Genetic polymorphism of conjugating enzymes and cancer risk: GSTM1, GSTT1, NAT1 and NAT2.
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Alleles↗
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[Genetic polymorphism of adrenergic beta 2 receptors].
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Humans↗
[Genetic polymorphisms in the renin-angiotensin system].
Gene coding for the main components of the renin-angiotensin system have been characterized and localized: angiotensinogen (AGT, chromosome 1q42), renin (REN, chromosome 1), angiotensin I-converting enzyme (ACE, chromosome 17), angiotensin II receptors (AT1R, chromosome 3 and AT2R, chromosome X). A positive linkage and association have been found between AGT and essential hypertension. M235T is also associated with plasma AGT concentration. In vitro studies suggest that a polymorphism (G-6A) which is in complete linkage disequilibrium with M235T and which is located in the promoter close to the start of transcription might explain this association with high blood pressure. The ACE I/D polymorphism explains about 30 to 40 per cent of the variance of plasma ACE levels. Although the ACE gene itself does not seem to play a role in blood pressure level, the corresponding chromosomal region has been linked to blood pressure in both spontaneously hypertensive rats and humans. In tissues, an increased ACE activity may explain the association between the ACE I/D polymorphism and coronary heart disease, left ventricular hypertrophy, neointimal proliferation in vessels and progression of diabetic and IgA nephropathy.
Angiotensin II↗
Risk of recurrent spontaneous abortion, cigarette smoking, and genetic polymorphisms in NAT2 and GSTM1.
Maternal smoking increases the risk of spontaneous abortion. Polymorphic N-acetyltransferase (NAT2) and glutathione S-transferase (GSTM1) affect metabolism of some mutagens found in tobacco smoke. Genotypes and smoking were studied in women with at least two spontaneous abortions (N = 32) and those with at least two livebirths (N = 179). Smoking slightly increased risk (odds ratio = 1.3; 95% confidence interval = 0.6-2.9), but NAT2 and GSTM1 did not. NAT2 or GSTM1 polymorphisms did not appreciably modify smoking-related risk.
Abortion, Spontaneous↗
Genetic polymorphism of glutathione S-transferases M1 and T1 as a risk factor in lung and bladder cancers.
A combined analysis of two polymorphic enzymes, glutathione S-transferase mu (GST M1) and q (GST T1) and their implication as cancer risk factors was performed in a case-control study of lung and bladder cancers. Using a multiplex polymerase chain reaction (PCR) based method, the frequency of the homozygous deleted GSTM1 and GSTT1 genotypes was examined in 117 lung cancer patients, 67 urinary bladder cancer patients, and in a community-based sample of 248 healthy, unrelated individuals. In both cancer groups the frequency of the GSTM1 null genotype was higher in comparison with that of the control group (59% and 59.7% vs. 49.6%), but this increase did not reach statistical significance (p > 0.05). After grouping by the smoking status, among smokers in both cancer groups (62.1% in lung cancer and 71.4% in the bladder cancer group, respectively) there were statistically significantly (p < 0.05) increased frequencies of the GSTM1 deletion genotype as compared to the control group (49.6%). Smokers with absence of the GSTM1 gene were at an approximately 1.7-fold higher risk for lung cancer (odds ratio--OR = 1.67, 95% confidence interval--CI 95% = 1.0-2.7, p = 0.04) and an approximately 2.5-fold higher risk for bladder cancer (OR = 2.54, CI 95% = 1.2-5.5, p = 0.02). As related to GSTT1, our study demonstrated an overall GSTT1 effect on bladder cancer risk. Individuals with absence of the GSTT1 gene were at an approximately 2.5-fold higher risk of developing bladder cancer. In the lung cancer cases, the frequency of the putatively high risk GSTT1 null genotype was not increased as compared with controls. No effect of smoking was found on risk of lung and bladder cancer associated with the GSTT1 0/0 genotype. In combined analysis, the obtained results suggested that individuals who were both GSTM1 null and GSTT1 null may be at increased risk because they lack both enzymes. The findings suggest that the GSTM1 null genotype may be associated with susceptibility to lung and urinary bladder cancer in dependence on the exposure to carcinogens in cigarette smoke and that the GSTT1 null genotype is not a critical factor in mediating the risk of lung cancer, but may be associated with an increased susceptibility to bladder cancer.
Aged↗
[Genetic polymorphism of 5 short tandem repeat loci in Hui population in Ningxia area].
OBJECTIVE: To analyze the genetic polymorphism of 5 short tandem repeat(STR) loci in Hui population in Ningxia area. METHODS: The genetic polymorphisms of five selected STR loci(D11S1984, D14S306, D14S617, D17S1290 and D19S433) in chromosomes 11, 14, 17 and 19 in 144 unrelated individuals in Hui population in Ningxia area were analyzed by PCR amplification, denaturing polyacrylamide gel electrophoresis(PAGE) and silver staining. RESULTS: 10, 8, 11, 13 and 8 alleles, 30, 25, 33, 40 and 23 genotypes of the 5 STR loci in Hui population in Ningxia were detected. The measured values of the heterozygosity of the 5 STR loci were 0.8413, 0.8033, 0.8331, 0.8369 and 0.7703; of the polymorphism information content were 0.8217, 0.7746, 0.8121, 0.8174 and 0.7332; of the discrimination power (DP) were 0.9516, 0.9257, 0.9611, 0.9660 and 0.9135. The calculated discrimination power was 0.9999995. The measured values of paternity exclusion were 0.7046, 0.6367, 0.6911, 0.7012 and 0.5801; the calculated paternity exclusion was 0.9958. The genotype distributions were in accordance with Hardy-Weinberg equilibrium. CONCLUSION: The 5 STR loci have better polymorphism in Hui population in the Ningxia area, and thus could serve as useful markers for population genetics research and for individual identification and paternity test in forensic medicine.
Asian People↗
Genetic polymorphisms of estrogen receptor alpha, CYP19, catechol-O-methyltransferase are associated with familial prostate carcinoma risk in a Japanese population.
BACKGROUND: Estrogen is one of the crucial hormones participating in the proliferation and carcinogenesis of the prostate glands. Genetic polymorphisms in the estrogen metabolism pathway might be involved in the risk of prostate carcinoma development. The authors evaluated the association between genetic polymorphisms in estrogen-related enzymes and receptors and the risk of developing familial prostate carcinoma. METHODS: In the current study, 101 cases with prostate carcinoma whose first-degree relatives had prostate carcinoma and 114 healthy age and residence-matched male controls were enrolled. The genotypes of estrogen receptor (ER) alpha, aromatase (CYP19), and catechol-O-methyltransferase (COMT) genes were analyzed. RESULTS: For single polymorphisms, a significant association of the T/T genotype of the PvuII site in the ER alpha gene (odds ratio [OR], 3.44; 95% confidence interval [CI], 1.97-5.99; P = 0.0028), and the C/T and T/T genotypes of the CYP19 gene (OR, 1.77; 95% CI, 1.02-3.09; P = 0.037) with prostate carcinoma risk, was observed. The G/A genotype of the COMT gene showed a weak tendency toward increased risk (OR, 1.48; 95% CI, 0.85-2.57; P = 0.18). Stratification of cases according to clinical stage and pathologic grade showed that the C/T and T/T genotypes of the CYP19 gene were associated significantly with high-grade carcinoma (OR, 2.59; 95% CI, 1.47-4.46; P = 0.048). The number of high-risk genotypes (the T/T in ER alpha, the C/T and T/T in CYP19, and the G/A in COMT) significantly increased the risk of developing prostate carcinoma (2 genotypes: OR, 3.00; 95% CI, 1.72-5.23; P = 0.008; 3 genotypes: OR, 6.30; 95% CI, 3.61-10.99; P = 0.002). CONCLUSIONS: Genetic polymorphisms of genes in the estrogen metabolism pathway were associated significantly with familial prostate carcinoma risk. Single nucleotide polymorphisms of low-penetrance genes are targets for understanding the genetic susceptibility of familial prostate carcinoma.
Adult↗
[Relationship between genetic polymorphisms of N-acetyltransferase and susceptibility to hepatocellular carcinoma].
OBJECTIVE: To study the possible relationship between genetic polymorphism of N-acetyltransferase 2 (NAT2) and susceptibility to hepatocellular carcinoma. METHODS: Genetic polymorphisms of the four NAT2 genes in 78 patients with hepatocellular carcinoma and 112 healthy controls were analyzed by means of real-time fluorescence light-Cycler. The difference in frequencies between the hepatocellular carcinoma patients and the controls were compared. RESULTS: The significant difference in slow acetylation genotype frequency was found between the controls and the hepatocellular carcinoma patients who were smokers (17.9% vs 37.5%, x(2)= 4.67, P<0.05) resulting in increased by 2.76 times the risk for hepatocellular carcinoma, but no evident difference between the controls and hepatocellular carcinoma patients who were non-smokers. CONCLUSION: The smokers with slow acetylation genotype of N-acetyltransferase 2 may be the population with high risk for hepatocellular carcinoma.
Acetylation↗
Glutathione S transferase-theta (GSTT1) genetic polymorphism among Chinese, Malays and Indians in Singapore.
Glutathione S-transferase-theta (GSTT1) is subject to a genetic polymorphism where approximately 50% of a Caucasian population are homozygous for the null allele. Because of the possible association of the polymorphism with increased cancer risk in individuals, we genotyped by polymerase chain reaction 187 normal Chinese, 167 normal Malays and 152 normal Indians from Singapore and Malaysia. The proportion of Chinese, Malays and Indians with the null genotype were 58%, 38% and 16% respectively and mirrored previously reported frequencies of the GSTM1 null genotype in these populations. The frequency of the combined GSTM1 and GSTT1 null genotypes among Chinese, Malays and Indians were 37%, 22% and 5% respectively. The similarity with predicted frequencies indicated no interaction between the two genetic polymorphisms.
Adolescent↗
Effect of CYP2C9 genetic polymorphisms on the efficacy and pharmacokinetics of glimepiride in subjects with type 2 diabetes.
Glimepiride, a sulfonylurea hypoglycemic agent, is metabolized by cytochrome P450 2C9 (CYP2C9) which is known to have genetic polymorphisms. To examine the effects of CYP2C9 genetic polymorphisms on the safety and efficacy of glimepiride in patients with type 2 diabetes, the responses to the glimepiride were measured in Japanese type 2 diabetic patients with the different CYP2C9 genotype. The reduction in the HbA(1c) was significantly larger (P<0.05) among the CYP2C9*1/*3 subjects than among the CYP2C9*1/*1 subjects. The long-term observations of 2 patients with a CYP2C9*1/*3 suggested that subjects with a CYP2C9*1/*3 respond well to glimepiride during the initial phase of treatment, but 1 patient have shown the weight gain over the long-term treatment. The pharmacokinetic study showed that the area under the concentration-time curve for glimepiride in the CYP2C9*1/*3 subjects was approximately 2.5-fold higher than that of the CYP2C9*1/*1 subjects. The intrinsic clearance of glimepiride by the CYP2C9*3 enzyme was lower than that by the CYP2C9*1 enzyme. These results suggested that the lower hydroxylation activity of glimepiride in the subject with type 2 diabetes and CYP2C9*1/*3 led to a marked elevation in the plasma concentrations of glimepiride and a stronger pharmacological effect of glimepiride.
Adult↗
[Studies on the adverse effects of fluvoxamine treatment in children with autistic disorder: correlation with genetic polymorphism in serotonin related genes].
Selective serotonin re-uptake inhibitors (SSRIs) have recently been applied to the children with autistic disorder. To create better treatment, we studied here clinical adverse effects of fluvoxamine and correlated them with genetic polymorphism of two genes, the promoter region of serotonin transporter gene (5-HTTLPR) and serotonin 2A receptor gene (5-HT2AR). Twenty-eight subjects, consisting of 23 boys and 5 girls, aged from 3 to 18 years old diagnosed as having autistic disorder were analyzed during fluvoxamine administration. The dosages and duration of fluvoxamine treatment are 1.5 to 3 mg/kg/day and 2 weeks to 17 months (mean 7.9 months), respectively. There were several clinical adverse effects such as sleep disturbance in 9 cases, climb up to high places in 8, gastrointestinal symptoms in 6, hyperactivities in 5, excitement in 4, general fatigability in 2 and urticaria in 1. Medication was discontinued in 2 patients with fatigability and 1 with sleep disturbance, diarrhea and poor appetite. There was no significant correlation between genetic polymorphism in 5-HTTLPR and the occurrence of clinical adverse effects of fluvoxamine. However hyperactivity was significantly more frequent in the subjects with 102T/102T polymorphism of 5-HT2AR, and patients with sleep disturbance were significantly less frequent in the subjects with 102C/102C polymorphism. We conclude that the clinical adverse effects such as climb up to high places and hyperactivity during fluvoxamine treatment may be relatively specific in children, and that genetic polymorphism of 5-HT2AR may be related to the appearance of clinical adverse effects.
Adolescent↗
[Analysis of genetic polymorphism of 7 STR loci on chromosome 12 in Shaanxi Han populations].
To analyze the genetic polymorphism of 7 STR loci (D12S1718,D12S1675, D12S358, D12S367, D12S1638, D12S1646 and D12S1682) on chromosome 12 in Shaanxi Hans. EDTA-blood specimens were collected from 80 unrelated individuals from Chinese Han population in Shaanxi province. The DNA samples were extracted and relevant fragments were amplified by polymerase chain reaction (PCR). The PCR products were analyzed by ABI 3100 Genetic Analyzer. The number of alleles and genotypes observed at loci D12S1718, D12S1675, D12S358, D12S367, D12S1638, D12S1646 and D12S1682 were 7, 10, 8, 8, 6, 9, 11 for alleles and 10, 17, 18, 18, 14, 18, and 26 for genotypes, respectively. The heterozygosities for the 7 STR loci were 44.28%, 66.10%, 78.89%, 77.89%, 73.69%, 74.55% and 82.39%, respectively. The distribution of allele frequencies of 7 STR loci on chromosome 12 was consistent with Hardy-Weinberg equilibrium and relatively high genetic polymorphism was observed in Shaanxi Han population.
Adult↗
Genetic polymorphisms of drug metabolism. Possible implications during development.
Genetic polymorphisms of drug metabolism can affect phase I and phase II reactions. Polymorphisms of cytochrome P450 activity or inducibility have been implicated in drug toxicity and in cancerogenesis. Polymorphisms of the detoxification processes may be important in the appearance of adverse responses to conventional doses of drugs. Pharmacogenetics now opens new ways to investigate the relations between genetic factors, xenobiotics and teratogenesis.
Aging↗
N-acetyltransferase 2 genetic polymorphism: effects of carcinogen and haplotype on urinary bladder cancer risk.
A role for the N-acetyltransferase 2 (NAT2) genetic polymorphism in cancer risk has been the subject of numerous studies. Although comprehensive reviews of the NAT2 acetylation polymorphism have been published elsewhere, the objective of this paper is to briefly highlight some important features of the NAT2 acetylation polymorphism that are not universally accepted to better understand the role of NAT2 polymorphism in carcinogenic risk assessment. NAT2 slow acetylator phenotype(s) infer a consistent and robust increase in urinary bladder cancer risk following exposures to aromatic amine carcinogens. However, identification of specific carcinogens is important as the effect of NAT2 polymorphism on urinary bladder cancer differs dramatically between monoarylamines and diarylamines. Misclassifications of carcinogen exposure and NAT2 genotype/phenotype confound evidence for a real biological effect. Functional understanding of the effects of NAT2 genetic polymorphisms on metabolism and genotoxicity, tissue-specific expression and the elucidation of the molecular mechanisms responsible are critical for the interpretation of previous and future human molecular epidemiology investigations into the role of NAT2 polymorphism on cancer risk. Although associations have been reported for various cancers, this paper focuses on urinary bladder cancer, a cancer in which a role for NAT2 polymorphism was first proposed and for which evidence is accumulating that the effect is biologically significant with important public health implications.
Acetylation↗
Glutathione S-transferase M1 and T1 genetic polymorphisms, alcohol consumption and breast cancer risk.
Alcohol consumption has been inconsistently associated with breast cancer risk. Recent studies suggest that genetic polymorphisms of glutathione S-transferases (GSTs) may modify this relation. To determine if breast cancer risk is associated with GSTM1 and GSTT1 genetic polymorphisms, and to evaluate the effect modification between GST genotypes and alcohol consumption in the risk of breast cancer, we conducted a case-control study in the state of Connecticut in the period 1998 and 2001. Cases were histologically confirmed, incident breast cancer patients in New Haven County, CT. Controls were randomly selected from women histologically confirmed to be without breast cancer. The study results show that, while GSTM1 genotypes were not associated with breast cancer risk, GSTT1-null genotype was associated with a significant 90% increased risk for postmenopausal women (OR=1.9, 95% CI 1.2-3.0). Analysis by GST genotypes and alcohol consumption shows that GSTM1A ever-drinking women had a 2.5-fold (OR=2.5, 95% CI 1.1-5.5) increased risk of breast cancer compared to the GSTM1A never-drinkers, and the risk increases with duration and daily amount of alcohol consumption. Postmenopausal women with GSTT1-null genotype, who consumed a lifetime of >250 kg of spirit-equivalents, had an almost seven-fold increased risk (OR=6.8, 95% CI 1.4-33.9), and drinking commencing at younger ages appears to carry a higher risk. An OR of 8.2 (95% CI 1.2-57.4) was observed for those with GSTM1A, and GSTT1-null genotypes who had consumed a lifetime of >250 kg of spirit-equivalents. In conclusion, alcohol consumption may increase breast cancer risk among those who carry susceptible GST genotypes.
Adolescent↗
Epidemiological studies on genetic polymorphism: study design issues and measures of occurrence and association.
As with other epidemiological studies, the design and analysis of a study including genetic polymorphisms generally involve relating a particular disease or health outcome to a particular exposure or genetic trait, while assessing the presence of systematic error, controlling random error and assessing effect modification (interaction) with other exposures or traits. In studies of determinants and mechanisms of disease, markers of genetic polymorphism are generally treated either as exposure variables or as effect modifiers. In epidemiological studies the study base can be completely enumerated, and the cases can be identified as either incident or prevalent cases (incidence and prevalence studies). Alternatively, the study may involve cases of the disease (or condition) under investigation and a control group sampled from the study base that generated the cases (incidence and prevalence case-control studies). Most available studies on metabolic polymorphism and cancer risk are incidence case-control studies. Their major methodological problem is the selection of controls, which may be an important source of bias. Another important limitation of many available studies is the small sample size, which may be inadequate for assessing statistical interaction when the metabolic polymorphism is treated as an effect modifier.
Case-Control Studies↗
[Source and significance of genetic polymorphism of selected parasitic protozoa].
The application of biochemical and molecular techniques in parasitological studies has provided increasing evidences of genetic polymorphism among parasite populations. This review presents possible origins of genetic variation within populations of various protozoan species. Since the mode of reproduction has an important influence on genetic polymorphism within parasite populations these considerations refer mainly to some protozoan parasites which have various life cycles, e.g. Giardia, Trypanosoma, Cryptosporidium, Toxoplasma. Also other factors associated with parasites (such as: transmission and passage history in laboratory conditions; occurrence in different hosts or geographic regions; selective pressure of drugs; competitive interactions between populations) that affect parasite genetic diversity are discussed. However, the number of examined isolates of parasites and genetic markers, assortment of methods, probes, primers and reagents used is also of significance. The significance of genetic variability in parasite populations is still the subject of much interest and controversy. A simple interpretation of such variation is impossible because of the complexity of host-parasite interactions. The knowledge of parasite diversity at the nucleic acids level has continually increased, but a corect interpretation of this phenomenon requires at least the same knowledge of genetic variability in host populations. Nevertheless, genetic variability in protozoan parasites has many important implications, e.g. for taxonomy, epidemiology, control and evolution. Genetic differences within parasite populations might also be associated with phenotypic variability, e.g. virulence, antigenicity, infectivity, drug sensitivity, host preference etc.
Animals↗
[The evaluation of 12 STR loci genetic polymorphism in Han population].
OBJECTIVE: To investigate the genetic polymorphism of 12 STR loci in 240 Han population and evaluate application of the 12 STR loci systems in forensic cases. METHODS: 12 STR loci were amplified with Muti-loci STR PCR system, which were genotyped with electrophoresis separation on dPAGE. RESULTS: 12 STR loci system had high power of discrimination (DP) and it was suited for analysis of dated bloodstain especially. CONCLUSION: The 12 STR loci systems is simple economy and practicality, which is useful in forensic identification and disputed paternity.
Alleles↗