > 25 μM, induction activity was restored in this variant's transactivation activity to a level five-fold greater as compared with wild-typePPARA*1with no ligand. The mutation in codon 131 (CGA to CAA, R131Q), designatedPPARA*2is less frequent thanPPARA*3,and the constitutive ligand independent activity was slightly higher thanPPARA*1.Increasing concentrations of Wy-14 643 activatedPPARA*2similar to that observed withPPARA*1.The biological significance of these novel PPARα alleles remains to be established. It will be of great interest to determine whether these alleles are associated with differential response to fibrate therapy.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Previous studies have demonstrated that subjects with one or twoA1alleles of dopamine D2receptor (DRD2) polymorphism at theTaq1A locus have lower DRD2density than those with noA1allele. The present study aimed to examine whether theTaq1ADRD2genotypes are related to therapeutic response to nemonapride, a selective dopamine antagonist, in schizophrenic patients. The subjects were 25 acutely exacerbated schizophrenic inpatients who had received no medication for at least 1 month before the study. The fixed dose (18 mg/day) of nemonapride was administered to each patient for 3 weeks. The clinical status was prospectively monitored by the Brief Psychiatric Rating Scale (BPRS) before, and 3 weeks after, the treatment. TheTaq1A genotypes (A1andA2alleles) were determined by the polymerase chain reaction method. Three patients were homozygous for theA1allele, 11 were heterozygous for theA1andA2alleles, and 11 were homozygous for theA2allele. The patients with one or twoA1alleles (n= 14) showed significantly higher percentage improvement in total BPRS and positive symptoms than those with noA1allele (n= 11) after 3-week treatment while the percentage improvement in other subgrouped symptoms (negative, anxiety-depression, excitement and cognitive symptoms) was similar between the two genotype groups. The present results suggest that theTaq1ADRD2polymorphism is related to early therapeutic response to nemonapride in schizophrenic patients, possibly by modifying the efficiency of DRD2antagonism of the drug in the central nervous system.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Most drug metabolizing cytochrome P450s (P450) are predominantly expressed in the liver. In contrast, humanCYP1B1is an extrahepatic P450 which is overexpressed in many tumours and has been strongly implicated in the activation of carcinogens. Rare allelic variants of theCYP1B1gene which encode an inactive protein have been identified. However, four polymorphisms which most likely do not abolish functionality have been described. In this report, we have characterized the functional consequences of these. A CYP1B1 cDNA, identical to a cDNA published previously, served as a template to introduce allelic changes either separately or in combination. The resulting effects on CYP1B1 activity were determined in membranes isolated fromEscherichia coliwhich coexpressed CYP1B1 together with P450 reductase. None of the allelic changes affected the CYP1B1 expression level. The allelic changes Arg48to Gly, Ala119to Ser and Asn453to Ser had little influence on theVmaxand theKmof the CYP1B1 mediated 2- and 4-hydroxylation of estradiol. In contrast, theKmof these metabolic pathways was increased at least three-fold by the allelic change Val432to Leu or by simultaneously changing Val432to Leu and Asn453to Ser. However, these alterations had little effect on the kinetic parameters of other CYP1B1 mediated reactions such as the epoxidation of (−)-trans-(7R,8R)-benzo[a]pyrene 7,8-dihydrodiol as determined by (r-7,t-8,t-9,c-10)-benzo[a]pyrene tetraol formation, or such as theO-dealkylation of ethoxyresorufin and the 1′-hydroxylation of bufuralol. Molecular modelling suggests that amino acid residue 432 of CYP1B1 may be involved in the interaction between CYP1B1 and P450 reductase. Since 4-hydroxyestradiol has been implicated in hormonal carcinogenesis and CYP1B1 is expressed in target tissues, the data presented demonstrate that polymorphisms in CYP1B1 have the potential to affect disease susceptibility.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The domestic cat has a significantly lower capacity to glucuronidate planar phenolic xenobiotics compared with most other mammalian species. The aim of this study was to determine the mechanistic basis for this anomaly. Current knowledge of the substrate specificity of UDP-glucuronosyltransferase (UGT) isoforms indicates that the cat may either lack or poorly express UGT1A6. Initially, a novel cloning technique was used to identifyUGT1Agenes expressed in cat liver. Only two unique UGT1A isoforms could be discriminated. The first (28% of clones) was most homologous to UGT1A1 (the bilirubin-UGT), while the second (72% of clones) showed homology to several isoforms, but could not be unambiguously identified, and was designated cat UGT1A02. Southern blot analysis confirmed the presence of a single UGT1A6-homologous region in the cat genome. Subsequent cloning and sequencing of the entire UGT1A6 exon 1 coding region revealed five deleterious genetic mutations. Identical mutations were found by sequencing of UGT1A6 exon 1 from five other unrelated cats. Four of these five genetic lesions were also identified in the UGT1A6 exon 1 region of a margay (Leopardus wiedii). Finally, RT-PCR of liver mRNA from four different cats confirmed the presence of UGT1A1 and UGT1A02, but not UGT1A6. In conclusion, UGT1A6 is a pseudogene in the domestic cat and in at least one other phylogenetically related species. Furthermore, cats appear to have a less diverse pattern of UGT1A isoform expression compared with other species. Such differences most likely reflect the highly carnivorous diet of Feliform species and resultant minimal exposure to phytoalexins.

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0960-314X    

出版商:OVID    

年代:2000

数据来源: OVID