Genetic polymorphism of microsomal epoxide hydrolase enzyme gene in preeclamptic females

IntroductionMicrosomal epoxide hydrolase enzyme is involved in xenobiotics detoxification. It catalyzes the phase I hydrolysis of epoxides and plays a role in the detoxification processes and in the metabolism of endogenous and exogenous compounds. Preeclampsia, which is one of the most serious complications of pregnancy, may be due to an imbalance between these compounds, such as lipid peroxides and oxygen-free radicals and detoxifying and scavenging substances. Two variants of human epoxide hydrolase enzyme with different enzyme activity have been described; exon 3 polymorphism is associated with lower enzyme activity whereas exon 4 polymorphism is associated with higher activity. The authors tried to investigate the association between these genetic polymorphisms and preeclampsia.MethodThirty preeclamptic females together with 30 normal pregnant females as controls were included in the study. Genotyping for exons 3 and 4 of microsomal epoxide hydrolase enzyme was done by polymerase chain reaction–restriction fragment length polymorphism.ResultsThere was no statistical significant difference in the distribution of exon 3 genotype between cases and controls (P = 0.4); on the other hand, a highly statistical significant difference was found between cases and controls as regard exon 4 genotype (P = 0.002).ConclusionThere may be an association between epoxide hydrolase enzyme polymorphism and the risk of preeclampsia.     

Genetic polymorphisms in biotransformation enzymes in Crohn's disease: association with microsomal epoxide hydrolase

BACKGROUND: Mucosal biotransformation enzymes can modify toxic compounds in the gut. As chemical or oxidative stress may be involved in the aetiology of Crohn's disease, genes encoding for enzymes involved in the prevention of such stress may be candidates for genetic susceptibility to Crohn's disease. Aim: To assess the association of Crohn's disease with genetic polymorphisms in cytochrome P450 1A1, glutathione S-transferases mu-1, pi-1, and theta-1, and epoxide hydrolase. METHODS: chi(2) square analysis was used to compare frequencies of polymorphisms between 151 patients with Crohn's disease and 149 healthy controls. RESULTS: In patients, a genetic polymorphism in exon 3 of the microsomal epoxide hydrolase gene was distributed significantly different compared with controls (chi(2)=23.7; p<0.0001). All other polymorphisms tested were equally distributed between patients and controls. CONCLUSIONS: Microsomal epoxide hydrolase may play a role in the pathophysiology of Crohn's disease. Furthermore, the epoxide hydrolase gene is located on chromosome 1q, close to a region previously linked to Crohn's disease.     

A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease

BACKGROUND AND AIMS: Factors influencing the progression of chronic hepatitis C virus (HCV) infection are poorly understood. Monocyte chemotactic protein-1 (MCP-1) is a potent chemokine, and its hepatic expression is up-regulated during chronic HCV infection mainly in activated hepatic stellate cells (HSC). In this study, we investigated the correlation of the functional -2518 MCP-1 promoter polymorphism with hepatic MCP-1 expression and the disease outcome in patients with HCV. METHODS: MCP-1 genotyping was performed in 206 patients and 139 healthy controls. Hepatic MCP-1 messenger RNA (mRNA) expression was quantified by real-time PCR in 58 HCV patients. Cytokine-induced MCP-1 secretion of activated human HSC (n = 13) was determined by enzyme-linked immunosorbent assay (ELISA). Mobility-shift assays were performed using probes corresponding to the MCP-1 promoter sequence (-2511 to -2528) with or without the A to G mutation at -2518. RESULTS: Frequency of MCP-1 genotypes did not differ between HCV patients and controls. However, carriers of the G allele were significantly more frequent in HCV patients with more advanced fibrosis and severe inflammation. In accordance, hepatic MCP-1 mRNA levels were significantly higher in patients with more advanced fibrosis and in patients carrying the G allele. Furthermore, cytokine-induced MCP-1 secretion of HSC isolated from carriers of the G allele was significantly higher, and there was binding activity in nuclear extracts from activated HSC specifically to the G allele, providing a potential mechanism for the differences seen. CONCLUSIONS: Inheritance of the -2518 MCP-1 G allele, which appears to affect hepatic MCP-1 expression, may predispose HCV patients to more severe hepatic inflammation and fibrosis.     

Association between polymorphisms of microsomal epoxide hydrolase and COPD: results from meta-analyses

Background and objective: COPD is a complex polygenic disease in which gene–environment interactions are very important. The gene encoding microsomal epoxide hydrolase (EPHX1) is one of several candidate loci for COPD pathogenesis and is highly polymorphic. Based χ on the polymorphisms of EPHX1 gene (tyrosine/histidine 113, histidine/arginine 139), the population can be classified into four groups of putative EPHX1 phenotypes (fast, normal, slow and very slow). A number of studies have investigated the association between the genotypes and phenotypes of EPHX1 and COPD susceptibility in different populations, with inconsistent results. A systematic review and meta‐analysis of the published data was performed to gain a clearer understanding of this association. Methods: The MEDLINE database was searched for case–control studies published from 1966 to August 2007. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Results: Sixteen eligible studies, comprising 1847 patients with COPD and 2455 controls, were included in the meta‐analysis. The pooled result showed that the EPHX1 113 mutant homozygote was significantly associated with an increased risk of COPD (OR 1.59, 95% CI: 1.14–2.21). Subgroup analysis supported the result in the Asian population, but not in the Caucasian population. When the analysis was limited to only the larger‐sample‐size studies, studies in which controls were in Hardy–Weinberg equilibrium and studies in which controls were smokers/ex‐smokers, the pooled results supported the conclusion. The EPHX1 139 heterozygote protected against the development of COPD in the Asian population, but not in the Caucasian population. The other gene types of EPHX1 113 and EPHX1 139 were not associated with an increased risk of COPD. The slow activity phenotype of EPHX1 was associated with an increased risk of COPD. The fast activity phenotype of EPHX1 was a protective factor for developing COPD in the Asian population, but not in the Caucasian population. However, the very slow activity phenotype of EPHX1 was a risk for developing COPD in the Caucasian population, but not in the Asian population. Conclusions: The polymorphisms of EPHX1 113 and EPHX1 139 are genetic contributors to COPD susceptibility in Asian populations. The phenotypes of EPHX1 were contributors to overall COPD susceptibility.     

Gene polymorphism for microsomal epoxide hydrolase and susceptibility to emphysema in a Japanese population.

Recently, it was reported that gene polymorphism for microsomal epoxide hydrolase (mEPHX), an enzyme involved in the first-pass metabolism of epoxide intermediates, was associated with susceptibility to emphysema. This association was examined in a Japanese population, performing polymerase chain reaction (PCR)-based direct sequencing and restriction fragment length polymorphism assays for variant forms of mEPHX. The subjects consisted of 79 smokers with moderate to severe emphysema diagnosed by lung computed tomography scans, 58 smokers without emphysema, with a comparable smoking history, and 114 consecutive subjects who undertook annual health checkups. The allele frequency of exon 3 Tyr113 to His113, which was reported to confer slow mEPHX activity, was substantially higher in the population control group compared with that of the Caucasian control subjects in a previous study. However, neither the genotype distribution of exon 3, nor that of exon 4 His139 to Arg139, was significantly different between the two groups of smokers. These data indicate that the gene polymorphism for mEPHX is not associated with susceptibility to emphysema in the Japanese population. The discrepancy between the two studies may be explained either by racial difference or by the selection bias of subjects in the previous study, which examined those who had only mild to moderate emphysema with lung cancer or those who were clinically diagnosed as having chronic obstructive pulmonary disease.     

Combined analysis of polymorphisms in glutathione S-transferase M1 and microsomal epoxide hydrolase in lung cancer patients

Many genes involved in the metabolism of carcinogens have been found to be polymorphic in the human population, and specific alleles are associated with increased risk of cancer at various sites. The etiology of most commonly occurring cancers cannot be explained by allelic variability at a single locus. A combined analysis of two polymorphic enzymes, glutathione S-transferase M1 (GSTM1), microsomal epoxide hydrolase (EPHX1)) and their implication as lung cancer risk factors was performed in a case- control study of non small cell lung cancer. Polymerase chain reaction (PCR) or PCR-RFLP-based methods were used to detect variant genotypes of GSTM1 and EPHX1 (113Tyr-113His in exon 3 and 139His-139Arg in exon 4) in 150 controls and group of lung cancer patients (n=121). The slow 113His EPHX1 allele tended to be more frequent among the patients (frequency 0.587) than among the controls (0.320) (Fisher s exact test, p=0.33). The combined EPHX1 homozygote genotype His113/His139 (predicted very slow activity) versus all other genotype combination was associated with an increased risk of lung cancer (OR=2.29; 95% C.I.=0.94- 5.82), particularly in non-smokers (OR=11.23; 95% C.I.=1.48- 88.41). Polymorphism in GSTM1 had no statistically significant impact on lung cancer risk alone (OR=1.09; 95% C.I.: 0.65-1.82). However, obtained the results revealed that combinations GSTM1 null with homozygote His113/His139 genotype (predicted very slow activity EPHX1) significantly increased lung cancer risk (OR=3.65; 95% C.I.: 1.04-16.07). No overall relationship between genotype combinations predicted high EPHX1 activity and lung cancer risk was confirmed in all followed respects. However, the number of investigated individuals in our study was relatively small, therefore these findings should be judged with circumspectness.     

中国北方汉族人微粒体环氧化物水解酶基因多态性与慢性阻塞性肺疾病易感性的关系

目的 探讨中国北方汉族人微粒体环氧化物水解酶基因多态性与慢性阻塞性肺疾病（COPD）易感性的关系。方法 应用聚合酶链反应限制性片段长度多态性法,检测微粒体环氧化物水解酶基因型在55例中国北方汉族人吸烟COPD患者和52例健康吸烟者中频率的分布。结果 55斧正吸烟COPD患者微粒体环氧化物水解酶外显子3的同源野生型,杂合型,同源突变型频率分布分别为27.3%(15/55)、27.3%(15/55),45.5%(25/55）,外显子4的同源野生型,杂合型,同源突变型频率分布分别为72.7%(40/55),18.2%(10/55),9.1%(5/55),与52例健康吸烟者的分布比较差异无显著性。结论 微粒体环氧化物水解酶基因与中国北方汉族人COPD易感性无关。     

Genetic polymorphisms in microsomal epoxide hydrolase and susceptibility to adult acute myeloid leukaemia with defined cytogenetic abnormalities

Acute myeloid leukaemia (AML) cases with different chromosomal abnormalities may reflect different aetiologies. Benzene exposure, from a number of sources including smoking, is one risk factor for AML. Individual susceptibility to benzene may depend on differences in expression of metabolizing enzymes. We tested the hypothesis that smoking as well as genetic polymorphisms in the microsomal epoxide hydrolase gene (HYL1), an enzyme involved in benzene metabolism, could be risk factors for AML with defined chromosomal abnormalities. Twenty-six AML cases with -7/del(7q) and 24 cases with t(8;21), as well as 43 cases with normal karyotype and 155 age-, sex- and residence-matched controls, were drawn from a large case-control study on adult acute leukaemia. Current smoking was significantly associated with the cytogenetic abnormalities t(8;21) or -7/del(7q) (OR = 4.9; 95%CI = 2.1-11.5) but not with a normal karyotype, relative to individuals who were not current smokers. A putative high activity HYL1 phenotype [exon 3, residue 113 (Tyr/Tyr) and exon 4, residue 139 (His/Arg or Arg/Arg)] was associated with a significantly increased AML risk in men with -7/del(7q) or t(8;21) (OR = 4.4; 95%CI 1.1-17.0) but not with a normal karyotype. This suggests that AML cases with defined chromosomal abnormalities could be related to specific carcinogen exposures and, furthermore, suggests that smoking and genetic polymorphisms in HYL1 could be risk factors for AML with -7/del(7q) or t(8;21).     

DNA oxidative damage in leukocytes correlates with the severity of HCV-related liver disease: validation in an open population study

BACKGROUND/AIMS: Oxidative DNA damage, identifiable in the formation of 8-hydroxydeoxyguanosine (8-OHdG), is relevant in the mutagenesis/carcinogenesis process. The aim of this study was to assess 8-OHdG levels in patients with hepatitis C virus (HCV) infection in relation to extent of liver damage and HCV genotype. METHODS: 8-OHdG levels were measured in DNA from circulating leukocytes of 110 anti-HCV positive subjects belonging to the population of the Dionysos study, subgrouped in: 50 anti-HCV+ with persistently normal ALT, 48 with chronic hepatitis and 12 with cirrhosis. Twenty normal subjects served as Controls. 8-OHdG levels were assayed by HPLC/electrochemical detector. RESULTS: 8-OHdG levels rose (P < 0.00001) from Controls to HCV+; chronic hepatitis and cirrhosis were associated with a further increase (P < 0.02 versus HCV+). Genotype 1 was associated with higher levels of 8-OHdG (P < 0.04). Multiple logistic regression analysis showed that, after correction for potential confoundings, 8-OHdG levels correlated (P < 0.02) with presence and extent of liver damage. CONCLUSIONS: An accumulation of 8-OHdG in circulating leukocytes is a reliable marker of the extent of liver damage in HCV+ patients and is present in particular in genotype 1 infection. This genomic damage may contribute to liver carcinogenesis by causing persistent DNA changes.     

A model to predict severe HCV-related disease following liver transplantation

Post-transplantation recurrence is increasing in patients with HCV. Early antiviral therapy may be of benefit in this setting. Thus, accurate and early prediction of progression may help select candidates for treatment. We developed a model based on pre- and/or early post-transplantation variables, which may predict progression to severe disease. Clinical and histologic outcomes were assessed in 554 liver recipients. A total of 1,353 biopsy specimens obtained after 1 year (median of 2 biopsies per patient; range, 1-8) were scored. Two outcome measures were used: cumulative probability of developing severe disease (fibrosis 3 and 4) within 5 years and actual progression to severe disease in 2 years. We used Cox proportional hazard survival analysis for the whole cohort. Predictors analyzed included HCV genotype and recipient, donor, and transplant-related variables. The cumulative risk of progressing to fibrosis 3 and 4 was significantly greater in patients transplanted recently (P <.001) and was present in all centers. Factors increasing this risk were genotype, induction with mycophenolate, donor age, short course of azathioprine, and prednisone (<12 months). To create a model of prediction, 285 patients with 2-year follow-up were used to create a logistic regression analysis. The estimated probability of being at high risk for severe disease was calculated from a formula that included donor age and recipient therapy as critical variables. In conclusion, we have developed a model that uses early post-transplantation variables to predict severe HCV recurrence. Accuracy of the model is not perfect (c-statistic 0.80), probably reflecting the complexity of HCV in the liver transplant setting.     

Survival and prognostic factors of HIV-infected patients with HCV-related end-stage liver disease

OBJECTIVE: To find the survival and the predictors of death of HIV-infected patients with hepatitis C virus (HCV)-related end-stage liver disease (ESLD). DESIGN AND METHODS: A prospective cohort study set in the infectious diseases units of four tertiary care public hospitals in Andalucía, Spain. From a multicentric cohort of 2664 HIV/HCV-co-infected patients, all consecutive patients with HCV-related cirrhosis who presented with the first hepatic decompensation from January 1997 to June 2004 were followed-up and 153 patients were included. The survival and the demographic, HIV-related and liver-related factors associated with death were evaluated. RESULTS: Ninety-five (62%) patients died during the follow-up. In 79 (85%) individuals, the cause of death was liver related. The median survival time was 13 months. Independent predictors of survival were Child score [hazard ratio (HR), 1.2; 95% confidence interval (CI), 1.08-1.37; P = 0.001], CD4+ cell count at decompensation lower than 100 cells/microl (HR, 2.48; 95% CI, 1.52-4.06; P < 0.001) and hepatic encephalopathy as the first hepatic decompensation (HR, 2.45; 95% CI, 1.41-4.27; P = 0.001). HAART was prescribed to 101 (66%) patients. The cumulative probability of survival in patients under HAART was 60% at 1 year and 40% at 3 years, versus 38 and 18%, respectively, in patients not treated with HAART (P < 0.0001). The HR (95% CI) of death in patients on HAART was 0.5 (0.3-0.9), (P = 0.03). CONCLUSIONS The survival of HIV/HCV-co-infected patients with ESLD is extremely poor. Immunosuppression and markers of severe liver disease predict liver-related mortality in these patients. HAART seems to be associated with a reduced liver-related mortality.     

Clinical outcomes following DAA therapy in patients with HCV-related cirrhosis depend on disease severity

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