CYP2E1 Genotype Research Articles

Genetic variations in CYP2A6, CYP2E1, GSTM1, GSTT1 genes and the risk of Nasopharyngeal carcinoma in North African population.

Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy associated with both genetic and environmental factors. Polymorphic deletions of the phase I and phase II genes involved in the detoxification of potential carcinogens may be a risk factor for nasopharyngeal carcinoma. In this study, we investigated the relationship between CYP2E1 (rs3813867), CYP2A6, GSTM1(rs1183423000) and GSTT1(rs1601993659) gene variations and NPC risk in North African countries with the highest incidence of NPC (Morocco, Algeria and Tunisia). and the evaluation of the potential use of these variants as potential biomarkers for NPC management. A total of 600 NPC cases and 545 controls frequency-matched on ethnicity, sex, age and childhood household type, were recruited from three North African countries (Morocco, Algeria and Tunisia) and analysed. Genotyping of CYP2A6 and CYP2E1(rs3813867) was performed by polymerase chain reaction restriction (PCR)-fragment length polymorphism (RFLP) analysis and the GSTM1 (rs1183423000) and GSTT1(rs1601993659) genetic variations were evaluated using the PCR technique. The genotype distributions of CYP2E1(rs3813867), CYP2A6, GSTM1(rs1183423000) and GSTT1(rs1601993659) genotypes did not differ significantly among NPC cases and controls (p>0.05). Furthermore, our data did not reveal any association with smoking and the studied variants, even when the samples were stratified by the duration period of smoking. In this large studied North African population, our findings suggest that the functional CYP2E1, CYP2A6, GSTM1 and GSTT1 variations did not influence NPC susceptibility.

Understanding Role of DNA Repair and Cytochrome p-450 Gene Polymorphisms in Cervical Cancer Patient Treated With Concomitant Chemoradiation.

Background: Evidences suggest that single nucleotide polymorphisms (SNPs) can be considered as potential biomarkers for disease progression and therapeutic response in cervical cancer. The present study investigated the association of CYP1A1 T>C (rs4646903), CYP1A1 A>G (rs1048943), CYP2E1 T>A (rs6413432), RAD51 G>C (rs1801320), XRCC1 G>A (rs25487), XRCC2 G>A (rs3218536) and XRCC3 C>T (rs861539) polymorphisms with treatment outcome of cisplatin based chemoradiation (CRT). Methods: Total 227 cervical cancer cases, treated with the same chemoradiotherapy regimen were selected for the study. Genotyping analysis was performed by PCR-restriction fragment length polymorphisms (PCR-RFLP). Treatment response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST). Association of all clinical data (responses, recurrence and survival of patients) and single nucleotide polymorphisms (SNPs) was analysed by using SPSS (version 21.0). Results: Patients with TA/AA genotype of CYP2E1 T>A polymorphism showed significantly poor response while those with GC/CC genotype of RAD51 G>C showed better response (p = 0.008, p = 0.014 respectively). Death was significantly higher in patients with GG genotypes of RAD51 G>C and XRCC1 G>A (p = 0.006, p = 0.002 respectively). Women with GC+CC genotype of RAD51 G>C and AG+GG of XRCC1 showed better survival and also reduced risk of death (HR = 0.489, p = 0.008; HR = 0.484, p = 0.003 respectively). Conclusion: Results suggested that CYP2E1 T>A (rs6413432), RAD51 G>C (rs1801320), and XRCC1 G>A (rs25487) polymorphisms may be used as predictive markers for clinical outcomes in cervical cancer patients undergoing cisplatin based concomitant chemoradiotherapy.

Effect of CYP2E1 gene polymorphisms on lamb odor and flavor in Indonesian sheep

The CYP2E1 gene (Cytochrome P450 2E1) plays an important role in the regulation of skatole and androstenone in liver tissue. The aimed of this study was to investigate of the effect of CYP2E1 gene polymorphisms on lamb odor and flavour in Indonesian sheep. A total sample of 100 rams consisting of 20 Javanese fat-tailed (JFT), 20 Javanese thin-tailed (JTT), 20 compass Agrinak sheep (CAS), 20 Barbados cross sheep (BCS), and 20 Garut composite sheep (GCS) aged 10–12 months old were used. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was performed to identify the polymorphism of CYP2E1 genes. The association of the CYP2E1 genotypes with lamb odor and flavour were performed using T-test. The result showed that there were polymorphisms in CYP2E1 gene indicated by three genotypes namely GG (401 bp), GT (138, 263, and 401 bp), and TT (138 and 263 bp). Gene frequency of CYP2E1 (g.50657948 T>G) was in Hardy-Weinberg Equilibrium (HWE). The GT genotype was common in the population studied. Association of the CYP2E1 genotypes with lamb odor and flavour revealed a significant association (P<0.05) with the skatole (MI). The GG genotype had the highest skatole when compared to other genotypes. The SNP g.50657948 T>G of CYP2E1 gene might be a useful candidate marker for selecting sheep meat with desirable odor and flavour.

CYP2E1, GSTM1, and GSTT1 genetic polymorphisms and their associations with susceptibility to antituberculosis drug-induced liver injury in Thai tuberculosis patients

Antituberculosis drug-induced liver injury (ATDILI) is the common adverse reaction of antituberculosis drugs. Glutathione S-transferases (GSTs), which are phase II metabolizing enzymes for detoxification, are recognized as potential mediators of hepatotoxicity. However, role of GSTs polymorphisms in ATDILI pathogenesis has never been observed in Thais. This study aimed to investigate associations between GSTs and ATDILI susceptibility. This retrospective case-control multicentered study was conducted by the collaboration from ten secondary and tertiary care hospitals across Thailand, including Northern, Central, and Southern parts of Thailand. We enrolled 80 tuberculosis (TB) patients with ATDILI and 174 those without ATDILI into the study. Polymerase chain reaction (PCR) was used to determine genetic polymorphisms of GSTM1 and GSTT1 genes. CYP2E1 genotyping data were derived from microarray data. We illustrated that GSTT1 null and GSTM1/GSTT1 dual null genotypes were correlated with an increased risk of ATDILI with odds ratio (OR) at 1.83 (95% confidence interval (CI), 1.00 to 3.35; P = 0.049) and 2.12 (95%CI, 1.02 to 4.38; P = 0.044), respectively. Interestingly, GSTT1 null and GSTM1/GSTT1 dual null genotypes were found to be correlated with an increased risk of ATDILI in Thai TB patients who carried CYP2E1 wild type phenotype with OR 2.99 (95%CI, 1.07 to 8.39; P = 0.037) and 3.44 (95%CI, 1.01 to 11.71; P = 0.048), respectively. Collectively, GSTT1 null and GSTM1/GSTT1 dual null genotypes were associated with a higher risk of ATDILI in Thai TB patients, which may serve as alternative genetic biomarkers for ATDILI.

CYP2E1-DEPENDENT VARIATIONS IN HEPATOCYTES DAMAGE DURING TREATMENT OF TUBERCULOSIS

Relevance. Investigation of polymorphism in a locus of CYP2E1 as the prognostic factor of drug-induced hepatotoxicity at anti-TB therapy is significant due to the influence of CYP2E1 on drug metabolism.&#x0D; The objective of the investigation is to analyze the association of rs2070676 СYP2E1 gene polymorphism with drug-induced hepatotoxicity by means of the clinical-laboratory values of serum transaminases at anti-TB treatment.&#x0D; Materials and methods. The study involved 47 patients with drug-susceptible tuberculosis first time discovered. 58 healthy volunteers comprised a control group. Laboratory indices were determined in venous blood three times: before the treatment as baseline; in 2 months of intensive therapy (isoniazid, rifampicin, ethambutol, pyrazinamide), then in 4 months of maintenance therapy (isoniazid, rifampicin). Serum activities of enzymes ALT, AST, and GGT were measured by standard algorithm on automatic analyzer BS-300. Analysis of rs2070676 polymorphism of CYP2E1 gene was performed by polymerase chain reaction using standard PureLink® Genomic DNA Kit for Purification of Genomic DNA; Manufacturer of INVITROGEN (USA). For statistical processing, IBM SPSS Statistics 23 was applied.&#x0D; Results. Investigation of serum ALT and AST in patients with major genotype CYP2E1 (C/C) showed the lower baseline ALT and AST levels comparing to the control group, which might be caused by suppression of hepatocytes functions at the development of the disease. Anti-TB treatment caused an increase in ALT and AST levels comparing to the baseline in patients with major CYP2E1 (C/C) genotype. In the group with C/G polymorphism, the baseline ALT level didn’t differ much from the baseline of the control group; it showed a decrease after intensive therapy and returned back to the initial level at maintenance therapy. This might be related to the certain protective property of СYP2E1 gene polymorphism. The AST level was increased after intensive therapy (to a smaller extent than for the patients with major C/C genotype) and remained on the same level at maintenance therapy. A study of GGT showed a gradual increase regardless of genotype.&#x0D; Conclusion. According to the data of the experiment, the status of hepatocytes in patients with tuberculosis at baseline and during treatment was different depending on the CYP2E1 genotype. The results of the experiment indicate that the CYP2E1 gene polymorphism has a certain protecting role. It reduces the level of drug metabolites and hepatotoxicity which causes mitochondrial dysfunction.

Biomarkers of susceptibility and effect in car painters exposed to organic solvents.

Introduction: Car painters are routinely exposed to organic solvents classified as carcinogenic and mutagenic substances. Objective: To characterize the population susceptibility and evaluate the genotoxic effects of exposure to organic solvents. Methods: A cross-sectional study comparing a group of car painters exposed to organic solvents with a non-exposed group. CYP2E1 polymorphisms and the presence of micronuclei in lymphocytes were determined. Results: One hundred twenty-two workers participated in the study: 62 who worked in car paint shops and were exposed to solvents, and 60 who were not exposed. There were statistically significant differences between the two groups regarding micronucleated cells and nucleoplasmic bridges frequencies (p= 0.042 and p= 0.046, respectively; exact likelihood ratio). Significant differences were found at the interaction between the CYP2E1 genotype c1c1 and occupational exposure to solvents, with higher frequencies of micronuclei (p= 0.013) and micronucleated cells (p= 0.015). However, when the frequencies of micronuclei, micronucleated cells and nucleoplasmic bridges in the exposure group were compared between the c1c1 and c2c2/c1c2 allele groups of the CYP2E1 polymorphism, statistically significant differences were found. Conclusions: This study confirms that when workers with CYP2E1 polymorphisms, specifically the c1c1 genotype, are exposed to organic solvents, they are more likely to have somatic cell mutations, a condition associated with increased susceptibility to diseases such as cancer

MO043IDENTIFICATION OF INDOXYL SULFATE PRODUCER PHENOTYPES BY ORAL TRYPTOPHAN CHALLENGE TEST: A MICROBIOTA-BASED PERSONALIZED NUTRITIONAL APPROACH

Abstract Background and Aims Indoxyl sulfate (IS), one of the most representative gut-derived uremic toxins, has been implicated in the pathogenesis of cardiovascular disease in patients with chronic kidney disease (CKD). However, current approaches to IS reduction are not optimized. IS is converted from indole, a gut bacterial metabolite of dietary tryptophan, by two hepatic enzymes CYP2E1 and SULT1A1 (Figure 1A). Given that the interplay between microbes and host is associated with various phenotypes of medical importance, we hypothesized that the effects of a particular diet on individuals differ from person to person. In the present study, we measured individualized IS production using a fixed-dose loading of tryptophan. We aimed to characterize variable IS producer phenotypes and identify person-specific host and microbiome features associated with the variability. Method We developed an oral tryptophan challenge test (OTCT) to determine the individual IS producing capacity. Plasma and urine samples were collected at baseline after overnight fasting, and were then collected at 4, 8, 12, 24, 36 and 48 hours after oral administration of L-tryptophan at a dose of 2 gm. All participants were on a low tryptophan diet during the pharmacokinetic study of IS production following OTCT. Positive (above baseline) components of the area under the curve (AUC) were calculated to indicate IS production because of the variable nature of the baseline IS. Information on dietary patterns was obtained using a semiquantitative food frequency questionnaire (FFQ) validated for assessment of major nutrients in the diets of Taiwanese vegetarians and omnivores. Tryptophan and IS concentrations were quantified by high performance liquid chromatography. CYP2E1 and SULT1A1 single nucleotide polymorphism genotyping was analyzed by TaqMan PCR assay. The gut microbiome was assessed by metagenomic next-generation sequencing. Results We enrolled 40 healthy volunteers to undergo the OTCT. The mean age of the participants was 33 ± 7 years; 27.5% were men (n=11), and 40% were vegetarians (n=16). Participants were stratified into quartiles of baseline-adjusted AUC of IS. High interpersonal variability in IS production following OTCT was observed (Figure 1B). The 10 participants in the highest quartile (Q4) were defined as high IS producers. The other 30 participants in the Q1, Q2, and Q3 were defined as low IS producers (Figure 1C, 1D). The high IS producers were all female (n=10; P=0.025) and more likely to be omnivores (n=8; P=0.136). Otherwise, there was no difference in the age, body mass index, blood pressure, eGFR, fasting blood glucose, lipid profiles, and baseline plasma IS concentrations between the 2 groups. The high and low IS producers were different with respect to the principal coordinate analysis of β-diversity of the gut microbiota. A prediction model was constructed based on the individual IS producing capacity as contributed by the gut microbiome features and host genotypes. Conclusion We found high variability of IS in the response to OTCT across individuals, suggesting that universal dietary recommendations may have limited utility. High IS producers should avoid consuming foods that contain high levels of tryptophan. Therefore, the OTCT can be used to identify IS-producer phenotypes and may serve as a personalized dietary guidance and optimize food choices. Potential clinical applications for the OTCT require further studies to validate its use in patients with CKD.

The role of some xenobiotic biotransformation genes snp in the development of acute pancreatitis

Genetically determined features of the xenobiotic biotransformation system play an important role in the development of acute pancreatitis (AP) and its complications. The aim of this study was to assess the contribution of 3 SNPs (CYP1A1 -462 T&gt;C rs1048943, CYP2E1 -1293 G&gt;C rs3813867 and ABCB1 -3435 G&gt;A rs1045642) to the development of AP and its complications. DNA samples were collected from 547 unrelated patients with AP (154 women and 393 men; mean age 48.9 ± 13.1 years) undergoing therapy at surgery departments of Kursk and 573 unrelated individuals without gastrointestinal diseases (161 women and 412 men; mean age 47.8 ± 12.1 years). The polymorphisms were genotyped by PCR using TaqMan probes for allele discrimination. Infected pancreatic necrosis (IPN) was observed in 97 patients; 101 patients developed a pseudocyst (PC); 111 patients had a peripancreatic necrosis (PN). AP was the most common in the carriers of the А allele in ABCB1 G&gt;A (rs1045642) (p = 0.0008). The carriers of the G/G genotype rarely developed both AP (p = 5·10–4) and its complications: IPN (p = 0.03R), PN (p = 0.036R), PC (p = 0.04R). The carriers of the G/C–C/C CYP2E1 G&gt;C (rs3813867) genotypes who had no long-term history of alcohol abuse rarely developed AP (p = 0.03). The carriers of the G/C CYP2E1 (rs3813867) genotype tended to develop pseudocysts (p = 0.05OD). AP was more frequently complicated by IPN (p = 0.009R), PN (p = 0.003R) and PC (p = 0.003D) in the carriers of the C/C CYP1A1 T&gt;C (rs1048943) genotype. A milder course of AP was typical for the carriers of the G/G ABCB1 G&gt;A (rs1045642) genotype; a more severe course was characteristic of the carriers of the C/C CYP1A1 T&gt;C (rs1048943) genotype.

Association between polymorphism of GSTP1, GSTT1, GSTM1 and CYP2E1 genes and susceptibility to benzene-induced hematotoxicity

Occupational exposure to benzene has been associated with leukemia, anemia, leukopenia, and thrombocytopenia. Genetic susceptibility to benzene toxicity in humans may be related to variations in benzene metabolizing genes. The main objective of this study was to ascertain whether polymorphism of GSTP1, GSTM1, GSTT1 and CYP2E1 genes might influence susceptibility to the adverse effects of benzene among employees of a petrochemical plant. In this cross-sectional study, 124 employees of a petrochemical plant who had been occupationally exposed to benzene and had one or more abnormal hematological parameter (cases) and 184 subjects with a similar exposure scenario, free from any abnormal hematological parameters (referent) were studied. Atmospheric concentrations of benzene were measured and GSTM1 and GSTT1 genotypes were evaluated using the multiplex polymerase chain reaction (PCR) technique. Additionally, GSTP1 and CYP2E1 genotypes were determined by PCR- restriction fragment length polymorphism (PCR–RFLP). The frequency of null GSTT1 genotype in cases was significantly higher than that of referent group (32.3 vs. 18.5%, OR 2.1, 95% CI 1.23–3.56, p = 0.004). The mean value of platelets in subjects with null GSTT1 genotype was significantly lower than that of individuals with positive GSTT1 genotype (p = 0.015). Conversely, the mean value of leukocytes was significantly higher in subjects with null GSTM1 genotype as compared to those with positive GSTM1 genotype (p = 0.026). Logistic regression analysis showed that, subjects with null GSTT1 genotype had a significantly higher risk for hematological disorders, as compared to those with positive GSTT1 genotype (OR 2.1, 95% CI 1.23–3.56). Moreover, subjects with both null GSTT1 and GSTM1 genotypes had a significantly higher risk for hematological disorders as compared to subjects with positive GSTT1 and GSTM1 genotypes (OR 2.35, 95% CI 1.14–4.8). The results of this study showed that, individuals carrying null GSTT1 or both null STT1 and GSTM1 genotypes had a higher risk and were more susceptible to benzene-induced hematological disorders.

CYP2E1 genotype and transaminase level of tuberculosis patients receiving fixed dose combination of antituberculosis

CYP2E1 genotype and transaminase level of tuberculosis patients receiving fixed dose combination of antituberculosis

Association of cytochrome P4502E1 and NAD(P)H:quinone oxidoreductase 1 genetic polymorphisms with susceptibility to large artery atherosclerotic ischemic stroke: a case-control study in the Turkish population.

Stroke, a major cause of death and disability, is described as interruption or severe reduction of blood flow in cerebral arteries. Oxidative stress plays an important role in the pathogenesis of atherosclerosis and carotid atherosclerosis is a risk factor for stroke. Combination of multiple environmental and genetic risk factors is thought to increase stroke. Therefore, investigation of the polymorphisms of enzymes is of crucial importance to determine the molecular etiology of the disease. To test this hypothesis, we performed a case-control study in which we compared the distribution of CYP2E1 and NQO1 genotypes between 245 large artery atherosclerotic ischemic stroke patients and 145 controls, using PCR-RFLP. A significant difference was observed between stroke patients and controls with respect to the CYP2E1*5B genotype (odds ratio; OR 8.069, P=0.011) and allele (OR 7.876, P=0.011) distribution. However, this polymorphism was not a significant predictor of disease status in logistic regression analysis. NQO1*2 polymorphism genotype distribution was significantly different between patients and controls (P=0.027) and heterozygote *1*2 genotype was found to be a protective factor against large artery atherosclerotic ischemic stroke in logistic regression analysis (OR 0.562, P=0.018). This is the first study conducted regarding the association of CYP2E1 and NQO1 genetic polymorphisms and large artery atherosclerotic ischemic stroke risk in Turkish population.

Role of CYP2E1 and NQO1 polymorphisms in oxidative stress derived cancer in Thais with and without dyslipidemia

Abstract Background Hyperlipidemia can induce the endogenous production of reactive oxygen species (ROS), which may cause carcinogenesis. Cytochrome P450 (CYP) 2E1 activity, induced by various factors including polyunsaturated fatty acids, effects the incidence of cancers, whereas NQO1, a flavoprotein, may protect against ROS. Objectives To investigate the effect of CYP2E1 and NQO1 polymorphism on oxidative stress status in Thais with and without dyslipidemia. Methods We included 1380 apparently healthy employees of the Electricity Generating Authority of Thailand in this study. We determined their CYP2E1 and NQO1 genotypes and related these to blood lipid profiles, and circulating levels of antioxidant enzymes, malondialdehyde (MDA), and reduced glutathione (GSH). Lifestyle-related factors were determined from questionnaires. Results All tested genotype frequencies were in Hardy-Weinberg equilibrium. The heterozygous and variant genotype distribution and allele frequency of CYP2E1 *5B were less common than CYP2E1 *6. Heterozygous NQO1 was the most prevalent form. The frequency of the mutated allele CYP2E1 *5B was 0.16, CYP2E1 *6 was 0.22, and NQO1 *2 was 0.43. Significant differences were observed for blood cholesterol, triglyceride, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol between normolipidemic participants, and those with hypercholesterolemia, hypertriglyceridemia, and combined hyperlipidemia. Participants in the hyperlipidemic subgroup who bore any variant alleles of genes had higher plasma MDA and GSH levels, and superoxide dismutase and glutathione peroxidase activity, but lower catalase activity when compared with normolipidemic participants bearing wild-type alleles. Conclusions Variations in genetic disposition and dyslipidemia can modify oxidative stress status. Relatively more free radicals may be generated in individuals in subgroups with hyperlipidemia bearing any variant alleles.

Risk factors of isoniazid-induced hepatotoxicity in Tunisian tuberculosis patients.

Previous studies have shown controversial results on whether acetylator status causes isoniazid-induced hepatotoxicity (IIH). Moreover, the contribution of CYP2E1, a hepatic enzyme implicated in the formation of hepatotoxins, to the risk of developing IIH remains unclear. The objectives of this study were (i) to assess the quantitative relationship between the level of isoniazid serum concentration and the incidence of IIH and (ii) to evaluate the extent of implication of the N-acetyltransferase-2 (NAT2) and CYP2E1 polymorphisms genes to induce this disorder. Seventy-one patients with tuberculosis receiving a conventional antituberculosis regimen were included. NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction. Three restriction enzymes, RsaI, PstI and DraI were used to detect CYP2E1 RFLP and four different restriction enzymes, KpnI, TaqI, BamHI and Ddel were used to determine NAT2 acetylator status. Therapeutic drug monitoring (TDM) of isoniazid (serum concentration performed 3 h after the morning dose: C3) was performed. Cases of isoniazid-induced hepatotoxicity were diagnosed according to Benichou et al. Receiver Operating Characteristics curve analysis was used to evaluate the relationship between risk factors and the incidence of IIH. Eleven (15.4%) patients have developed IIH. Demographic factors, including age, weight and gender were not associated with the incidence of hepatotoxicity. High serum concentration of isoniazid (C3) was found to be a risk factor of IIH (area under the curve: 0.74, P=0.007, 95% confidence interval (95% CI): 0.56-0.93), with a cutoff value at 3.69 mg l-1 (odds ratio (OR): 13.2, P=0.0007, 95% CI: 2.9-59). Multivariate analysis showed that only a C3 over 3.69 mg l-1 remains a risk factor of IIH. NAT2 and CYP2E1 variants were not found to increase the risk of IIH when analyzed separately. However, combined analysis of the NAT2/CYP2E1 gene polymorphisms showed that patients with both DraI C/D and slow acetylator have an increased risk of IIH compared with other combined NAT2/CYP2E1 genotype profiles (OR: 8.41, P=0.01, 95% CI: 1.54-45.76). Our results suggest that a serum concentration of isoniazid over 3.69 mg l-1 and a combined genotype CYP2E1 DraI(C/D)/slow acetylator are major risk factors for IIH. Therefore, TDM of isoniazid and the determination of both NAT2 and CYP2E1 genotypes could be useful for the prediction and prevention of IIH in Tunisian tuberculosis patients.

Association of CYP2E1 genetic polymorphism with risk of Oral pre cancer and cancer in North Indian population

Purpose: To evaluate the association of CYP2E1 promoter (-1091) C/T polymorphisms with the susceptibility of Oral pre cancer and cancer patients in North Indian population. Methods: A total 250 patients with oral pre cancer and cancer, 250 controls were genotypes for the CYP2E1 (C1091T) gene polymorphism. Genotypes were identified by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). Genotype frequencies were evaluated by Chi-square test and Odds ratio (OR) relative risk. Results: The average CYP2E1(C1091T) genotype frequencies of CC, CT and TT were calculated 80.80%, 5.20%, 14.00% in cases and 54.80%, 13.20% and 32.00% in healthy controls; respectively. Conclusion: We conclude that the CYP2E1 (C1091T) polymorphism was significantly associated in Oral pre cancer and cancer patients.

Characterization of polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 and relationship to the alcoholism in a Colombian population

Identify and characterize polymorphisms of genes ADH2, ADH3, ALDH2 and CYP2E1 in a Colombian population residing in the city of Bogotá and determine its possible relationship to the alcoholism. ADH2, ADH3, ALDH2, and CYP2E1 genotypes a population of 148 individuals with non-problematic alcohol and 65 individuals with alcoholism were determined with TaqMan probes and PCR-RFLP. DNA was obtained from peripheral blood white cells. Significant difference was found in family history of alcoholism and use of other psychoactive substances to compare alcoholics with controls. When allelic frequencies for each category (gender) were considered, frequency of A2 allele carriers in ADH2 was found higher in male patients than controls. In women, the relative frequency for c1 allele in CYP2E1 was lower in controls than alcoholics. The ALDH2 locus is monomorphic. No significant differences in allele distributions of the loci examined to compare two populations were observed, however when stratifying the same trend was found that these differences tended to be significant. This study allows us to conclude the positive association between family history of alcoholism and alcoholism suggesting that there is a favourable hereditary predisposition. Since substance dependence requires interaction of multiple genes, the combination of genotypes ADH2 * 2, CYP2E1 * 1 combined with genotype homozygous ALDH2 * 1 found in this study could be leading to the population to a potential risk to alcoholism.

Association of Polymorphisms of Phase I Metabolizing Genes with Sister Chromatid Exchanges in Occupational Workers Exposed to Toluene Used in Paint Thinners.

This study investigated genetic damage in paint workers mainly exposed to toluene as it is a major solvent used in paint thinners. Sister chromatid exchange (SCE) assay was used as biomarker of genotoxicity. Blood samples were collected from 30 paint workers and 30 control subjects matched with respect to age and other confounding factors except for exposure to toluene. SCE frequency was found to be significantly higher in paint workers (4.81 ± 0.92) as compared to control individuals (1.73 ± 0.54) (p < 0.05). We also investigated influence of polymorphisms of CYP2E1 and CYP1A1m2 genes on SCE frequency. Our results showed that there was significant increase in frequencies of SCE among the mutant genotypes of CYP2E1 and CYP1A1m2 as compared to wild genotypes. Our study indicated that long term exposure of toluene can increase genotoxic risk in paint workers.

Family history of cancer and the risk of squamous cell carcinoma of oesophagus: a case-control study in Kashmir, India.

Background:Only a few studies have examined the association between family history of cancer (FHC) and the risk of oesophageal squamous cell carcinoma (ESCC) in high incidence areas of ESCC. We conducted a case–control study to evaluate the relationship between FHC and ESCC risk in Kashmir, India, with analysis of detailed epidemiological data and information on multiple gene polymorphisms.Methods:We collected detailed information on FHC and a number of socio-demographic and lifestyle factors, and also obtained blood samples for genetic analysis from 703 histopathologically confirmed ESCC cases and 1664 individually matched controls. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs).Results:Participants who had FHC showed a strong association with ESCC risk, and the risk was stronger when first-degree relatives (FDRs) had FHC (OR=6.8; 95% CI=4.6–9.9). Having a sibling with a cancer showed the strongest association (OR=10.8; 95% CI=6.0–19.3), but having a child with a cancer was not associated with ESCC risk. A history of any cancer in the spouse was also associated with ESCC risk (OR=4.1; 95% CI=1.6–10.2). Those with two or more relatives with FHC were at a higher risk of ESCC. After restricting FHC to familial ESCC only, the above associations were strengthened, except when spouses were affected with ESCC (OR=2.5; 95% CI=0.7–8.9). When we examined the associations between several single-nucleotide polymorphisms and ESCC in those with and without FHC, the associations of variant genotypes in cytochrome P450 (CYP) 2C19 and CYP2D6 and the wild genotype of CYP2E1 with ESCC were much stronger in those with FHC. The FHC had an additive interaction with several risk factors of ESCC in this population.Conclusion:Our results showed that FHC was strongly associated with ESCC risk in Kashmir. It seems both genetic factors and shared environment are involved in this association.

Polymorphic Variants of Cytochrome P450: Relevance to Cancer and Other Diseases.

Associations of cytochrome P450 (CYP) polymorphisms with risk of disease development have been reported widely. For lung cancer, a large number of studies on CYP1A1, CYP2D6, and CYP2A6 polymorphisms have been performed. However, recent studies, including meta-analyses and genome-wide association studies, suggest that only the CYP2A6 association, where genotypes associated with low activity decrease susceptibility possibly due to slower nicotine metabolism, appears significant. Associations with lung cancer susceptibility have also been reported for CYP1A2, CYP1B1, and CYP2E1 polymorphisms but these, though biologically plausible, have not been well replicated. For cancers where exposure to xenobiotics other than tobacco smoke affects risk, CYP polymorphisms may also be relevant. Examples include CYP3A for hepatocellular carcinoma due to aflatoxin exposure, CYP1A2 for colon cancer associated with heterocyclic arylamine exposure and CYP2E1 for nitrosamine-related nasopharyngeal cancer. For other diseases, a well-established example relates to CYP1B1 where homozygosity for rare mutations occurs in primary congenital glaucoma. Rare CYP1B1 mutations and possibly polymorphisms may also contribute to risk for more common forms of glaucoma. CYP2C isoforms and CYP2J2 contribute to extrahepatic metabolism of arachidonic acid to epoxyeicosanoic acids which have effects in the cardiovascular system. Genotype for these isoforms may be relevant to risk of cardiovascular disease but evidence is still lacking. CYP2C19 poor metabolizers may be at increased risk of endometriosis, and CYP2E1 genotype may modulate risk of development of alcoholic liver disease. In conclusion, CYP polymorphisms are relevant to risk for some diseases but this may have been overstated in earlier studies.

Screening of susceptibility genes and multi-gene risk analysis in gastric cancer.

The aim of the study was to explore the relations between the genetic polymorphism and the susceptibility to the gastric cancer in Chinese Han population, and to analyze the multi-genes risk in the development of gastric carcinoma. A case-control study of 1:1 matching was performed on 564 individuals with primary gastric carcinoma in Nanjing, China. The genotypes of CYP2E1, GSTMl, GSTTl, NAT2, ALDH2, MTHFR, XRCCl, IL-1β, VDR, and TNF were detected by molecular biological techniques (PCR-RFLP and AS-PCR). Sole gene and gene-gene interactions were analyzed using Logistic regression model. The effect of multi-genes on gastric carcinoma was analyzed using multi-gene risk analysis model, which focused on the effect of multi-gene interaction on the development of gastric carcinoma. The genotypes involved in the susceptibility of gastric carcinoma were CYP2E1(c1/c1), NAT2M1(T/T), NAT2M2(A/A), XRCC1194(T/T), NAT2 phenotype (slow acetylator), MTHFR1298(A/C), and VDR TaqI(T/T), respectively. Multi-gene risk analysis model was introduced to analyze the effect of these genes on the gastric carcinoma. The results showed that there was a strong relation between odds ratio (OR) value of polygene combination and the gene frequency. With the increase of susceptibility gene frequency, the risk distribution curve of gastric carcinoma would shift to a more dangerous phase and exhibit a quantitative relation. Our results demonstrated that the OR of each gene can be utilized as an index to assess the effect of multiple susceptible genes on the occurrence of gastric carcinoma.

Genetic polymorphisms of CYP2E1 and GSTM1 loci and susceptibility to anti-tuberculosis drug-induced hepatotoxicity.

Host genetic factors that influence predisposition to anti-tuberculosis drug-induced hepatotoxicity (DIH) are not clear in the Indian population. To investigate the possible association of DIH with polymorphism at the RsaI site of the 5-prime untranslated region of CYP2E1 and GSTM1 'null' mutations. In this prospective study, 113 tuberculosis (TB) patients with DIH and 201 TB patients receiving anti-tuberculosis treatment without developing hepatotoxicity (non-DIH) constituted cases and controls, respectively. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to analyse genetic polymorphisms of CYP450 2E1 at the RsaI site and 'null' GSTM1 mutations. PCR-RFLP results were compared between 185 non-DIH and 105 DIH patients A high frequency of c1c1 genotypes of CYP2E1 was commonly encountered, and the difference between DIH and non-DIH patients was not significant (75.14% vs. 77.14%). The genotypic distribution of c2c2 was significantly higher in the DIH than in the non-DIH group (4.8% vs. 0.5%, OR 8.58, P = 0.03). However, adjustment for age, sex and serum albumin differences yielded an OR of 2.75, making it non-significant (P = 0.26). Homozygous 'null' mutation frequencies at the GSTM1 gene in DIH and non-DIH patients were observed that were not significantly different (40% and 37%, respectively, P = 0.61). RsaI variants of the CYP2E1 gene and GSTM1 'null' mutation were not associated with risk of DIH in a north Indian population.