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PubMed2005

Modern cancer epidemiological research: genetic polymorphisms and environment.

Individual cancer susceptibility seems to be related to factors such as changes in oncogenes and tumor suppressor genes expression, and differences in the action of metabolic enzymes and DNA repair regulated by specific genes. Epidemiological studies on genetic polymorphisms of human xenobiotics metabolizing enzymes and cancer have revealed low relative risks. Research considering genetic polymorphisms prevalence jointly with environmental exposures could be relevant for a better understanding of cancer etiology and the mechanisms of carcinogenesis and also for new insights on cancer prognosis. This study reviews the approaches of molecular epidemiology in cancer research, stressing case-control and cohort designs involving genetic polymorphisms, and factors that could introduce bias and confounding in these studies. Similarly to classical epidemiological research, genetic polymorphisms requires considering aspects of precision and accuracy in the study design.

Carcinogens, Environmental↗
PubMed1985

An apparent genetic polymorphism for a protein present in the hypothalamus of Sprague-Dawley rats.

Using two-dimensional gel electrophoresis, an apparent genetic polymorphism was detected in the hypothalamus of a group of inbred Sprague-Dawley rats. The proteins involved in this polymorphism have a molecular weight of 57,000 daltons and isoelectric points ranging from 6.1 to 6.3. These proteins met four criteria that should be met before a positional shift on two-dimension gels can be attributed to a genetic polymorphism. This is the first report of the existence of a genetic polymorphism in the brains of a group of inbred Sprague-Dawley rats. The functional significance of this polymorphism is currently under investigation.

Animals↗
PubMedDate not supplied

Genetic polymorphisms of NAD(P)H quinone oxidoreductase, CYP1A1 and microsomal epoxide hydrolase and lung cancer risk in Nanjing, China.

Genetic variations in metabolic activation or detoxification enzymes have been thought to contribute to individual differences in lung cancer susceptibility. Genetic polymorphisms of NAD(P)H quinone oxidoreductase (NQO1), cytochrome P4501A1 (CYP1A1) and microsomal epoxide hydrolase (HYL1) have been associated with increased lung cancer risk in Asian populations. In the present study, the possibility of an association of NQO1, CYP1A1 and HYL1 genetic polymorphisms with lung cancer was examined among residents in Nanjing, China. A total of 84 lung cancer patients and 84 control subjects were matched by age, gender, occupation and smoking status. No significant association was observed for these genetic polymorphisms with the overall incidence of lung cancer. When the groups were stratified according to smoking status, we found that smokers carrying the HYL1*2 allele had a higher relative risk for lung cancer Odds ratio ((OR), 5.66; 95% confidence interval (95% CI), 1.71-18.68). The association was also found with squamous cell carcinoma (OR, 3.23; 95% CI, 1.00-10.38). Our results suggest that HYL1*2 polymorphism might be a risk factor for smoking-associated lung cancer in China.

Adenocarcinoma↗
PubMed1999

Technologies for detecting genetic polymorphisms in pharmacogenomics.

BACKGROUND: Pharmacogenomics is an emerging scientific discipline examining the genetic basis for individual variations in response to therapeutics. METHODS AND RESULTS: Genetic polymorphisms are a major cause of individual differences in drug response. Metabolic phenotyping can be accomplished by administering a probe drug or substrate and measuring the metabolites and clinical outcomes. However, this approach tends to be labor intensive and requires repeated sample collection from the individual being tested. Alternatively, genotyping allows determination of individual DNA sequence differences for a particular trait. Commonly used genotyping methods include gel electrophoresis-based techniques, such as polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism analysis, multiplex PCR, and allele-specific amplification. Fluorescent dye-based high-throughput genotyping procedures are increasing in popularity, including oligonucleotide ligation assay, direct heterozygote sequencing, and TaqMan (Perkin Elmer, Foster City, CA) allelic discrimination. High-density chip array and mass spectrometry technologies are the newest advances in the genotyping field, but their wide application is yet to be developed. Novel mutations/polymorphisms also can be identified by conformation-based mutation screening and direct high-throughput heterozygote sequencing. CONCLUSIONS: Rapid and accurate detection of genetic polymorphisms has great potential for application to drug development, animal toxicity studies, improvement of human clinical trials, and postmarket monitoring surveillance for drug efficacy and toxicity.

Clinical Laboratory Techniques↗
PubMed2000

Genetic polymorphisms and coronary artery disease in the south of France.

Vascular disease is a multifactorial disease that involves atherosclerotic and thrombotic factors. Genetic polymorphisms have been associated with myocardial infarction and angina pectoris. The aim of the present study was to assess the relationship between some genetic polymorphisms and myocardial infarction (MI) or vasospastic angina pectoris in a population from southern France. Genetic polymorphisms of the renin angiotensin system (the D/I polymorphism of the ACE gene and the A1166C polymorphism of the angiotensin II type 1 receptor [AT1R]) and of haemostatic factors (the -675 4G/5G polymorphism of the plasminogen-activator inhibitor 1[PAI-1] gene, and the G to T common point mutation in exon 2, codon 34 of the Factor XIII A-subunit gene) were examined. We assessed the genotype distribution in consecutive coronary artery disease (CAD) patients with MI (n = 201) and vasospastic angina pectoris (n = 43) and in 244 healthy controls comparable in age, sex, body mass index and total cholesterol level. The genotype distribution of AT1R polymorphism was significantly different between controls and patients, the prevalence of the C allele carriers being higher in patients with MI after the age of 45 than in control individuals (61 vs 45%, p <0.01), leading to an odds ratio (OR) of 2 (CI: 1.2-3.4). When looking at the group of patients with vasospastic angina the difference was even higher (76 vs 45%, p <0.01) yielding an OR of 4.3 (CI: 1.4-17.4). Genotype distributions of ACE, PAI-1 and Factor XIII polymorphisms were similar in patients and in controls. This study is in favor of a role of ATIR gene polymorphism in myocardial infarction and vasospastic angina.

Adolescent↗
PubMed1998

[Pharmacologic and toxicologic results in genetic polymorphisms (review)].

Paper provides a survey of the basic knowledge on the genetic polymorphism of enzymes involved in the metabolism of medicinal drugs and other xenobiotics. The major implications of this phenomenon have been described, namely the interindividual variability in the therapeutic effect of drugs differently metabolised by the polymorphically determined enzymes, or the interindividual variability in the susceptibility to neoplastic processes related to the polymorphically determined enzymes metabolising xenobiotics. Recent advances in the understanding of the molecular genetics of enzymes metabolising drugs and other xenobiotics (particularly cytochrome P-450, glutathione S-transferase, N-acetyltransferase, UDP-glucoronosyltransferases and others), help to understand the molecular basis of several genetic polymorphisms. Present article reviews the current status of studies on polymorphism of xenobiotics-metabolising enzymes and brings a discussion to their pharmacotherapeutical relevance and to their significance for identification of susceptible individuals/subgroups in the carcinogen exposed population.

Enzymes↗
PubMed1996

L-myc, GST M1 genetic polymorphism and hepatocellular carcinoma risk among chronic hepatitis B carriers.

In order to assess associations between the genetic polymorphism of L-myc and glutathione S-transferase M1 (GST M1) and the risk of hepatocellular carcinoma (HCC), a total of 46 surgically treated HCC patients who were seropositive in hepatitis B surface antigen (HBsAg) and 88 HBs-Ag positive controls were recruited for this study. L-myc and GST M1 genetic polymorphism was examined using a polymerase chain reaction-based restriction fragment length polymorphism assay on DNA extracted from liver and peripheral blood samples. There was no significant difference in GST M1 genotypes between HCC patients and matched controls. A gene dosage trend of association with HCC risk was observed for L-myc genotype. The dose-response relationship remained statistically significant in the multiple logistic regression analysis.

Age Factors↗
PubMed2004

Genetic polymorphism of the renin-angiotensin system on the development of primary vesicoureteral reflux.

BACKGROUND: The familial clustering of vesicoureteral reflux (VUR) has suggested a genetic basis. This study was designed to investigate the genetic polymorphism of the renin-angiotensin system (RAS) in Korean children. METHODS: Genetic polymorphism of angiotensin-converting enzyme (ACE) and angiotensin II receptor genes was evaluated in 67 primary VUR patients and compared to 58 controls with no urological abnormalities. To detect the relation of the risk factors of primary VUR with the genetic polymorphism, the distribution of ACE, AT1 and AT2 genotypes after stratification by risk factors was also studied in the primary VUR patients. RESULTS: The incidence of AT2 A-1332G transition was significantly lower in primary VUR patients (p = 0.047). Furthermore, in the case of combination of ACE and AT2 gene, a significantly lower incidence of primary VUR was seen with II genotype of ACE and A-1332G transition in the AT2 receptor gene (p = 0.003). Concerning the risk factors of primary VUR, there were no biologically significant results. CONCLUSIONS: These findings indicate that a lower incidence of AT2 A-1332G transition is seen in primary VUR patients, at least in the Korean population. Also, in the case of combination of ACE and AT2 gene, the combination of ACE II genotype and AT2 A-1332G transition occurs infrequently in primary VUR.

Female↗
PubMed1998

Genetic polymorphisms in glutathione S-transferase mu and theta, N-acetyltransferase, and CYP1A1 and risk of gliomas.

The role of genetic polymorphisms in modulating susceptibility to carcinogenic exposures has been well explored for tobacco-related neoplasms but not for other neoplasms including gliomas. It is relevant to explore these polymorphisms because certain carcinogenic exposures such as nitrosamines are implicated in the risk of gliomas. We therefore conducted a pilot case-control study to examine the role of polymorphisms in GSTM1, GSTT1, NAT2 (rapid, intermediate, and slow acetylation), and CYP1A1 and risk of glioma. Ninety patients diagnosed with glioma were ascertained as part of an ongoing genetic epidemiological study and were age, gender, and race matched with 90 healthy controls. We used PCR based methodology to determine the prevalence of the above genetic polymorphisms using sequences and PCR conditions directly adapted from studies reported previously. We calculated univariate odds ratios and performed multiple logistic regression to assess interactions between polymorphisms. We found no statistically significant associations between the null genotypes of GSTM1 and GSTT1, and CYP1A1 and risk of gliomas. However, there was an intriguing pattern with NAT2 acetylation status (odds ratios, 1.81, 1.34, and 0.61 for rapid, intermediate, and slow acetylation, respectively; P = 0.10 for trend). It is unlikely that any single polymorphism is sufficiently predictive of risk, and a panel of markers integrated with epidemiological data should be conducted on a large number of study subjects to fully understand the role of genetic polymorphisms and brain tumor risk.

Adult↗
PubMed2002

Genealogical trees, coalescent theory and the analysis of genetic polymorphisms.

Improvements in genotyping technologies have led to the increased use of genetic polymorphism for inference about population phenomena, such as migration and selection. Such inference presents a challenge, because polymorphism data reflect a unique, complex, non-repeatable evolutionary history. Traditional analysis methods do not take this into account. A stochastic process known as the 'coalescent' presents a coherent statistical framework for analysis of genetic polymorphisms.

Animals↗
PubMed2006

The effects of genetic polymorphisms of IL-1 and TNF-A on Helicobacter pylori-induced gastroduodenal diseases in Korea.

OBJECTIVE: To evaluate whether or not genetic polymorphism of IL-1B, IL-1RN, and TNF-Alpha is an important factor in the different expression of gastroduodenal diseases after Helicobacter pylori infection. METHODS: This study consisted of 1360 subjects: control, gastric cancer (GC, intestinal type, and diffuse type), benign gastric ulcer (BGU), duodenal ulcer, and first-degree gastric cancer relative (GCR). IL-1Beta-511 and TNF-A-308 biallelic polymorphism were genotyped by 5' nuclease polymerase chain reaction (PCR) assays, and PCR-restriction fragment length polymorphism (PCR-RFLP). IL-1RN penta-allelic variable number of tandem repeats was genotyped by PCR. RESULTS: There was no difference in the genetic polymorphism of IL-1Beta-511, IL-1RN and TNF-A in the patients with gastric cancer regardless of H. pylori positivity compared with control. However, the frequencies of IL-1B-511 C/T (OR: 0.5, 95% CI: 0.3-0.7) and T carrier (OR: 0.6, 95% CI: 0.4-0.8) were lower in the H. pylori-positive BGU patients. The IL-1RN 2/2 was higher (OR: 5.5, 95% CI: 1.1-28.5) in the H. pylori-positive GCR. There was no significance in the polymorphism of TNF-Alpha-308 regardless of H. pylori-induced gastroduodenal diseases. CONCLUSIONS: The IL-1Beta-511 T-carrier polymorphism has a negative effect on the development of H. pylori-positive BGU, and high frequency of IL-1RN 2/2 was found in the H. pylori-positive relatives of GC patients, which suggest that this genetic polymorphism could play some role in the H. pylori-induced gastroduodenal diseases in Korea.

Adult↗
PubMed2002

Symposium overview: genetic polymorphisms in DNA repair and cancer risk.

A symposium, Genetic Polymorphisms in DNA Repair and Cancer Risk, was presented at the 40th Annual Meeting of the Society of Toxicology, held in San Francisco, California, in March 2001. A brief report of the symposium was published (Kaiser, Science 292, 837-838, 2001). Molecular epidemiological studies have shown that polymorphic variants of genes involved in the metabolism and repair of carcinogens can act as cancer susceptibility genes. These variants of drug metabolic and DNA-repair enzymes either increase the activation of chemical carcinogens or decrease the cells' ability to detoxify/repair mutagenic damages. Although on an individual basis these variant alleles may only slightly change catalytic activity and increase cancer risk, their polymorphic frequency in the human population may contribute to a high proportion of cancer cases. Studies conducted over the past few years have identified variant alleles for a number of DNA-repair genes, some of which have been shown to change DNA-repair capacity. Identifying these genotypic alterations in DNA-repair enzymes and their association with cancer may help to elucidate the mechanisms of cancer etiology and to predict both disease risk and response to cancer therapy, since most antineoplastic treatments mediate their effects through DNA damage.

Carrier Proteins↗
PubMed1987

Orosomucoid (ORM) typing by isoelectric focusing: evidence for gene duplication of ORM1 and genetic polymorphism of ORM2.

It has been demonstrated that the genetic polymorphism of human serum orosomucoid (ORM) is controlled by polymorphic ORM1 and monomorphic ORM2 loci. In this study a Japanese family was encountered in which several members had puzzling electrophoretic patterns consisting of four bands. The ORM patterns were due to the products of a duplicated ORM1 locus haplotype (ORM1 2.1) or the products of new variant alleles at the ORM2 locus. The ORM1 2.1 haplotype is very common in the Japanese population, occurring at an allele frequency of 0.16. The increased occurrence of ORM12-1 and the heterogeneity in band intensity among ORM12-1 phenotypes could be explained in terms of a duplicated gene ORM1 2.1. The ORM2 locus proved to be polymorphic, with six alleles in the Japanese population.

Alleles↗
PubMed2006

Association studies of genetic polymorphism, environmental factors and their interaction in ischemic stroke.

Genetic background plays an important role in susceptibility to ischemic stroke. Our aim was to investigate the association of genetic polymorphisms and ischemic stroke and to evaluate their interaction with environmental risk factors in the Chinese population. Angiotensin-converting enzyme (ACE) gene I/D polymorphism, apolipoprotein E (ApoE) gene polymorphism, methylenetetrahydrofolate reductase (MTHFR) gene 677C/T polymorphism, and beta fibrinogen (Fgbeta) gene 148C/T polymorphism were analyzed in 100 patients and 100 matched controls. The subjects were genotyped by polymerase chain reaction (PCR) amplification and denaturing high-performance liquid chromatography (DHPLC) analysis. Persons with the Fgbeta CT/TT, MTHFR CT/TT, and ACE ID/DD genotypes had an elevated incidence of ischemic stroke (OR 3.907, 95% CI, 1.160-13.162, P=0.028). Smokers with the Fgbeta CT/TT or APOEepsilon4epsilon3 genotype, as well as individuals with the Fgbeta CT/TT genotype who consumed alcohol were more likely to develop a stroke. The data indicate that certain unfavorable genotypic combinations act synergistically in the development of ischemic stroke in the Chinese population. Synergism was also observed between genotype and environmental risk factors. This study may facilitate the development of a strategy to effectively prevent ischemic strokes.

Adult↗
PubMed1998

Genetic polymorphism of properdin factor B (BF) in domestic rabbit.

Genetic polymorphism of plasma properdin factor B (BF) was detected in domestic rabbit, Oryctolagus cuniculus, by means of isoelectric focusing and immunoblotting. The analysis of 298 individuals, corresponding to one French and two Portuguese populations, revealed the existence of six alleles, of which BF*A, B and C were common alleles, and D, F and G were rare ones.

Alleles↗
PubMed1996

[Genetic polymorphism of antithrombin III in five Chinese populations].

The genetic polymorphisms of antithrombin III (AT III) in 5 Chinese populations were studied by isoelectric focusing on polyacrylamide gels followed by immunoblotting. The products of two alleles at the antithrombin III locus together with 1 AT III anodic variant and 3 cathode variants were observed. The results revealed that the predominant allele of AT III blood group system in Chinese populations was AT III *1, with frequencies between 0.9773-0.9850. Frequencies of AT III *2 ranged from 0.0091 to 0.0169. These results indicate that the polymorphic information content of AT III blood group system in Chinese populations is limited.

Alleles↗
PubMed2002

[Primary study on genetic polymorphism and population difference of locus DYF155S1].

OBJECTIVE: To understand the genetic polymorphism and population difference of locus DYF155S1 on human Y chromosome. METHODS: Using minisatellite variant repeat mapping-polymerase chain reaction (MVR-PCR), automated fluorescence detection, DNA sequence analysis, the authors studied the locus DYF155S1 of two chimpanzee and 10 human subjects from each of the following 8 groups: Northern China Hans, Southern China Hans, the Zang (Tibetan) nationality, the Uighur nationality, Japanese, Korean, Black African, White African. RESULTS: In this study, loci DYF155S1 and DYF155S2 have been detected. There is no difference in all of the samples on the locus DYF155S2; each sample contains one type 4 repeat unit, which is the ancestor gene of locus DYF155S1. On locus DYF155S1, each individual has its specific DNA sequence. The arrangement of the repeat units differs greatly in races: arrangement 3134 in the yellow race, arrangement 134 in the white race, and arrangement null3a1a4a4 in the black race were most common. The average number of the type 4 repeat unit in the white race is much higher than that in the yellow race. The authors also found two new types of repeat unit: type 6 and type 7. Type 6 is the result of the T22A substitution on type 1, which was observed in Japanese (3 samples). Type 7 is resulted from the T22A substitution on type 3, which was observed in the Zang nationality (4 samples), Southern China Hans(1 sample), and Korean (1 sample). CONCLUSION: Locus DYF155S1 has great genetic polymorphism and obvious population difference. Its significance should receive more attention in forensic science and human genetics research.

Animals↗
PubMed2006

SULT1E1 genetic polymorphisms modified the association between phytoestrogen consumption and bone mineral density in healthy Korean women.

Sulfotransferase 1E1 (SULT1E1) catalyze estrogen into sulfate conjugation and is involved in the metabolism of phytoestrogen. A community-based cross-sectional study was conducted on 397 Korean women, to evaluate the association between genetic polymorphisms of SULT1E1 and bone mineral density (BMD) and the combined effect of the genetic polymorphism and phytoestrogen intake for BMD in Korean women. BMDs of the distal radius and the calcaneus were measured by dual-energy X-ray absorptiometry. Genotypes of SULT1E1 IVS1-447 C>A, IVS4-1653 T>C, and *959 G>A were determined by the 5'-nuclease assay (TaqMan). Phytoestrogen intake was estimated by a food-frequency questionnaire validated against multiple 24-hour recalls. Women with the SULT1E1 *959 GG genotype had a 4.5% lower BMD at the distal radius (P (trend )= 0.05) and a 7.9% lower BMD at the calcaneus compared to those with AA genotype (P (trend) < 0.01), whereas the SULT1E1 IVS1-447 CC genotype and IVS4-1653 TT genotype were not associated with BMD. There was no significant trend of BMD with the numbers of CTG-containing haplotypes, but calcaneal BMDs significantly differed between SULT1E1 CTA-CTA haplotype and CTG-CCA haplotype (P < 0.05). When stratified by SULT1E1 genotype, the correlation between phytoestrogen consumption and BMD at the calcaneus was noteworthy in women with SULT1E1 *959 GG genotype (r = 0.25, P = 0.01) or SULT1E1 IVS 4-1653 TT genotype (r = 0.15, P = 0.02). This trend remained significant only in postmenopausal women (r = 0.36, P = 0.01) after multiple testing was corrected by the false discovery rate method. In conclusion, the genetic polymorphism of SULT1E1 *959 G > A was associated with BMD at the distal radius and calcaneus, and the association between phytoestrogen consumption and calcaneal BMD might be modified by this genetic polymorphism.

Absorptiometry, Photon↗