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PubMed2001

Risk assessment: the importance of genetic polymorphisms in man.

Many genetic polymorphisms in metabolism enzymes are important for the risk of cancer as shown in a large number of case-control studies. The relative risk estimates have shown large variations between such population studies. However, in most studies the relative risk estimates are in the range of 2. Some polymorphisms are effect modifiers, i.e. without exposure they have no consequence and the effect of exposure can appear independent of the genotype. Genetic polymorphisms in metabolism of environmental toxicants plays a significant role in exposures to traffic generated air pollution in Copenhagen, revealing statistically significant higher levels of chromosomal aberrations in non-smoking bus drivers with glutathion-S-transferase M1, GSTM1 null and N-acetyltransferase 2, NAT2 slow genotypes. Combined with cohort studies showing positive associations between high chromosomal levels and increased cancer risk, such results indicate effect modification regarding cancer risk. In risk assessment the safety 'factor' of 10 is generally accepted to allow for variation in individual susceptibility. Reviewing the literature justifies the factor of 10 when considering single polymorphisms. However in an individual with several susceptible metabolism genotypes as well as other determinants of susceptibility, e.g. defective DNA repair, poor-nutritional state, etc. the risk may increase far above a safety of 10.Historically, genetic polymorphisms have been taken into consideration in employment and currently the application in insurance situations is criticised.

Arylamine N-Acetyltransferase↗
PubMed1980

An electrophoretic polymorphism that mimics a true genetic polymorphism in Triturus cristatus carnifex (Amiphibia, Urodela).

Phosphoglucomutase electrophoretic patterns have been studied in 60 tail homogenates of Triturus cristatus carnifex. Our results show that the same sample produces a different electrophoretic pattern with homogenate ageing; a new band of intermediate mobility appears, together with the one produced by the fresh preparation. The phenomenon can mimic a true genetic polymorphism when differently stored samples are analyzed.

Animals↗
PubMed2001

Genetic polymorphisms and chromosome damage.

Genetic polymorphisms that affect xenobiotic metabolism or cellular response to DNA damage can modulate individual sensitivity to genotoxins. Information on the effects of such polymorphisms on the level of chromosome damage may facilitate the identification of risk groups and increase the sensitivity of cytogenetic endpoints as biomarkers of genotoxic exposure and effect. Glutathione S-transferase M1 (GSTM1) is an important detoxification enzyme which, due to a homozygous gene deletion (null genotype), is lacking from about 50% of Caucasians. A higher level of DNA adducts and chromosome damage has been detected in lymphocytes of tobacco smokers and bus drivers who lack the GSTM1 gene. Other polymorphic glutathione S-transferases include GSTM3, GSTP1, and GSTT1. The GSTT1 null genotype (10-20% of Caucasians) has been associated with an increased "baseline" level of sister chromatid exchanges (SCEs) in lymphocytes. N-acetyltransferase 2 (NAT2), metabolizing xenobiotics with primary aromatic amine and hydrazine structures, is another important polymorphic phase II enzyme. Subjects having the NAT2 slow acetylator genotype appear to show an increased baseline frequency of lymphocyte CAs in the absence of identified environmental exposure. Besides human biomonitoring studies, genetic polymorphisms may be important in explaining individual variation in genotoxic response observed in genetic toxicology tests with human cells. Several studies have suggested that blood cultures from GSTT1 null and GSTM1 null individuals have increased in vitro sensitivity to various genotoxins. The best-known example is probably the diepoxybutane sensitivity of GSTT1 null donors. Recently discovered polymorphisms affecting DNA repair may be expected to be of special importance in modulating genotoxic effects; the first available studies have suggested that the exon 10 Arg399Gln polymorphism of XRCC1 gene (X-ray repair cross-complementing group 1) could affect individual genotoxic response. In conclusion, the genetic polymorphism of GSTM1 influences the frequency of chromosome damage in exposed humans, while that of GSTT1 and NAT2 affect the "baseline" level of such damage. Both GSTM1 and GSTT1 genotypes may shape the in vitro genotoxic response of human lymphocytes. The significance of DNA repair polymorphisms is presently unclear.

Chromosome Aberrations↗
PubMed1976

Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan. III. Identification of genetic effects using 12 polymorphic genetic blood marker systems.

Four of 12 unlinked polymorphic marker systems were identified as predictors of normal serum cholesterol levels. Consistent effects between males and females and with other studies suggest that these marker loci are themselves involved in cholesterol determination or are closely linked to the involved loci. Two-locus combinations suggest that an 8-9 mg/100 ml difference in nonfasting serum cholesterol may be predicted between phenotypic classes which are not rare in frequency.

Blood Group Antigens↗
PubMed2001

A randomized open trial for comparison of proton pump inhibitors, omeprazole versus rabeprazole, in dual therapy for Helicobacter pylori infection in relation to CYP2C19 genetic polymorphism.

BACKGROUND AND AIM: The genetic polymorphism of cytochrome P450 (CYP) 2C19 has been shown to influence the efficacy of Helicobacter pylori eradication therapy with a proton pump inhibitor (PPI) and amoxicillin (so-called dual therapy). Omeprazole, a widely used PPI, and rabeprazole, a new PPI, are metabolized in different pathways in terms of CYP2C19 genetic polymorphisms. In this study, we compared the efficacy of omeprazole and rabeprazole in a 2-week dual therapy in relation to CYP2C19 polymorphism. METHODS: One hundred and ninety-nine patients with peptic ulcer disease were randomly assigned to receive one of the following regimens: 500 mg t.i.d. amoxicillin together with either 20 mg b.i.d. omeprazole or 10 mg b.i.d rabeprazole. The eradication of H. pylori was evaluated by using a bacterial culture and a [(13)C]-urea breath test at 1--2 months after completion of treatment. Cytochrome P4502C19 polymorphism was analyzed by using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Intention-to-treat-based cure rates for the omeprazole or rabeprazole regimens were 66.3% (95% CI, 56--75) and 62.4% (95% CI, 52--71), respectively, without significant difference. Cytochrome P4502C19 genetic polymorphism did not influence the cure rates in either of these regimens. We analyzed various factors associated with treatment failure (PPI, CYP2C19 genotype, and smoking habit) by using multiple logistic regression; smoking was the only significant independent factor for treatment failure. CONCLUSION: Omeprazole and rabeprazole were equally effective in combination with amoxicillin in eradicating H. pylori, irrespective of the PPI used (omeprazole or rabeprazole) and CYP2C19 genetic polymorphism. Smoking significantly decreased the cure rate of H. pylori infection in the dual therapy.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2004

Drug-gene interactions between genetic polymorphisms and antihypertensive therapy.

Genetic factors may influence the response to antihypertensive medication. A number of studies have investigated genetic polymorphisms as determinants of cardiovascular response to antihypertensive drug therapy. In most candidate gene studies, no such drug-gene interactions were found. However, there is observational evidence that hypertensive patients with the 460 W allele of the alpha-adducin gene have a lower risk of myocardial infarction and stroke when treated with diuretics compared with other antihypertensive therapies. With regard to blood pressure response, interactions were found between genetic polymorphisms for endothelial nitric oxide synthase and diuretics, the alpha-adducin gene and diuretics, the alpha-subunit of G protein and beta-adrenoceptor antagonists, and the ACE gene and angiotensin II type 1 (AT(1)) receptor antagonists. Other studies found an interaction between ACE inhibitors and the ACE insertion/deletion (I/D) polymorphism, which resulted in differences in AT(1) receptor mRNA expression, left ventricular hypertrophy and arterial stiffness between different genetic variants. Also, drug-gene interactions between calcium channel antagonists and ACE I/D polymorphism regarding arterial stiffness have been reported. Unfortunately, the quality of these studies is quite variable. Given the methodological problems, the results from the candidate gene studies are still inconclusive and further research is necessary.

Adrenergic beta-Antagonists↗
PubMed2005

Myeloperoxidase genetic polymorphisms modulate human neutrophil enzyme activity: genetic determinants for atherosclerosis?

OBJECTIVE: Myeloperoxidase (MPO), an abundant leukocyte hemoprotein has been linked to atherosclerosis and cardiovascular disease. We previously found new genetic polymorphisms in MPO gene. The purpose of this study was to evaluate the influences of these polymorphisms on human neutrophil MPO activity by means of haplotype analysis. METHODS AND RESULTS: Neutrophils from 102 blood donors were isolated and MPO activity was measured, while subjects were genotyped for polymorphisms located in MPO gene 5'non-coding region (-1940A > G, -638C > A, -463G > A and -129G > A) and in coding region (V53F, M251T, A332V, I642L and I717V). Single-point analysis showed that the -638C > A and the V53F polymorphisms were significantly associated with MPO activity, and haplotype analysis confirmed that two haplotypes, one carrying the -638A allele and the other carrying the 53F allele, resulted an increase in MPO activity. CONCLUSION: Since MPO is suspected to be a bio-marker in cardiovascular disease, -638C > A and V53F polymorphisms associated with increased enzymatic activity could be genetic determinants for cardiovascular disease risk.

Alleles↗
PubMedDate not supplied

[Role of genetic polymorphism in risk assessment].

Genetic polymorphism is an important factor of individual susceptibility to drugs or to toxic substances in environmental and occupational exposure. Although polymorphism is never the only responsible of a disease, it can modify both the level of risk for adverse effects and the levels of biomarkers after exposure to some toxic agents. In this paper two important groups of polymorphic enzymes, responsible of the detoxification of exogenous substances, were examined: paraoxonase-1, involved in the metabolism of some organophosphorus insecticides, and glutathione S-transferases, involved in the detoxification of numerous epoxide metabolites. Particularly the role of GSTT1 and GSTM1 polymorphism on the biological indicators of 1,3-butadiene has been evaluated. Moreover, the influence of delta-aminolevulinic acid dehydratase, enzyme involved in the sinthesys of the eme, on the biological indicators of exposure and effect to lead has been also examined.

Aryldialkylphosphatase↗
PubMed2002

Aspirin resistance and genetic polymorphisms.

Differences in genetic makeup or polymorphisms can affect individual drug response. Detecting genetic variation may help predict how a patient will respond to a drug and could be used as a tool to select optimal therapy, tailor dosage regimens, and improve clinical outcomes. The data are replete relative to the therapeutic efficacy of aspirin (ASA) for the prevention of ischemic events. However, there is a paucity of published data on the relationship between polymorphisms and the clinical effects on ASA. Prothrombotic genetic variations that may contribute to ASA resistance, and increased risk of cardiovascular events may involve: (1) a polymorphism on the cyclooxygenase-1 (COX-1) gene affecting Ser529; (2) overexpression of COX-2 mRNA on platelets and endothelial cells; (3) polymorphism PLA1/A2 of the gene encoding glycoprotein IIIa (GPIIIa); and (4) the homozygous 807T (873A) polymorphism allied with increased density of platelet GP Ia/IIa collagen-receptor gene. Because of the possible increased risk of ischemic vascular events, carriers of these genetic polymorphisms may be resistant to the antithrombotic effects of ASA and should be considered for additional or alternative treatment.

Animals↗
PubMed1983

Genetic polymorphism in C8 beta-chains. Evidence for two unlinked genetic loci for the eighth component of human complement (C8).

Genetic polymorphism in the beta-subunit of the eighth component of human complement, C8, was defined by isoelectric focusing of serum in polyacrylamide gel in the presence of urea and development of specific patterns of hemolysis in an overlay gel containing antibody-sensitized erythrocytes and C8 beta-chain-deficient serum. Bands of hemolysis induced by serum from unrelated Caucasians suggested autosomal codominant inheritance of three structural alleles at a single locus, C82: C82 degrees A (acidic), C82 degrees B (basic), and C82 degrees A1 (very acidic) with frequencies of 0.952, 0.044, and 0.004, as well as the probable null allele C82 degrees Q0. The distribution of phenotypes agreed with the Hardy-Weinberg equilibrium. The previously described genetic polymorphism in human C8 defined with the use of "complete" C8 (C8 alpha-gamma-chain)-deficient serum was distinct from and independent of the inherited structural variation at C82. Therefore, the locus for C8 alpha-gamma-chains has been redesignated C81, and has the alleles C81 degrees A, C81 degrees A1, and C81 Q0. Linkage studies failed to show close linkage between the two loci for C8, C81, and C82, and between C82 and the major histocompatibility complex or C6.

Alleles↗
PubMed2004

No association between the genetic polymorphisms within RTN4 and schizophrenia in the Chinese population.

The RTN4 gene on chromosome 2p13-14 has been reported to be over-expressed in schizophrenia by a cDNA subtractive hybridization experiment between postmortem human frontal cerebral cortices from Canadian schizophrenia individuals and neurological controls. The same study also reported a high prevalence of homozygous CAA insertion in the schizophrenia. In a replication attempt to investigate the role of RTN4 in the etiology of schizophrenia, we genotyped the CAA insertion polymorphism and other three genetic polymorphisms (a TATC deletion in the 3'-untranslated region and two single nucleotide polymorphisms in the 5' region) within RTN4 and conducted a case-control study in the Chinese population. There were no significant discrepancies in allele and genotype frequencies of the four polymorphisms individually and haplotype distribution between the cases and the controls. Our current data suggest that the genetic polymorphisms within RTN4 are unlikely to confer an increased susceptibility to schizophrenia in the Chinese population.

Adult↗
PubMed2002

[Genetic polymorphisms in drug-metabolizing enzymes].

Genetic polymorphisms in drug-metabolizing enzymes are responsible for interindividual differences in the disposition of numerous drugs. The poor metabolizers (PMs) are derived from mutant alleles of cytochrome P450 (CYP), and those PMs are more susceptible to the development of adverse drug reactions, when the parent drug is pharmacologically active, or are showing a lack of therapeutic efficacy, when a prodrug is administered and its active metabolite(s) is not formed. This article reviews the basic knowledge of genetic polymorphisms of CYP-related drug-metabolizing enzymes and the clinical implications for a safer and more efficient drug therapy.

Alleles↗
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↗
PubMed2002

Genetic polymorphisms in lung disease: bandwagon or breakthrough?

The study of genetic polymorphisms has touched every aspect of pulmonary and critical care medicine. We review recent progress made using genetic polymorphisms to define pathophysiology, to identify persons at risk for pulmonary disease and to predict treatment response. Several pitfalls are commonly encountered in studying genetic polymorphisms, and this article points out criteria that should be applied to design high-quality genetic polymorphism studies.

Animals↗
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↗