CYP2E1 RsaI Polymorphism Research Articles

CYP genetic variants and toxicity related to anti-tubercular agents: a systematic review and meta-analysis

BackgroundTreatment with anti-tuberculosis drugs may cause patients to experience serious adverse effects. Genetic factors, such as polymorphisms of CYP genes, may increase the likelihood of a patient experiencing such adverse drug reactions. In this systematic review and meta-analysis, we synthesised evidence for associations between CYP genetic variants and anti-tuberculosis drug-related toxicity outcomes.MethodsWe searched MEDLINE, PubMed, EMBASE, BIOSIS and Web of Science to identify relevant studies. We performed meta-analyses to obtain an effect estimate for each genetic variant on each outcome, and stratified all analyses by country. We qualitatively assessed the methodological quality of the included studies.ResultsWe included data from 28 distinct cohorts of patients in the review. We identified many areas of concern with regard to the quality of included studies. Patients with homozygous mutant-type or heterozygous genotype at the CYP2E1 RsaI polymorphism were significantly less likely to experience hepatotoxicity than patients with homozygous wild-type genotype (odds ratio [OR] = 0.75, 95% confidence interval [CI] 0.56–1.00; p = 0.047, I2 = 58.2%). No significant differences were observed for the CYP2E1 DraI and PstI polymorphisms. For the 96-bp deletion-insertion single-nucleotide polymorphism (SNP) of the CYP2E1 gene, homozygous mutant-type significantly increased hepatotoxicity risk compared with homozygous wild-type (OR = 8.20, 95% CI 1.38–48.68, I2 = 0%); no significant difference was observed for heterozygous genotype compared with homozygous wild-type (OR = 0.77, 95% CI 0.19–3.21, I2 = 0%).ConclusionsGenerally, we identified that coverage of the association between SNPs of CYP genes and anti-tuberculosis drug-related toxicity outcomes is incomplete. We observed significant associations between the RsaI and 96-bp deletion-insertion SNPs of the CYP2E1 gene and anti-tuberculosis drug-related hepatotoxicity. We were unable to comment on the impact of ethnicity on the investigated associations, as information on participants’ ethnicity was sparsely reported in the included studies.Systematic review registrationPROSPERO registration number: CRD42017068448.

CYP2E1 and GSTM1 gene polymorphisms, environmental factors, and the susceptibility to lung cancer.

To investigate the relationships between the CYP2E1 RsaI polymorphism, GSTM1 polymorphism, and the susceptibility to lung cancer, along with the interactions between environmental factors and these genes. A case-control study was carried out to explore the independent effect of gene polymorphisms on risk of lung cancer, and the combined effects of gene loci. The stratification analysis of age, sex, smoking, and drinking combined with positive loci was also analyzed, and any interaction was identified. The logistic regression analysis showed that there were statistical relationships between the CYP2E1 RsaI TT genotype and lung cancer, GSTM1 (-) and lung cancer. The combined effect's analysis of these 2 loci showed that, with an increase in the number of risk alleles, the risk of lung cancer also increased (supposing 0 risk allele as the reference group). Subjects carrying 3 risk alleles had the highest risk of developing lung cancer with an adjusted OR=10.38 (95% CI 2.10-51.35). Stratified analysis showed that, in women, nonsmoking subjects, or nondrinking subjects, the combined effects could increase the risk of lung cancer; no heterogeneity was found between these layers except sex. The interaction analysis showed that, supposing the male, GSTM1 (+) genotype as the reference, the female, GSTM1 (-) genotype had a significantly increased risk of lung cancer (OR=2.17 [1.01-4.70]); when the non-smoking, GSTM1 (+) genotype subjects was the reference group, smoking, GSTM1 (+) genotype subjects and smoking, GSTM1 (-) genotype subjects had significantly higher risk of lung cancer (OR=2.00 [1.01-3.96], OR=2.89 [1.28-6.54]). CYP2E1 RsaI TT genotype was a protective factor against the development of lung cancer, while GSTM1 (-) genotype was a risk factor for lung cancer. Increases in the number of the risk alleles also increased lung cancer risk. GSTM1 (-) genotype, sex, and smoking status might interact in the incidence of lung cancer.

Association between the CYP2E1 polymorphisms and lung cancer risk: a meta-analysis.

The previous, published data on the association between CYP2E1 RsaI (rs2031920), DraI (rs6413432) polymorphisms and lung cancer risk remained controversial. Hence, we performed a meta-analysis to investigate the association between lung cancer and CYP2E1 RsaI (5,074 cases and 6,828 controls from 34 studies), and CYP2E1 DraI (2,093 cases and 2,508 controls from 16 studies) in different inheritance models. Overall, significantly decreased lung cancer risk was observed (dominant model: odds ratio (OR) 0.80, 95 % confidence interval (95 % CI) 0.71-0.90; heterozygote model: OR 0.80, 95 % CI 0.70-0.90; additive model: OR 0.82, 95 % CI 0.72-0.94) when all the eligible studies were pooled into the meta-analysis of CYP2E1 RsaI polymorphism. In further stratified and sensitivity analyses, significantly decreased lung cancer risk was found among Asians (dominant model: OR 0.81, 95 % CI 0.71-0.93; heterozygous model: OR 0.81, 95 % CI 0.69-0.95), population-based studies (dominant model: OR 0.69, 95 % CI 0.54-0.88; recessive model: OR 0.39, 95 % CI 0.16-0.91; additive model: OR 0.67, 95 % CI 0.53-0.84; homozygous model: OR 0.34, 95 % CI 0.14-0.80; heterozygous model: OR 0.70, 95 % CI 0.54-0.91), hospital-based studies (dominant model: OR 0.80, 95 % CI 0.69-0.93; additive model: OR 0.84, 95 % CI 0.70-1.00; heterozygous model: OR 0.80, 95 % CI 0.68-0.95), lung AC (heterozygous model: OR 0.84, 95 % CI 0.71-1.00), smokers (dominant model: OR 0.72, 95 % CI 0.55-0.94), and non-smokers (dominant model: OR 0.74, 95 % CI 0.61-0.91). There was no significant association between CYP2E1 DraI polymorphism and the risk of lung cancer when all the eligible studies were pooled into the meta-analysis. However, in further stratified and sensitivity analyses, significant association was observed among smokers (dominant model: OR 0.49, 95 % CI 0.35-0.69). In summary, this meta-analysis indicates that CYP2E1 RsaI polymorphism is associated with lung cancer risk among Asians, CYP2E1 RsaI polymorphism may be associated with lung adenocarcinoma risk, and CYP2E1 RsaI and DraI polymorphisms may be associated with decreased lung cancer risk in smokers.

RsaI but not DraI polymorphism in CYP2E1 gene increases the risk of gastrointestinal cancer in Malaysians: a case–control study

ObjectivesOur study aimed to investigate the association of CYP2E1 C-1019T RsaI and T7678A DraI polymorphisms and factors such as age, gender and ethnicity to the risk of gastrointestinal cancer (GIC)...

Genetic variants of the cytochrome P450 and glutathione S‐transferase associated with risk of bladder cancer in a south‐eastern Chinese population

To evaluate the association between genetic polymorphisms of CYP2E1 RsaI and GSTM1 and development of bladder cancer in a south-eastern Han Chinese population. We hypothesized that the CYP2E1-1019T>A and GSTM1 polymorphisms were associated with risk of bladder cancer. In a hospital-based case-control study of 202 case patients with newly diagnosed bladder transitional cell carcinoma and 272 cancer-free controls frequency-matched by the age and sex, we genotyped these two polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism method. We found that the GSTM1 null genotype was associated with an increased risk of bladder cancer (adjusted odds ratio [OR] = 1.73, 95% confidence interval [CI] = 1.17-2.56) compared with those with the non-null genotype, but the CYP2E1-1019T>A polymorphisms did not show any association. In the stratification analysis of the GSTM1 polymorphism, we found that the increased risk was more pronounced among subgroups aged < or =60 years (OR = 2.02, 95% CI = 1.08-3.77), smokers (OR = 1.94, 95% CI = 1.11-3.38) and non-drinkers (OR = 3.86, 95% CI = 1.28-11.60). GSTM1 polymorphism (but not CYP2E1 RsaI polymorphism) appears to contribute to the etiology of bladder cancer in a south-eastern Chinese population.

Association of metabolic gene polymorphisms with alcohol consumption in controls

The objectives were to study the association between metabolic genes involved in alcohol metabolism (CYP2E1 RsaI, CYP2E1 DraI, ADH1C, NQO1) and alcohol consumption in a large sample of healthy controls. Healthy subjects were selected from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). Subjects with information on both alcohol consumption and at least one of the studied polymorphisms were included in the analysis (n=2224). Information on the amount of alcohol consumption was available for a subset of subjects (n=844). None of the studied genes was significantly associated with drinking habits. A significant heterogeneity with age was observed when studying the association between CYP2E1 RsaI and alcohol drinking. CYP2E1 RsaI polymorphism was significantly associated with being a never drinker at older ages (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.2–4.8; at ages above 68 years), while the association was reversed at ages below 47 years (OR 0.5, 95% CI 0.2–1.4). For subjects with detailed information on alcohol intake, no association between alcohol quantity and polymorphisms in metabolic genes was observed; subjects carrying the NQO1 polymorphism tended to drink more than subjects carrying the wild-type alleles. Therefore, no significant association between CYP2E1 RsaI, CYP2E1 DraI, ADH1C, NQO1 polymorphisms and alcohol consumption was observed in healthy controls.

RsaI polymorphism at the cytochrome P4502E1 locus and risk of hepatocellular carcinoma

BACKGROUND: CYP2E1, the coding gene for the ethanol inducible cytochrome P4502E1, is polymorphic at the RsaI restriction site in the 5' flanking region. The mutant allele c2 has a higher transcriptional activity than the wild-type gene c1. P4502E1 catalyses the activation of several environmental carcinogens at a rate that is increased, if only moderately, by longterm ethanol intake. AIMS: To establish the distribution of CYP2E1 RsaI polymorphism in patients with hepatocellular carcinoma and to evaluate its possible role in the multifactorial pathogenesis of this tumour. SUBJECTS: 101 (84 males) patients with hepatocellular carcinoma and 178 (128 males) healthy controls of the same ethnic (white) and Spanish origin. METHODS: After extraction of DNA from white blood cells, alleles c1 and c2 of CYP2E1 were identified by restriction fragment length polymorphism (RFLP) with endonuclease RsaI. RESULTS: Homozygous c1c1: 90 patients and 169 controls; heterozygous c1c2: 11 and 9; homozygous c2c2: none (non-significant difference). C2 allele frequencies: 0.055 in patients, 0.025 in controls (non-significant difference) and 0.108 in the 37 patients who had drunk more than 50 g of ethanol/day (p = 0.0035, odds ratio versus controls: 4.67; 95% confidence limits 1.57 to 13.81). CONCLUSION: The carrier state of one copy of the c2 CYP2E1 gene increases the risk of hepatoma in previously regular ethanol users with chronic liver disease.

RsaI polymorphism at the cytochrome P4502E1 locus and risk of hepatocellular carcinoma.

CYP2E1, the coding gene for the ethanol inducible cytochrome P4502E1, is polymorphic at the RsaI restriction site in the 5' flanking region. The mutant allele c2 has a higher transcriptional activity than the wild-type gene c1. P4502E1 catalyses the activation of several environmental carcinogens at a rate that is increased, if only moderately, by longterm ethanol intake. To establish the distribution of CYP2E1 RsaI polymorphism in patients with hepatocellular carcinoma and to evaluate its possible role in the multifactorial pathogenesis of this tumour. 101 (84 males) patients with hepatocellular carcinoma and 178 (128 males) healthy controls of the same ethnic (white) and Spanish origin. After extraction of DNA from white blood cells, alleles c1 and c2 of CYP2E1 were identified by restriction fragment length polymorphism (RFLP) with endonuclease RsaI. Homozygous c1c1: 90 patients and 169 controls; heterozygous c1c2: 11 and 9; homozygous c2c2: none (non-significant difference). C2 allele frequencies: 0.055 in patients, 0.025 in controls (non-significant difference) and 0.108 in the 37 patients who had drunk more than 50 g of ethanol/day (p = 0.0035, odds ratio versus controls: 4.67; 95% confidence limits 1.57 to 13.81). The carrier state of one copy of the c2 CYP2E1 gene increases the risk of hepatoma in previously regular ethanol users with chronic liver disease.