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PubMed1997

Genetic polymorphisms in human drug-metabolizing enzymes: potential uses of reverse genetics to identify genes of toxicological relevance.

The human mind was engaged with fundamental questions on the nature of heredity long before the study of genetics became a scientific discipline. Many traits, such as height, eye color, blood pressure, or cancer susceptibility, have been known to run in families, although the genes or combination of genes that underlie these observable characteristics remain unknown in most cases. Differences in susceptibility to environmental agents in humans are likewise determined by variations in genetic background--genetic polymorphisms. In this article, we review the current status of studies on human polymorphisms in drug-metabolizing enzymes and discuss various approaches to the analysis of genetic polymorphisms. We expect that in the near future, novel methods in genetic analysis of human populations will be likely to play a key role in the identification of genes of toxicological relevance.

Cytochrome P-450 Enzyme System↗
PubMed1998

A genetic polymorphism in the regulatory sequences of human CYP2E1: association with increased chlorzoxazone hydroxylation in the presence of obesity and ethanol intake.

To pursue the hypothesis that differences in the regulatory region of CYP2E1 are partially responsible for the intersubject variation in in vivo CYP2E1 activity, restriction enzyme digestion and Southern blotting of 36 human DNA samples were performed. The fractionated DNA was hybridized with a genomic probe to the upstream region of CYP2E1 from positions -2710 to -580. After digestion with the restriction enzyme XbaI, most subjects (69%) were homozygous for the expected band representing the XbaI fragment from positions -2270 to -408, whereas 31% had an unexpected, slightly larger band. Analyses of Southern blots of the same DNA samples cut by other restriction enzymes were consistent with the larger band containing an estimated 100-bp insertion and localized the mutation to a region from positions -2270 to -1672. To determine the functional significance of this mutation, in vivo CYP2E1 metabolic ability was determined in the same subjects using the 6-hydroxylation of chlorzoxazone as a probe. The presence of the insertion mutation was associated with greater CYP2E1 metabolic ability, but only among individuals who either were obese or had recently consumed ethanol (p < 0.01, both). These data are consistent with a DNA insertion that is associated with altered CYP2E1 induction. The incidence of the mutation was 31% among 65 African Americans and 6.9% among 58 Caucasians (p < 0.01). Thus, this CYP2E1 regulatory polymorphism not only enhances CYP2E1 metabolic ability, but is sufficiently common to impact susceptibility to CYP2E1-related diseases in at least two ethnic groups.

Alcohol Drinking↗
PubMed1999

Detection of three genetic polymorphisms in the 5'-flanking region and intron 1 of human CYP1A2 in the Japanese population.

Interindividual variability of the activity of CYP1A2 may be expected to affect cancer susceptibility, since the enzyme is capable of activating several carcinogens. In the present study, we found three new polymorphisms in the 5'-flanking region (CYPIA2/B) and intron 1 (CYPIA2/C and CYP1A2/D) of CYP1A2 in Japanese by using polymerase chain reaction-single strand conformation polymorphism. We developed methods to detect these polymorphisms by polymerase chain reaction-restriction fragment length polymorphism and performed a population study (159 subjects) to estimate the frequencies of the alleles. The frequencies of the CYP1A2/A (adenine), CYP1A2/B (thymine-deleted), CYP1A2/C (guanine) and CYP1A2/D (adenine) variants were 21.1, 42.0, 8.2 and 61.3%, respectively. The results of family study supported the idea that these CYP1A2 genotypes are inherited with an autosomal codominant transmission.

Cytochrome P-450 CYP1A2↗
PubMed2000

Genetic polymorphism of the CCK gene in patients with alcohol withdrawal symptoms.

BACKGROUND: Cholecystokinin (CCK) is considered to play an important role in the central nervous system via its interaction with other neurotransmitters such as dopamine, serotonin, gamma-aminobutyric acid, substance P, and enkephalins. We investigated the relationship between the C to T substitution in the Sp1 binding cis-element of the CCK gene promoter region (at position -45 numbered from initiation codon) and alcohol withdrawal symptoms. METHODS: We examined 214 Japanese men with alcoholism (93 with delirium tremens, 49 with hallucination, 38 with seizure, and 93 with none of these symptoms) and 98 age-matched Japanese male controls by using a polymerase chain reaction-based single strand conformational polymorphism analysis. RESULTS: Patients who displayed hallucination were significantly more likely to possess the C allele than control subjects (chi2 = 8.17, p = 0.017, Bonferroni correction: p = 0.064). In addition, we investigated the influence of CCK gene polymorphism on alcohol consumption among the control subjects but found no significant relationship. CONCLUSIONS: Our data suggested that the C allele at -45 locus of the CCK gene was higher in patients with hallucination than the control group at a rate that was not quite significant after Bonferroni correction for multiple testing.

Adult↗
PubMed1999

Laboratory methods for the determination of genetic polymorphisms in humans.

The determination of genetic polymorphisms for susceptibility to human disease has been rapidly increasing since the introduction of the polymerase chain reaction (PCR). In most laboratories the ability exists to conduct studies on more than 10,000 persons, and the prospect of even larger investigations is approaching. Many methods can be used for genotyping individuals but some are more common and less expensive than others. Newer methods will allow for automation. As the number of studies on genetic polymorphisms increases it is to be expected that more pitfalls will be encountered. While larger studies will reduce the importance of misclassification, quality control methods will have to be applied to the processing of large numbers of samples.

DNA↗
PubMed2000

Genetic polymorphism of CYP2A6 in the German population.

Genetic polymorphism of drug metabolizing enzymes (DME) can lead to severe toxicity or therapeutic failure of pharmacotherapy. Additionally, genetically determined differences in the activity of the metabolic enzymes can increase an individual's susceptibility to certain types of chemically induced cancers and possibly other diseases. Cytochrome P450 is one of the most important metabolic systems of the organism involved in the oxidation of different xenobiotics. This contribution summarizes and updates the information concerning the genetic polymorphism of the CYP2A6 isoform of the cytochrome P450. A special emphasis is put upon the genotyping techniques of CYP2A6 with a comparative analysis of their predictable sensitivity and specificity given on the example of the German population.

Aryl Hydrocarbon Hydroxylases↗
PubMed1993

Genetic polymorphism of human interleukin-1 alpha.

Interleukin-1 alpha (IL-1 alpha) has been implicated in the pathogenesis of infectious, autoimmune and inflammatory diseases. There is, however, very little information on the cis-acting sequences involved in IL-1 alpha regulation or whether there is any variation in the structure of the gene. It is known that intron 6 of IL-1 alpha shows a 5 x 46 bp tandem repeat in the genomic sequence. We have studied this region of the gene. Amplification by polymerase chain reaction showed different sized products from different individuals, most being of higher molecular weight than the expected size of 620 bp. Sequencing demonstrated that the polymorphism was due to a variable number of repeats of the 46 bp sequence. This was confirmed by restriction fragment length analysis of genomic DNA. Altogether, 72 unrelated individuals were tested and 6 alleles ranging from 5 to 18 repeats were found, the most frequent allele (62%) containing 9 repeats. This polymorphism may be of interest in gene function, since each repeat contains three potential binding sites for transcriptional factors: an SP1 site, a viral enhancer element and a glucocorticoid-responsive element. The latter, at least, demonstrates site-specific protein binding by electromobility shift assay. The functional significance of the polymorphism and its allelic frequency in inflammatory and autoimmune diseases are currently under investigation.

Base Sequence↗
PubMed1997

Human erythrocyte protein L-isoaspartyl methyltransferase: heritability of basal activity and genetic polymorphism for thermal stability.

Protein L-isoaspartyl methyltransferase (PIMT) is believed to play an important role in the disposition of age-damaged proteins by catalyzing the repair of abnormal isoaspartyl linkages resulting from the spontaneous deamidation of asparaginyl residues or isomerization of aspartyl residues. As a step toward testing the hypothesis that human disease- or age-related pathology might be associated with a deficiency in PIMT, we investigated basal activity and thermal stability of PIMT in erythrocyte lysates from 299 U.S. family members. Thermal stability was measured because it is a sensitive measure of variation in amino acid sequence. Basal activity was normally distributed with a mean+/-SD of 558+/-43 units/ml erythrocytes. Statistical analysis of the data revealed that basal PIMT activity exhibited a high degree of heritability. Enzyme thermal stability showed a skewed bimodal frequency distribution, and segregation analysis of family member pedigrees was consistent with Mendelian inheritance of two major alleles. No DNA was available from the family samples, so we tested two additional population samples for a known Ile/Val polymorphism at codon 119 and for PIMT activity and thermal stability, using blood donated by 25 Norwegians and by 20 Koreans. Single-stranded conformational polymorphism analysis using polymerase chain reaction revealed a 100% correlation between thermal stability grouping and this polymorphism. The high thermal stability samples were all homozygous Ile, the low thermal stability samples were all homozygous Val, and the intermediate thermal stability samples were all heterozygous. Furthermore, this polymorphism was responsible, in part, for the variation observed in basal erythrocyte PIMT activity. These results will help provide a foundation for future studies aimed at correlating levels of PIMT activity, or other properties of this enzyme, with human disease.

Aging↗
PubMed1990

T-cell receptor genes in tassel-eared squirrels (Sciurus aberti). I. Genetic polymorphism and divergence in the Abert and Kaibab subspecies.

The role of environmental factors in the evolution and maintenance of diversity of antigen receptor gene families which participate in the immune response in mammals is inadequately understood. In order to elucidate the impact of these factors, we have undertaken the analysis of these gene families in the tassel-eared squirrel (Sciurus aberti) which has been separated into discrete subspecies by geographic barriers and whose food resources can be quantitated for estimating environmental quality. In this communication we describe the initial analysis of the complexity and polymorphism of sequences related to T-cell receptor (Tcr) alpha and beta chain genes in two subspecies, Sciurus aberti aberti (Abert) and Sciurus aberti kaibabensis (Kaibab) which have identical habitats and are separated by the Grand Canyon in Arizona, USA. Genomic blot analysis of 60 Abert and 62 Kaibab individuals collected over a 3-year period was performed with mouse Tcrb and Tcra cDNA probes. Sequences homologous to Tcrb-C, Tcrb-J1, and Tcrb-J2 genes were observed in all individuals from both subspecies; although Tcrb-J1 fragments were monomorphic. Tcrb-C and Tcrb-J2 fragments were polymorphic with both species- and subspecies-specific sequences. A single, monomorphic Tcra-C fragment was observed in addition to multiple Tcra-V fragments homologous to the mouse Tcra-V1 subfamily. Abert samples exhibited greater numbers of Tcra-V1 fragments as well as greater polymorphism than Kaibab samples. Heterozygosity estimates of Tcrb-C and Tcra-V1 sequences were determined for annually collected samples and compared with the yearly estimates of availability of hypogeous fungi, one of the major diet items of tassel-eared squirrels. In the Kaibab annual collections, Tcra-V1 heterozygosity declined with the decline in food resource, whereas heterozygosity of Tcrb-C sequences was inversely related to food resource. Similarly, a reduction in food resource for Abert squirrels in 1985 coincided with an increase in Tcrb-C heterozygosity in the same year. These results suggest that the diversity of gene families which participate in the immune response in mammals may be affected by environmental factors.

Animals↗
PubMed2001

E1 mice epilepsy shows genetic polymorphism for S-Adenosyl-L-homocysteine hydrolase.

E1 mice are an animal model of human epilepsy (idiopathic complex partial seizures). We have previously demonstrated abrupt poly(A)(+) RNA expression in liver from 1-day-old E1 mouse [Mita et al., 1991. Devl. Brain Res. 64, 27-35]. In the present study, we constructed a cDNA library of the poly(A)(+) RNA. By analyzing cDNA clones and nucleotide sequences, we found a clone that was homologous to a rat gene of S-adenosyl-L-homocysteine hydrolase (EC 3.3.1.1.) (SAHH) (a key enzyme in the active methyl transfer pathway) and showed the gene polymorphism/RFLP(PstI) between the epileptic strain, E1, and the non-epileptic mother strain, ddY, as indicated in a gel electrophoresis by cleaving 2.6 kb with PstI into 1.9 kb and 0.7 kb fragment bands. F1(E1xddY) showed the heterozygosity. An attempt to determine the mutation on the genomic SAHH gene in the E1 disclosed a single nucleotide polymorphism indicated by a C-->T transition in the 8th intron, by which the PstI site was created. SAHH enzymatic activity in the liver in 1-day-old E1 mice was slight (approximately 10%), and in fact was significantly lower than that of the control ddY. Results suggested that the abrupt primary mRNA transcribed on the SAHH gene in the liver of 1-day-old E1 mice was processed partially or incompletely because of the presence of the point mutation in the intron. Accordingly, poor energy supply by the insufficient SAHH enzymatic activity in the brain postnatally may be responsible for epileptogenesis in this animal model. It is concluded that a single nucleotide SAHH gene polymorphism may be associated with epilepsy in E1 mice.

Adenosylhomocysteinase↗
PubMed2000

Characterization of genetic polymorphism in the goat beta-lactoglobulin gene.

Two new variants have been detected and characterized for the goat beta-lactoglobulin gene at the cDNA level and confirmed at the genomic level. The two polymorphisms are located on exon 7 of the gene. One of the polymorphic sites is produced by a single nucleotide substitution in position +4601, allowing a polymerase chain reaction--restriction fragment length polymorphism (PCR-RFLP) genotyping procedure to be developed using SacII restriction enzyme. The other polymorphic position contains a 10 bp long insertion at position +4641 that can be detected by capillary electrophoresis of the PCR product amplified with a fluorescent primer. The association of these two polymorphisms was also investigated, resulting in the description of two new alleles. Both of these contained the point mutation at the SacII site, with or without the 10 bp insertion at position +4641. The distribution of these new polymorphisms was studied in a population of males of four different goat breeds. The gene frequencies for these variants were similar in Spanish and French breeds.

Alleles↗
PubMed2001

Genetic polymorphism of the caprine kappa casein gene.

Polymorphism in the goat kappa casein gene was studied using the base excision sequence scanning (BESS) method and sequencing. Seven polymorphic sites, corresponding to single nucleotide transversions were detected. Three of these were silent mutations while the other four produced amino acid substitutions. The association between these polymorphic sites was investigated, which resulted in the identification of three goat kappa casein alleles, designated A, B, and C. Protocols for rapid genotyping of the C variant were developed by polymerase chain reaction-restriction fragment length polymorphism using Alw44I and BseNI restriction endonucleases. The occurrence of this allele was found to be very low in Spanish breeds but more frequent in the French Saanen goat. Further studies among different goat populations are necessary to establish the distribution of these alleles and their effects on the quality and functional properties of milk.

Alleles↗
PubMed1999

A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaque development.

BACKGROUND AND OBJECTIVES: Atherosclerosis is a multifactorial disease, in part characterized by chronic inflammatory changes in the vessel wall and loss of normal physical and biochemical interactions between endothelial cells and smooth muscle cells. Previous studies [Hu J., Cotgreave IA. J Clin Invest; 99: 1-5] have provided molecular links between inflammation and myoendothelial communication via gap junctions, suggesting that these structures may be important in the development of the atherosclerotic vessel phenotype. In order to strengthen this premise, the aim of the present work was to probe for structural polymorphisms in connexin 37, a gap junctional protein uniquely expressed in endothelial cells, and to assess for potential genotypic segregation in individuals displaying atherosclerotic plaque. METHODS AND RESULTS: Computer-based comparisons of Expressed Sequence Tags (ESTs) predicted a polymorphism in the human gap junctional protein connexin 37 (cx37). The C1019-T mutation results in a proline to serine shift at codon 319 (cx37*1-cx37*2). A Restriction Fragment Length Polymorphism (RFLP) assay, involving the insertion of a novel Drd I cleavage site in the proline variant revealed a statistically significant over-representation of the cx37*1 allele in association with atherosclerotic plaque-bearing individuals (Odds-ratio for the homozygote = 2.38, Chi2 = 7.693, P = 0.006), in comparison to individuals lacking plaque, irrespective of a history of hypertension. CONCLUSIONS: These data suggest that the C1019-T polymorphism in cx37 may provide 'single gene marker', which could be useful in assessing atherosclerotic plaque development, particularly in cardiovascular risk groups such as those with borderline hypertension.

Adult↗
PubMed1986

Genetic polymorphism and exon changes of the constant regions of the human T-cell rearranging gene gamma.

The genomic nucleotide sequences of the constant-region (C) genes of the human T-cell rearranging gene gamma are given. These sequences show considerable allelic and nonallelic variation. Allelic variants exist at both C gamma 1 and C gamma 2 loci in coding regions (as well as in restriction enzyme sites). Both C gamma genes are in the same transcriptional orientation. Moreover, the organization of the nonallelic C gamma genes reveals some interesting features: the C gamma 1 gene, like the mouse C gamma gene, has three exons, whereas the C gamma 2 gene has four exons, including a duplicated second exon that would create a putative protein with an enlarged constant region. However, these two duplicated exons in C gamma 2 have lost the cysteine residue that is thought to be involved in the interchain disulfide bridge.

Alleles↗
PubMed1993

Genetic polymorphism of cytochrome P450 CYP2D6 in Zimbabwean population.

The objective of this study was to determine the CYP2D6 genotype of a black Zimbabwean population. Genotyping was carried out using Eco RI and Xba I RFLP, and allele-specific PCR amplification. Of 114 Zimbabwean samples analysed, no individual homozygous for any of the defect allelic forms CYP2D6A, CYP2D6B or CYP2D6D or combinations thereof was found. The allele frequencies of the three defect genes were 0, 1.8 and 3.9%, respectively. No subject carrying the Xba I 44 kb haplotype, indicative for poor metabolizers among Caucasians, was identified, whereas five individuals being heterozygous with a 29/42 kb haplotype were seen. Three out of the four CYP2D6B alleles found were associated with the 29/42 kb haplotype. Our findings are in agreement with the 0-2% prevalence of poor metabolizers (PMs) in the black populations previously phenotyped. The very low frequency of the CYP2D6B allele in the Zimbabwean population is different from very recent data from black Americans (allele frequency = 8.5%) and might indicate the Caucasian ancestry of this allele. Taken together, our data indicate important interethnic differences in the CYP2D locus between Caucasian, Asian and different black populations.

Base Sequence↗