Relationship in healthy subjects between CYP2E1 genetic polymorphisms and the 6-hydroxylation of chlorzoxazone: a putative measure of CYP2E1 activity.
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Adolescent↗
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Genetic polymorphism of human CYP2E1: characterization of two variant alleles.
Ethanol-inducible CYP2E1 is an enzyme of major toxicological interest because it metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. CYP2E1 has also been implicated in alcohol liver disease because of its contribution to oxidative stress. Previously, polymorphic alleles with mutations in introns and in the 5'-flanking regulatory region have been described, and their presence has been related to the incidence of alcohol liver disease and lung cancer. In the present investigation, we investigated whether any functional mutations are linked to the above-mentioned rare alleles and also screened for mutations in the open reading frame using single-stranded conformation polymorphism and genomic DNA from almost 200 individuals belonging to either a Chinese, an Italian, or a Swedish population. Two new CYP2E1 gene variants were found with functional mutations: one (CYP2E1*2) in which a G1168A point mutation in exon 2 caused an R76H amino acid substitution, and the other (CYP2E1*3) in which a G10059A base substitution in exon 8 yielded a V3891 amino acid exchange. The corresponding CYP2E1 cDNAs were constructed, subcloned into the pCMV4 expression vector, and expressed in COS-1 cells. The cellular levels of CYP2E1 mRNA, CYP2E1 protein, and rate of chlorzoxazone hydroxylation were monitored. The CYP2E1*3 cDNA variant was indistinguishable from the wild-type cDNA on all variables investigated, whereas CYP2E1*2 cDNA, although yielding similar amounts of mRNA, only caused 37% of the protein expression and 36% of the catalytic activity compared with the wild-type cDNA. Complete screening by single-stranded conformation polymorphism of the three populations studied revealed that these variant alleles were rare. We conclude that the human CYP2E1 gene is functionally surprisingly well conserved compared with other cytochrome P450 enzymes active in drug metabolism, which suggests an important endogenous function in humans.
Alleles↗
[Genetic polymorphism of human CYP2E1: new allels detected in exons and exon-intron junctions].
Cytochrome P450-2E1 (CYP2E1) is a major component of the microsomal ethanol-oxidizing system (MEOS) and is also involved in the metabolism of a variety of foreign compounds including carcinogens. It has been shown that there is an interindividual variation in the expression of human hepatic CYP2E1. Gene-environmental interactions have been suggested to account for the difference. In this study, we screened nine exons of the human CYP2E1 gene for detecting allelic variants in genomic DNA samples obtained from 115 Japanese controls, 96 Japanese alcoholics and 124 American control subjects. A novel missense mutation in exon 2 (V72L) was found in Japanese controls, and another missense mutation in exon 8 (D394G) was detected in American Caucasians. In addition, two novel silent mutations in exon 6 (T303T) and exon 8 (F420F) were found in Japanese controls and alcoholics. Especially the silent mutation in exon 8 was highly polymorphic among three population groups. The mutation in exon 2 (V72L) was detected only in Japanese controls, but not in alcoholics although it shows no significant difference. Gene frequency of the silent mutation in exon 8 was significantly higher in Japanese than American Caucasians (34.8% vs 21.0%, p < 0.02). Our data indicated that nucleotide replacement in the open reading frame is no major factor responsible for alcoholism. However, functional significance of the two novel missense mutations remains to be detailed.
Alcoholism↗
Genetic polymorphism in bladder cancer.
Individual variation in the genetic constitution of humans may affect the host responses to constant assaults from exogenous and endogenous carcinogens, which will eventually impact cancer risk, disease prognosis and clinical outcome. Bladder cancer is one of the most common cancers in the world. In this review, the published research articles studying the association between genetic polymorphisms and bladder cancer risk and disease progression are summarized. Genetic polymorphisms are categorized based on their primary cellular functions: genes in carcinogen metabolism, DNA repair, cell cycle control, inflammation, apoptosis, methylation, genes functioning as G proteins, and cell adhesion molecules. Furthermore, we discuss a number of limitations of current genetic susceptibility research and suggest future directions in molecular epidemiology study. This review presents an overview of current molecular epidemiology of bladder cancer and provides a useful resource for understanding the pathogenesis of bladder cancer.
Apoptosis↗
Genetic polymorphism of human peptidase C, PEPC (E.C.3.4.1.1): formal genetic and population data.
Human peptidase C, PEPC (E.C.3.4.1.1), exhibits a previously undescribed genetic polymorphism, detectable in red cells or leukocytes by starch gel electrophoresis. Segregation analyses on 161 families with 469 offspring support the formal genetic hypothesis of two codominant alleles at an autosomal locus. Since four rare variants have previously been described, we named the polymorphic allele PEPC*6. Gene frequencies from southwestern Germany were PEPC*1 = 0.721 +/- 0.018; PEPC*6 = 0.276 +/- 0.018, and PEPC*R = 0.003 +/- 0.002.
Alleles↗
[Feasibility of genetic polymorphisms analysis using genomic DNA obtained from human buccal cells].
BACKGROUND & OBJECTIVE: Using DNA samples obtained from buccal cells for genetic polymorphism analysis in molecular epidemiological studies has been repeatedly reported, but whether DNA from food remnants in mouth influences the result is still concerned. This study was to compare genetic polymorphisms of buccal cell DNA with those of buffy coat DNA, and with plant and animal DNA from foods to rule out the possibility of interference from food remnants, to improve technique of buccal cell collection and elevate DNA yield. METHODS: Buccal cells were collected from mouthwash (40 ml/case) of 62 subjects, and fixed with isopropyl alcohol; buffy coats of peripheral blood were collected from 30 of these subjects. Common foods (rice, greengrocery, soybean, apple, pork, beef, chicken, and duck) were also collected. DNA of all samples was extracted by chloroform-phenol method. NAT2, GSTM1, GSTT1, CYP1A1, and CYP2E1 genetic polymorphisms were assayed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Alu (human mutual DNA sequence) was also tested. RESULTS: DNA yield of 62 individual mouthwash samples was (135.15+/-64.30) microg (22.36-330.70 microg); 30 individual mouthwash samples contained 75%-95% oral epithelial cells with DNA yield of (143.44+/-61.64) microg (51.01-283.58 microg). DNA yield of 30 buffy coat samples was (91.19+/-38.01) microg (30.83-178.63 microg). Electrophoresis showed that all 62 buccal cell samples and 30 buffy coat samples contained DNA fragments in high molecular weight; beta-globin, Alu, NAT2, GSTM1, GSTT1, CYP1A1, and CYP2E1 gene fragments were successfully amplified from 61 buccal cells samples and 30 buffy coat samples, which showed no difference between the 2 kinds of samples from individual collections; these gene fragments were not amplified from all food DNA samples. CONCLUSIONS: The majority of DNA from mouthwash is human-origin. A little amount of food remnants would not influence the measurements of genetic polymorphisms. The genetic polymorphisms show no difference between buccal cell samples and buffy coat samples.
Aged↗
XPD and XRCC1 genetic polymorphisms are prognostic factors in advanced non-small-cell lung cancer patients treated with platinum chemotherapy.
PURPOSE: Platinum agents cause DNA cross-linking and oxidative damage. Genetic polymorphisms of DNA repair genes are associated with differential DNA repair activity and may explain interindividual differences in overall survival after therapy with platinum agents for non-small-cell lung cancer (NSCLC). METHODS: We used polymerase chain reaction-restriction fragment length polymorphism to evaluate genetic polymorphisms of the XPD (Asp312Asn) and XRCC1 (Arg399Gln) DNA repair genes in 103 patients with stage III (54%) and IV (46%) NSCLC treated with platinum-based chemotherapy. RESULTS: Median age was 58 years (range, 32 to 77 years), 49% were females, and there were 86 deaths. Median follow-up period was 61.9 months. Median survival time (MST) was 14.9 months; by stage, MST was 28.6 months (IIIA), 16.0 months (IIIB), and 9.3 months (IV). Genotypes were not associated with stage. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival (P =.003 and P =.07, respectively, by log-rank test). Similarly, when we compared combinations of variant alleles across both polymorphisms, we found that a greater number of variant alleles was associated with decreasing overall survival (P =.009, log-rank test). These polymorphisms independently predicted overall survival even after taking into account stage, performance status, and chemotherapy regimen. CONCLUSION: Genetic polymorphisms in XPD and XRCC1 may be important prognostic factors in platinum-treated patients with advanced NSCLC.
Adult↗
Genetic polymorphism of complement component C8.
Extensive genetic polymorphism of complement component C8 was demonstrated by isoelectric focusing of serum or plasma samples followed by immunoblotting procedures. Using these methods, we could detect both alpha-gamma (C81) and beta (C82) chain polymorphisms in the same gel. Two-dimensional (2D) electrophoresis of C8 immunoprecipitates was used to obtain further information of the C8 patterns. Evidence was obtained that the C81 polymorphism resides in the structural gene of the C8 alpha chain. Both C8 systems show autosomal, chiefly codominant inheritance, and the distribution of phenotypes agrees with the Hardy-Weinberg equilibrium. Our findings suggest at least five different alleles in the C81 system; the gene frequencies of the two most common ones, C81*A and C81*B being 0.59 and 0.39, respectively. In C82 we found evidence for at least three codominant alleles, the gene frequencies for the two most common ones, C82*B and C82*A being 0.94 and 0.05, respectively. In addition, family studies disclosed the existence of a null allele, C82*Q0.
Alleles↗
Genetic polymorphism of human urine deoxyribonuclease I.
A genetic polymorphism of human urine deoxyribonuclease I (DNase I) has been detected by the technique of polyacrylamide gel isoelectric focusing (IEF-PAGE) followed by immunoblotting with anti-DNase I antibody. Family studies showed that the three common phenotypes - DNASE1 1, 1-2, and 2 - and the other four rare phenotypes - DNASE1 1-3, 2-3, 2-4, and 3-4 - represent homozygosity or heterozygosity for four autosomal codominant alleles, DNASE1*1, *2, *3, and *4. The frequencies of the DNASE1*1, DNASE1*2, DNASE1*3, and DNASE1*4 alleles in a studied Japanese population were 0.5453, 0.4396, 0.0117, and 0.0034, respectively.
Deoxyribonuclease I↗
[Study on the genetic polymorphisms of human glutathione-S-transferase A1 in Hakka population in South China].
OBJECTIVE: Glutathione-S-transferase A1 (GSTA1) is one of the major phase II detoxification enzymes in the cytosol, which genetic polymorphisms distribution is different in different ethnic, national and regional population. Up to now, GSTA1 genetic polymorphisms has been rarely reported in China. The purpose of the study was to investigate the distribution of genetic polymorphisms of human GSTA1 in Hakka population in South China. METHODS: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were used to identify the genotypes of GSTA1 gene and the data were analyzed with SPSS10.0 software. RESULTS: The GSTA1 genetic polymorphisms were detected in 480 samples. The frequency of GSTA1 * A/ * A,GSTA1 * A/ * B and GSTA1 * B/ * B were 77.1%, 21.7% and 1.2% respectively. And the GSTA1 genetic polymorphism distribution was in accordance with the Hardy-Weinberg equilibrium rule. There were no difference in the GSTA1 genetic polymorphisms among the different groups of age or gender. Logistic regression analysis showed that there were no association between the GSTA1 genetic polymorphism and family history of hypertension, coronary heart disease, stroke, lung cancer and nasopharyngeal cancer, et al. CONCLUSION: The GSTA1 gene existed polymorphism among Hakka in South China.
Adolescent↗
Significance of genetic polymorphisms in glutathione S-transferase multigene family and lung cancer risk.
A vast number of studies are focused on investigating genetic polymorphism in order to estimate genetic contribution to the development of cancer. Possible cancer susceptibility genes have been sought among oncogenes, tumor suppressor genes, DNA repair genes and genes encoding phase I and phase II enzymes. Large individual differences in the biotransformation of xenobiotics have been explained on the basis of genetic polymorphisms in some detoxifying enzymes, regardless of environmental and occupational exposure. Among these enzymes, glutathione S-transferases (GST) constitute a large multigene family of phase II enzymes involved in detoxification of potentially genotoxic chemicals. Five genetic polymorphisms of GST have been well documented. Total or partial deletions and (or) single nucleotide polymorphisms in alleles encoding GSTM1, GSTM3, GSTPI, GSTT1, GSTZ1 are associated with reduction of enzymatic activity toward several substrates of different GST isoenzymes. In addition, molecular epidemiology studies indicate that a single genetic polymorphism of glutathione S-transferase appears to be a moderate lung cancer risk factor. However, the risk is higher when interactions with more GST polymorphisms and other risk factors (e.g. cigarette smoking) occur. Individuals with decreased rate of detoxification, with "high risk" glutathione S-transferase genotypes have a slightly higher level of carcinogen-DNA adducts and more cytogenetic damages.
DNA Adducts↗
Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes.
Genetic variations have been associated with a predisposition to common diseases and individual variations in drug responses. Identification and genotyping a vast number of genetic polymorphisms in large populations are increasingly important for disease gene identification and pharmacogenetics. Commonly used gel electrophoresis-based genotyping methods for known polymorphisms include polymerase chain reaction (PCR) coupled with restriction fragment-length polymorphism analysis, allele-specific amplification, and oligonucleotide ligation assay. Fluorescent dye-based DNA fragmentation has been extensively used for high-throughput microsatellite or short tandem-repeat genotyping. TaqMan and molecular beacon genotyping are commonly used homogeneous solution hybridization technologies. Because of the ease of experimental assay design, single nucleotide polymorphism (SNP) genotyping methods based on single-base extension are in rapid development, such as fluorescence homogenous assays, pyrosequencing and mass spectrometry. Non-PCR based genotyping assays such as Invader trade mark assays are promised to genotype directly from genomic DNA without the requirement of PCR amplification. The DNA microarray is a solid phase genotyping format that is rapidly developing for parallel genotyping of a large number of SNPs simultaneously. Advanced technologies to identify genetic polymorphisms rapidly, accurately, and cost effectively will fundamentally change the practice of medicine by allowing physicians to prescribe medicine based on a patient's genetic make-up.
Alleles↗
Analysis of several hundred genetic polymorphisms may improve assessment of the individual genetic burden for coronary artery disease.
BACKGROUND: Single polymorphisms of different genes have been associated with coronary artery disease (CAD). The aim of this study was to evaluate the benefit of analyzing multiple genetic polymorphisms as a compound unit to assess the individual genetic burden for CAD. METHODS AND RESULTS: The study population consisted of 100 case patients with, and 100 control patients without, angiographically proven CAD. The patients were matched for age, sex, and numbers of standard cardiac risk factors. Sixteen different genetic polymorphisms were analyzed using polymerase chain reaction-based technologies. None of these polymorphisms showed a significant difference in the allele frequency between case and control patients. Eight genes with a higher allele frequency in the case group (delta allele frequency >0.05) were defined as risk alleles (RA) and subsequently tested as a compound unit. A risk stratification for 64.5% of all patients was possible when eight genes with their 16 RA were included in the analysis. With more than eight RA per individual, the odds ratio for developing CAD was 3.21 (95% CI 1.77-5.82, P<0.001). However, there was still an overlap in the number of RA in case and control patients. A computer simulation estimated that more than 200 polymorphisms were needed for a reasonable genetic discrimination for patients at risk for CAD. CONCLUSIONS: An increasing number of risk alleles are associated with an elevated risk for CAD. An analysis of multiple polymorphisms, some several hundred, each with a small impact, may allow improved assessment of the individual genetic burden for CAD. Larger studies are needed to prove this hypothesis.
Journal Article↗
Ethnic-related differences in the frequency distribution of genetic polymorphisms in the CYP1A1 and CYP1B1 genes in Japanese and Caucasian populations.
1. Race-related differences in the frequency distribution of genetic polymorphisms in the CYP1A1 and CYP1B1 genes were studied in 39 Japanese and 45 Caucasians. 2. Four types of CYP1A1 polymorphism, namely m1 (a nucleotide change at T6235C in the 3'-flanking region), m2 (A4889G at exon 7), m3 (T5639C in the 3'-flanking region) and m4 (C4887A at exon 7), and three types of CYP1B1 genetic polymorphism, namely m1 (C488G and G701T leading to Arg48Gly and Ala119Ser exchanges respectively), m2 (C1294G leading to a Leu432Val exchange) and m3 (A1358G leading to an Asn453Ser exchange) were studied. 3. The distribution of the m1-, m2-, m3-, and m4-types of CYP1A1 polymorphism in the Japanese population was 30.8, 17.9, 0 and 0% respectively; those in Caucasians were 3.3, 6.7, 0 and 2.2% respectively. Two types (m1, and m2) of CYP1B1 polymorphism were expressed at 14.1 and 21.8% respectively in the Japanese, and by 28.9 and 37.5% respectively in the Caucasian. Ethnic differences were also noted in the m3-type CYP1B1 polymorphism in which the incidence in Caucasians was 23.9%, whereas no cases in the 39 Japanese subjects were observed. 4. No apparent association was found in the incidence in each of the genetic polymorphisms of CYP1A1 and CYP1B1 genes, nor in methylenetetrahydrofolate reductase gene, except that the occurrence of the m2-type of CYP1A1 genetic polymorphism was related to that of the m1-type CYP1A1 polymorphism in the Japanese population. 5. These results suggest that there are race-related differences in the occurrence of genetic polymorphisms in both CYP1A1 and CYP1B1 genes in Japanese and Caucasian populations and that these differences in P450 genetic polymorphisms may, in part, cause differences in the occurrence of lung and breast cancers in these ethnic groups.
Alleles↗
Genetic polymorphisms in cytochrome P450 enzymes: effect on efficacy and tolerability of HMG-CoA reductase inhibitors.
Adverse drug reactions are common; they are responsible for a number of debilitating side effects and are a significant cause of death following drug therapy. It is now clear that a significant proportion of these adverse drug reactions, as well as therapeutic failures, are caused by genetic polymorphism, genetically based interindividual differences in drug absorption, disposition, metabolism, or excretion. HMG-CoA reductase inhibitors are generally very well tolerated and easy to administer with good patient acceptance. There are only two uncommon but potentially serious adverse effects related to HMG-CoA reductase inhibitor therapy: hepatotoxicity and myopathy. The occurrence of lethal rhabdomyolysis in patients treated with cerivastatin has prompted concern on the part of physicians and patients regarding the tolerability of HMG-CoA reductase inhibitors. Apart from pravastatin and rosuvastatin, HMG-CoA reductase inhibitors are metabolized by the phase I cytochrome P450 (CYP) superfamily of drug metabolizing enzymes. The best-characterized pharmacogenetic polymorphisms are those within this enzyme family. One of these enzymes, CYP2D6, plays an important role in the metabolism of simvastatin. It has been shown that the cholesterol-lowering effect as well as the efficacy and tolerability of simvastatin is influenced by CYP2D6 genetic polymorphism. Because the different HMG-CoA reductase inhibitors differ, with respect to the degree of metabolism by the different CYP enzymes, genotyping may help to select the appropriate HMG-CoA reductase inhibitor and the optimal dosage during the start of the treatment and will allow for more efficient individual therapy. A detailed knowledge of the genetic basis of individual drug response is potentially of major clinical and economic importance.
Cytochrome P-450 Enzyme System↗
Family-based association study between G72/G30 genetic polymorphism and schizophrenia.
Genetic variations in G72/G30 have been reported to be associated with schizophrenia and bipolar disorders in several case-control studies. This gene is located in a genomic region known to contain susceptibility genes for schizophrenia. As case-control studies carry an increased risk of confounding through population stratification, we investigate whether the rs947267 (A/C) polymorphism is associated with schizophrenia in a family-based association study. This polymorphism is located within the G72/G30 gene and has been previously associated with bipolar disorders. The sample consisted of a total of 216 Chinese families that included an affected offspring and parents. Transmission disequilibrium analysis revealed a significant association between the G72/G30 rs947267 polymorphism and schizophrenia (P=0.016), with the A allele more commonly transmitted to patients. Further analysis stratified by sex showed that the A allele was significantly more overtransmitted than nontransmitted in the trios of male probands (P=0.031), but not in the trios of female probands. Our family-based association study supports the suggestion that the G72/G30 gene may be implicated in susceptibility to schizophrenia and there may be an interaction between this gene and sex in the pathogenesis of schizophrenia.
Adult↗
[Bioethics in studies on genetic polymorphisms].
In studies on human genetic polymorphisms, such as single nucleotide polymorphisms (SNPs), little immediate benefit is expected for the individuals contributing the test samples. Such lack of immediate benefits should be noted in the informed consent form obtained prior to sample collection. Ethical considerations are indispensable in obtaining human samples for any type of human gene analysis, and researchers should respect the human rights of the contributors of the samples. Considerable differences in the guidelines for human gene analysis are seen between internationally distributed guidelines and the guidelines of the Japanese government. Lack of education in human genetics in medical schools in Japan could be a reason underlining this difference, and improvement of such situation is needed.
Bioethics↗
Genetic polymorphisms in Parkinson's disease.
The search for genetic polymorphisms relevant to Parkinson's disease etiology and pathogenesis has been motivated by recent thinking emphasizing the potential significance of gene-environment interactions. Especially influential to this research have been the MPTP model of PD induction, hypotheses concerning oxidative stressor reactions, and epidemiological observations of an inverse relation between cigarette smoking and PD risk. This brief review summarizes trends in genetic polymorphism research, with examples provided by investigations of cytochrome P450 enzymes, monoamine oxidase, superoxide dismutase, and mitochondrial genes.
Animals↗