EPHX1 Polymorphisms Research Articles

Effects of gene polymorphisms of CYP1A1, CYP1B1, EPHX1, NQO1, and NAT2 on urinary 1-nitropyrene metabolite concentrations

Nitropyrene (1-NP) is a specific indicator of exposure to diesel exhaust and is partly metabolized to 1-aminopyrene (1-AP) and N-acetyl-1-aminopyrene (1-NAAP), which are excreted in urine. This study was conducted to evaluate the effects of gene polymorphisms of metabolic enzymes for 1-NP on the urinary concentrations of 1-AP and 1-NAAP. The study participants were 70 South Koreans who were occupationally or environmentally exposed to diesel exhaust. To evaluate 1-NP exposure levels, we sampled airborne particulate matters with a personal air sampler and measured urinary 1-AP and 1-NAAP concentrations. The genetic polymorphisms of the 1-NP metabolic enzymes (CYP1A1, CYP1B1, EPHX1, NQO1, and NAT2) were determined by direct sequencing. The mean 1-NP exposure level was 20.40 pg/m3, and the mean urinary concentrations of 1-AP and 1-NAAP were 0.074 nM and 0.213 nM, respectively. The correlation coefficient between the 1-NP exposure level and urinary 1-AP concentrations was 0.0138 and that between the 1-NP exposure level and urinary 1-NAAP concentrations was 0.1493, and neither correlation coefficient was statistically significant. The correlation coefficient between the 1-NP exposure level and urinary 1-AP concentrations showed statistically significant differences according to the CYP1A1 and CYP1B1 genotypes, and that between the 1-NP exposure level and urinary 1-NAAP concentrations was significantly different according to the CYP1A1, CYP1B1, and NAT2 genotypes. The urinary concentration of 1-NAAP is a better biomarker for exposure to 1-NP or DEPs because the former is higher, easier to measure, and more strongly correlated with 1-NP exposure levels than that of 1-AP. The relationship between 1-NP exposure and urinary 1-AP or 1-NAAP concentration depends on the single nucleotide polymorphism types of CYP1A1, CYP1B1, NQO1, and NAT2.

ABCB1 c.3435C>T and EPHX1 c.416A>G polymorphisms influence plasma carbamazepine concentration, metabolism, and pharmacoresistance in epileptic patients.

The gene polymorphisms of ABCB1, EPHX1, and SCN1A were found to influence carbamazepine (CBZ) metabolism and resistance in epilepsy patients, but the relevance remains controversial. To reveal the relationships among the gene polymorphisms of ABCB1, EPHX1, SCN1A and the metabolism and resistance of CBZ, the databases of PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals, China Biology medicine disc and Wan Fang were retrieved for suitable studies up to April 2021. 18 studies containing 3293 epilepsy patients were included. The result revealed the gene polymorphism of ABCB1 c.3435C>T is significantly associated with altered concentration-dose ratios of CBZ (CDRCBZ) (CC vs. CT, OR=0.25 (95% CI: 0.08-0.42), P=0.004), and EPHX c.416A>G gene polymorphism may also significantly adjusted the concentration-dose ratios of carbamazepine-10, 11-trans dihydrodiol (CDRCBZD) (AA vs. GG, OR=0.48 (95% CI: 0.01-0.96), P=0.045; AG vs. GG, OR=0.68 (95% CI: 0.16-1.20), P=0.010, respectively) and the ratio of CBZD:carbamazepine-10,11-epoxide (CBZE) (CDRCBZD:CDRCBZE) (AG vs GG, OR=0.83 (95% CI: 0.31-1.36), P=0.002). Furthermore, ABCB1 c.3435C>T polymorphism was also observed to be significantly influenced CBZ resistance (CC vs TT, OR=1.78 (95% CI: 1.17-2.72), P=0.008; CT vs TT, OR=1.60 (95% CI: 1.12-2.30), P=0.01; CC+CT vs TT, OR=1.61 (95% CI: 1.15-2.26), P=0.006, respectively). Therefore, CBZ metabolism and resistance in patients with epilepsy may be adjusted by the gene polymorphisms of ABCB1 c.3435C>T and EPHX1 c.416A>G which provides the further scientific basis for clinical individualized therapy of epilepsy. However, larger sample size studies are still needed to provide further conclusive evidence.

Genetic polymorphisms in the mEHgene in relation to tobacco smoking: role in lung cancer susceptibility and survival in north Indianpatients withlungcancerundergoing platinum-based chemotherapy.

Aim: Epoxide hydrolase is involved in oxidative defenses and isresponsible for the activation of carcinogens. The relationship between EPHX1 polymorphisms (Tyr113His and His139Arg)and overall survival (OS) and lung cancer (LC) riskwas investigated. Methods: The study comprised 550 cases and 550 controls. Genotyping and statistical analysis were applied. Results: The variant genotypes of EPHX1 polymorphisms exhibited no association with LC risk. The Tyr113His polymorphism exhibited twofold increased odds of lymph node invasion (p=0.04). The Tyr/His genotype is a risk factor for smokers. Subjects carrying thecombined genotype for His139Arg showed better median survival time(MST)and theheterozygous genotype revealed better MST in the case of small-cell lung cancer(SCLC; 11.30 vs 6.73months;log-rank test: p=0.02). The heterozygous genotype (His139Arg) had longer MST in patients receiving cisplatin/carboplatin and irinotecan (11.30 vs 7.23;log-rank test: p=0.007) Conclusion: The Tyr113His polymorphism is associated with LC risk in smokers and is a potential prognostic factor for OS inpatients withSCLCafter irinotecan.

The Cumulative Effect of Gene-Gene Interactions Between GSTM1, CHRNA3, CHRNA5 and SOD3 Gene Polymorphisms Combined with Smoking on COPD Risk.

BackgroundChronic obstructive pulmonary disease (COPD) is a multifactorial disorder which is affected by external and internal risk factors. People with no external risk factors may be significantly affected and develop pulmonary disease. The study aimed to define gene–gene and gene–environmental effects on COPD.MethodsA case control study involved 181 COPD patients and 292 healthy individuals, with peripheral blood sampling and adequate questionnaires. Genotyping was done with various types of PCR design for GSTM1 (null del), GSTT1 (null del), EPHX1 (rs2234922 and rs1051740), GSTP1 (rs1695 and rs1138272), CHRNA3 (rs1051730 and rs12914385), CHRNA5 (rs16969968 and rs17486278), and SOD3 (rs1799895 and rs699473) gene polymorphisms. Gene–gene and gene–environmental interactions were investigated using multidimensional regression analysis.ResultsFrequency of risk alleles of rs1051730 (p = 0.001), rs16969968 (p <0.001), and rs1799895 (p <0.001) polymorphisms were significant in univariate analysis. For gene–gene interaction, GSTM1 null, rs1051730, rs16969968, and rs1799895 polymorphisms independently contributed to risk of COPD and any combinations of the risk genotypes have a higher risk of disease. A cumulative effect of the four risk polymorphisms increased the risk of COPD for the smoking index (cOR = 13.6, p <0.001), cigarettes per day (cOR = 32.08, p <0.01), nicotine dependence (cOR = 12.0, p <0.01), and smoking status (cOR = 17.02, p <0.01) for gene–environmental interaction.ConclusionSeveral pivotal genes showed distinct effects for COPD, and some synergistic effects affected the disease progression. The development of COPD was synergistically increased with gene–gene and gene–environmental risk factors.

Genetic variants associated with severe cutaneous adverse drug reactions induced by carbamazepine.

Carbamazepine (CBZ) is one of the most common causative drugs of severe cutaneous adverse drug reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reactions with eosinophilia and systemic symptoms. Although genetic polymorphisms of the human leucocyte antigens (HLA) are well recognized key elements for the susceptibility to CBZ-induced SCARs, some evidence suggest that polymorphisms of microsomal epoxide hydrolase 1 (EPHX1) may also contribute to the risk of these SCARs. This study investigated the association between the HLA and EPHX1 polymorphisms on CBZ-induced SCARs in large sample sizes and well-defined SCARs patients. Ninety-one CBZ-induced SCARs Thai patients and 144 CBZ-tolerant patients were enrolled in the study. The genotypes of HLA-A, HLA-B and EPHX1 were determined. Only 2 HLA alleles including HLA-B*15:02 and HLA-A*24:07 were statistically significant association with CBZ-induced SJS/TEN. The highest risk was observed in patients with HLA-B*15:02 allele (OR = 44.33, 95% confidence interval = 20.24-97.09, corrected P-value = 6.80 × 10-29 ). Moreover, HLA-B75 serotypes were significantly associated with CBZ-induced SJS/TEN groups with an odds ratio of 81.00 (95% confidence interval = 32.39-202.56, corrected P-value = 3.84 × 10-34 ). There is no association between EPHX1 c.337 T > C polymorphism and all phenotypes of CBZ-induced SCARs. The HLA-B*15:02 allele is the strongest genetic marker for the prediction of SJS/TEN induced by CBZ in Thai population. Screening for other alleles in the HLA-B75 serotype increases sensitivity for prediction of a life-threatening SCARs caused by CBZ.

Alteration in antioxidant status in slow and fast alleles of EPHX1 gene polymorphisms among wood workers.

Occupational wood dust exposure may be associated with various health effects, especially in wood industry. These effects may be due to inducing oxidative stress which is related to inflammations. Biochemical assessment of antioxidant enzyme activities illustrated role of oxidative stress (OS) on its depletion. Super oxide dismutase, glutathione peroxidase (GPx) and catalase (CAT) were analyzed in 50 exposed workers and 50 control subjects. Also, macrophage inflammatory protein-2 was assessed among these workers as it was produced upon dust exposure. Microsomal epoxide hydrolase (EPHX1) enzyme shared in the protective mechanism against wood dust oxidative stress. It plays a dual role in the metabolism of environmental pollutants, detoxification, and bioactivation. Gene polymorphisms of EPHX1 may be associated with variations in enzyme activity. Polymorphisms in exons 3 and 4 have resulted in either decreased (slow conjugating allele) or increased (fast conjugating allele) activity in vitro. We aimed to evaluate the associations between EPHX1 polymorphisms and change in antioxidant status (SOD, CAT, and GPx) among wood dust exposed workers. EPHX1 genotyping in exon 3 and exon 4 polymorphisms was carried out by PCR-RFLP. Our result shows a significant reduction in enzymatic antioxidants (SOD, CAT, and GPx) levels with significant rise in MIP-2 levels in worker group. Also, there are significant variations in SOD, CAT, and GPx levels as well as in MIP-2 in different genotypes of EPHX polymorphisms in exon 3 or 4 (specially in Hist-Hist genotypes in both exons). We can conclude an alteration in antioxidant status in both slow and fast allele of EPHX gene polymorphisms with release of MIP-2 protein in wood workers.

Regulation of cardiovascular biology by microsomal epoxide hydrolase.

Microsomal epoxide hydrolase/epoxide hydrolase 1 (mEH/EPHX1) works in conjunction with cytochromes P450 to metabolize a variety of compounds, including xenobiotics, pharmaceuticals and endogenous lipids. mEH has been most widely studied for its role in metabolism of xenobiotic and pharmaceutical compounds where it converts hydrophobic and reactive epoxides to hydrophilic diols that are more readily excreted. Inhibition or genetic disruption of mEH can be deleterious in the face of many industrial, environmental or pharmaceutical exposures and EPHX1 polymorphisms are associated with the development of exposure-related cancers. The role of mEH in endogenous epoxy-fatty acid (EpFA) metabolism has been less well studied. In vitro, mEH metabolizes most EpFAs at a far slower rate than soluble epoxide hydrolase (sEH) and has thus been generally considered to exert a minor role in EpFA metabolism in vivo. Indeed, sEH inhibitors or sEH-deficiency increase EpFA levels and are protective in animal models of cardiovascular disease. Recently, however, mEH was found to have a previously unrecognized and substantial role in EpFA metabolism in vivo. While few studies have examined the role of mEH in cardiovascular homeostasis, there is now substantial evidence that mEH can regulate cardiovascular function through regulation of EpFA metabolism. The discovery of a prominent role for mEH in epoxyeicosatrienoic acid (EET) metabolism, in particular, suggests that additional studies on the role of mEH in cardiovascular biology are warranted.

Association between EPHX1 polymorphisms and carbamazepine metabolism in epilepsy: a meta-analysis.

BackgroundEPHX1 gene polymorphisms were recently acknowledged as an important source of individual variability in carbamazepine metabolism, but the result of that association still remains controversial. Aim of the review To obtain a more precise estimation of the associations between EPHX1 polymorphisms and carbamazepine metabolism and resistance. Methods The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure, Chinese Science and Technique Journals Database, China Biology Medicine disc and Wan fang Database were searched for appropriate studies regarding the rs1051740 and rs2234922 polymorphisms of EPHX1 up to September 2019. The meta-analysis was carried out using the Review Manager 5.3 software. The mean difference and 95% confidence interval were applied to assess the strength of the relationship. Results A total of 7 studies involving 1118 related epilepsy patients were included. EPHX1 rs1051740 polymorphism was significantly associated with adjusted concentrations of both carbamazepine (CC vs. TT: P = 0.02; CC vs. CT + TT: P = 0.005) and carbamazepine-10,11-epoxide (CC vs. CT + TT: P = 0.03). Furthermore, EPHX1 rs2234922 polymorphism was also observed to be significantly associated with decreased adjusted concentrations of carbamazepine-10,11-trans dihydrodiol (GG vs. GA + AA: P = 0.04) and CBZD:CBZE ratio (GG vs. AA: P = 0.008; GG vs. GA + AA: P = 0.0008). Nevertheless, the pooled analysis showed that the EPHX1 polymorphisms had no significant effect on CBZ resistance. Conclusion EPHX1 rs1051740 and rs2234922 polymorphisms may affect the carbamazepine metabolism; but carbamazepine resistance was not related to any of the single nucleotide polymorphisms investigated. These findings provided further evidence for individualized therapy of epilepsy patients in clinics.

The potential risk of certain SNPs in EPHX1, NQO1, and PON1 genes among B-Non-Hodgkin Lymphoma patients: An Egyptian case-control study

BackgroundXenobiotic metabolizing enzymes (XME) comprising epoxide hydrolase (EPHX1), NAD(P)H quinone-oxidoreductase 1 (NQO1) and paraoxonase 1 (PON1) are considered crucial for homeostasis and clearance of xenobiotics which involve external as well as internal carcinogens. Polymorphisms of xenobiotic-metabolizing genes are suggested to be implicated in the pathogenesis of various types of cancers. Aim of the workThe aim of the current study was to investigate the influence of inherited genetic polymorphisms of the xenobiotic metabolizing enzymes EPHX1, NQO1 and PON1 on the susceptibility and development of Non-Hodgkin's Lymphomas in a cohort of Egyptian population. Patients and methodsA total of 100 patients with B-non Hodgkin's lymphoma (B-NHL) with mean age of 52 years, together with 75 age and sex matched healthy controls were enrolled in the study for evaluation of Inherited genetic polymorphisms in the xenobiotic metabolizing enzymes EPHX1 (Tyr-His, rs 1,051,740), NQO1 (C609T rs 1,800,566) and PON1 (Codon 192) A-G, Gly (A)-Arg (B), re662 (Q192R) using Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR- RFLP) assay. ResultsThe comparison between the distribution of the different genotypes of EPHX1 (T/C), NQO1 (C/T), PON1 (A/G) revealed no statistically significant difference between the patient and control groups except for the PON1 GG homozygote phenotype (p = 0.016). Further analysis of the influence of the studied genetic polymorphisms on the characteristics of the disease showed that there was no statistical difference between B-NHL patients harboring the wild or the polymorphic genotypes regarding their clinical status and laboratory data. ConclusionThe study suggests that there is no correlation between (EPHX1 and NQO1, PON1) genetic polymorphisms and the risk of B-NHL. However, In PON1 polymorphism, the homozygosity (GG) was significantly higher in the control group (13.3%) compared to B-NHL patients (3%) with a P-value = 0.016. So, better understanding of the functional consequences of EPHX1, NQO1 and PON1 genetic polymorphisms as well as involvement of larger cohort would provide a foundation for future studies of these genes in the pathogenesis of different types of NHL.

Associations of AHR, CYP1A1, EPHX1, and GSTP1 genetic polymorphisms with small-for-gestational-age infants

Objective To investigate the influences of aryl hydrocarbon (AHR), cytochrome P450 (CYP1A1), epoxide hydrolase 1 (EPHX1), and glutathione S-transferase P1 (GSTP1) genetic polymorphisms on small-for-gestational-age (SGA) infants. Methods This nested case-control study (126 cases and 381 controls) was based on a prospective cohort study in Shanxi Province, China. We collected the general information of subjects using questionnaire and identified their single nucleotide polymorphisms by the MassARRAY genotyping platform. Results The polymorphisms of CYP1A1 (rs4646421 and rs4646903) and EPHX1 (rs1051740) were significantly associated with SGA. Neonates of women with EPHX1 (rs1051740) and GSTP1 (rs1695) variant alleles were at a significantly increased risk of SGA compared with the reference group (OR = 5.26; 95% CI, 1.08–25.66), as were neonates of women with CYP1A1 (rs4646903) and EPHX1 (rs1051740) variant alleles (OR = 7.11; 95% CI, 1.55–32.62). The results of strata analysis by AHR (rs2282883 and rs17137566) showed that the associations between the polymorphisms of CYP1A1 (rs4646421 and rs4646903) EPHX1 (rs1051740), GSTP1 (rs1695) and SGA were of significance in women with variant heterozygous or homozygous genotype. Conclusions CYP1A1 (rs4646421 and rs4646903), EPHX1 (rs1051740), and GSTP1 (rs1695) genetic variances might increase the risk of SGA. AHR (rs2282883 and rs17137566) resulted in estimated effects varying across strata on CYP1A1 (rs4646421 and rs4646903), EPHX1 (rs1051740), and GSTP1 (rs1695).

The effect on congenital heart diseases of maternal EPHX1 polymorphisms modified by polycyclic aromatic hydrocarbons exposure.

Polycyclic aromatic hydrocarbons (PAHs) may be 1 of etiologic factors responsible for congenital heart diseases (CHDs). Variations of the microsomal epoxide hydrolase (EPHX1) gene, as well as their possible interactions with PAHs exposure, may increase susceptibility to CHDs.This case-control study investigated the risk of CHDs in relation to the EPHX1 polymorphisms and assessed the interactions between these polymorphisms and PAHs exposure in 357 mothers of CHDs fetuses and 270 control mothers. Logistic regression models for the risk of CHDs were applied to determine the effect of genetic polymorphisms using additive, recessive, and dominant genetic models, as well as gene-exposure interactions. Multiple testing was adjusted by applying the false discovery rate (FDR).None of the maternal genetic polymorphisms of EPHX1 was associated with CHDs occurrence. Only the single nucleotide polymorphism rs1051740 was associated with an increased risk of right-sided obstructive malformations under the recessive model (adjusted odds ratio [aOR] = 1.852, 95% confidence interval [CI]: 1.065, 3.22) before FDR correction. A possible modifying effect of PAHs exposure on genetic polymorphisms of EPHX1 was found in susceptibility to CHDs, though no multiplicative-scale interactions between maternal exposure to PAHs and polymorphisms of EPHX1 gene were seento affect the risk of CHDs.The role of EPHX1 gene polymorphisms for CHDs need to be further evaluated, in particularly by interacting with PAHs exposure.

Association between EPHX1 polymorphism rs1051740 and the risk of ovarian cancer: a meta-analysis

Objective We carried out a meta-analysis of case-control studies to determine whether epoxide hydrolase 1 (EPHX1) gene polymorphism rs1051740 was related to the risk of ovarian cancer. Methods Electronic databases were searched for relevant articles published in English or Chinese language. We calculated crude odds ratios (ORs) with their 95% confidence intervals (95% CIs) to assess the relationship of EPHX1 polymorphism rs1051740 with ovarian cancer risk. In addition, subgroup analyses were also conducted based on ethnicity and control source. Between-study heterogeneity was inspected with Q test and I 2 statistic. Results Five eligible studies with a total of 1919 ovarian cancer patients and 1829 controls were ultimately included in the present meta-analysis. Overall results demonstrated that the association between EPHX1 polymorphism rs1051740 and ovarian cancer risk had no statistical significance either in total analysis or in subgroup analyses by ethnicity and source of control. Conclusion EPHX1 polymorphism rs1051740 may have no independent effect on ovarian cancer susceptibility.

EPHX1 rs1051740 T>C (Tyr113His) is strongly associated with acute myeloid leukemia and KMT2A rearrangements in early age.

Experimental and epidemiological data have shown that acute myeloid leukemia in early-age (i-AML) originates prenatally. The risk association between transplacental exposure to benzene metabolites and i-AML might be influenced by genetic susceptibility. In this study, we investigated the relationship between genetic polymorphisms in CYP2E1, EPHX1, MPO, NQO1, GSTM1 and GSTT1 genes, and i-AML risk. The study included 101 i-AMLs and 416 healthy controls. Genomic DNA from study subjects was purified from bone marrow or peripheral blood aspirates and genotyped for genetic polymorphisms by real-time PCR allelic discrimination, Sanger sequencing and multiplex PCR. Crude and adjusted odds ratios (OR, adjOR, respectively) with 95% confidence intervals (95% CI) were assessed using unconditional logistic regression to estimate the magnitude of risk associations. EPHX1 rs1051740 T>C was associated with i-AML risk under the co-dominant (adjOR 3.04, P = 0.003) and recessive (adjOR 2.99, P = 0.002) models. In stratified analysis, EPHX1 rs1051740 was associated with increased risk for i-AML with KMT2A rearrangement (adjOR 3.06, P = 0.045), i-AML with megakaryocytic differentiation (adjOR 5.10, P = 0.008), and i-AML with type I mutation (adjOR 2.02, P = 0.037). EPHX1 rs1051740-rs2234922 C-G haplotype was also associated with increased risk for i-AML (adjOR 2.55, P = 0.043), and for i-AML with KMT2A rearrangement (adjOR 3.23, P = 0.034). Since EPHX1 enzyme is essential in cellular defense against epoxides, the diminished enzymatic activity conferred by the variant allele C could explain the risk associations found for i-AML. In conclusion, EPHX1 rs1051740 plays an important role in i-AML's genetic susceptibility by modulating the carcinogenic effects of epoxide exposures in the bone marrow.

Pharmacogenetics of adverse reactions to antiepileptic drugs

IntroductionAdverse drug reactions (ADRs) are a major public health concern and a leading cause of morbidity and mortality in the world. In the case of antiepileptic drugs (AEDs), ADRs constitute a barrier to successful treatment since they decrease treatment adherence and impact patients’ quality of life of patients. Pharmacogenetics aims to identify genetic polymorphisms associated with drug safety. This article presents a review of genes coding for drug metabolising enzymes and drug transporters, and HLA system genes that have been linked to AED-induced ADRs. DevelopmentTo date, several genetic variations associated with drug safety have been reported: CYP2C9*2 and *3 alleles, which code for enzymes with decreased activity, have been linked to phenytoin (PHT)-induced neurotoxicity; GSTM1 null alleles with hepatotoxicity induced by carbamazepine (CBZ) and valproic acid (VPA); EPHX1 polymorphisms with teratogenesis; ABCC2 genetic variations with CBZ- and VPA-induced neurological ADRs; and HLA alleles (e.g. HLA-B*15:02, -A*31:01, -B*15:11, -C*08:01) with cutaneous ADRs. ConclusionsPublished findings show that there are ADRs with a pharmacogenetic basis and a high interethnic variability, which indicates a need for future studies in different populations to gather more useful results for larger number of patients. The search for biomarkers that would allow predicting ADRs to AEDs could improve pharmacotherapy for epilepsy.

Polymorphisms of vitamin K-related genes (EPHX1 and VKORC1L1) and stable warfarin doses

The aim of this study was to investigate the possible effects of EPHX1 and VKORC1L1 polymorphisms on variability of responses to warfarin. Sixteen single nucleotide polymorphisms (SNPs) in 201 patients with stable warfarin doses were analyzed including genes of VKORC1, CYP2C9, CYP4F2, GGCX, EPHX1 and VKORC1L1. Univariate analysis was conducted for the association of genotypes with stable warfarin doses. Multiple linear regression analysis was used to investigate factors that independently affected the inter-individual variability of warfarin dose requirements. The rs4072879 of VKORC1L1 (A>G) was significantly associated with stable warfarin doses; wild homozygote carriers (AA) required significantly lower stable warfarin doses than those with the variant G allele (5.02±1.56 vs. 5.96±2.01mg; p=0.001). Multivariate analysis showed that EPHX1 rs1877724 and VKORC1L1 rs4072879 accounted for 1.5% and 1.3% of the warfarin dose variability. Adding EPHX1 and VKORC1L1 SNPs to the base model including non-genetic variables (operation age, body weight and the therapy of ACEI or ARB) and genetic variables (VKORC1 rs9934438, CYP2C9 rs1057910, and CYP4F2 rs2108622) gave a number needed to genotype of 34. This study showed that polymorphisms of EPHX1 and VKORC1L1 could be determinants of stable warfarin doses.

Polymorphisms in ABCB1 and EPHX1 Genes Influence Drug Effectiveness In refractory Epilepsy: A retrospective study

Aim: Thirty percent of epileptic patients are refractory to treatment. We investigated the association between the number of seizures in refractory epileptic patients and potential interactions between their antiepileptic medications (AEDs) and single nucleotide polymorphisms in genes ABCB1, CYP2C9 and EPHX1. Methods: Thirty-three adult patients were included and tested for genetic variations using the Neuropharmagen® test. Retrospective data on AED therapy and number of seizures during the 12 months before inclusion were extracted from clinical records. Results: Patients displaying potential single nucleotide polymorphisms × AED interactions had a median of 14.5 seizures during the previous 12 months (IQR 5.5–105.0), compared to a median of 7.0 seizures (IQR 4.0–12.0) in patients without these interactions (univariate p = 0.051, adjusted p = 0.034). Conclusion: Refractory patients carrying genetic variations potentially affecting their AED medication experienced a significantly higher number of seizures. Thus, genotyping could help to better control epilepsy in some refractory patients.

EPHX1 Y113H polymorphism is associated with increased risk of chronic obstructive pulmonary disease in Kazakhstan population

Chronic obstructive pulmonary disease (COPD) is a type of obstructive lung disease characterized by long term poor airflow which worsens over time. It is considered to be one of the top five chronic diseases of the world in terms of morbidity and mortality. Genetic variability has been found to contribute to the development of COPD. Although association between gene polymorphisms in EPHX1 and TNF-a genes and chronic obstructive pulmonary disease (COPD) have been found but till date no genetic association studies have been done in the COPD affected Kazakhstan population. The aim of the present work was to investigate the association between the Y113H polymorphism (rs1051740) in EPHX1 gene and −308G/A polymorphism (rs1800629) in TNF-a gene and COPD in Kazakhstan population. A case-control study was conducted in Astana and Akmola regions of Kazakhstan, involving 55 cases with COPD and 52 healthy individuals who served as the controls. The polymorphisms were determined using conventional PCR and Sanger sequencing method. Results show that for the EPHX1 gene Y113H polymorphism, the presence of an “C” allele (TC/CC genotype) was significantly overrepresented in the COPD patients compared to the controls. For the TNF-a gene −308G/A polymorphism, no significant difference was found between the two groups. Thus we found that, Y113H polymorphism in EPHX1 gene contributed to increased susceptibility to COPD in the Kazakhstan population.

Effect of EPHX1 polymorphism on breast cancer risk in women of the Russian Far East: A population-based case–control study

Effect of EPHX1 polymorphism on breast cancer risk in women of the Russian Far East: A population-based case–control study

Modification of the association of bisphenol A with abnormal liver function by polymorphisms of oxidative stress-related genes

Some studies suggested oxidative stress as a possible mechanism for the relation between exposure to bisphenol A (BPA) and liver damage. Therefore, we evaluated modification of genetic polymorphisms of cyclooxygenase 2 (COX2 or PTGS2), epoxide hydrolase 1 (EPHX1), catalase (CAT), and superoxide dismutase 2 (SOD2 or MnSOD), which are oxidative stress-related genes, on the relation between exposure to BPA and liver function in the elderly. We assessed the association of visit-to-visit variations in BPA exposure with abnormal liver function by each genotype or haplotype after controlling for age, sex, BMI, alcohol consumption, exercise, urinary cotinine levels, and low density lipoprotein cholesterol using a GLIMMIX model. A significant association of BPA with abnormal liver function was observed only in participants with COX2 GG genotype at rs5277 (odds ratio (OR)=3.04 and p=0.0231), CAT genotype at rs769218 (OR=4.16 and p=0.0356), CAT CT genotype at rs769217 (OR=4.19 and p=0.0348), SOD2 TT genotype at rs4880 (OR=2.59 and p=0.0438), or SOD2 GG genotype at rs2758331 (OR=2.57 and p=0.0457). Moreover, we also found higher OR values in participants with a pair of G-G haplotypes for COX2 (OR=2.81 and p=0.0384), G-C-A haplotype for EPHX1 (OR=4.63 and p=0.0654), A-T haplotype for CAT (OR=4.48 and p=0.0245), or T-G-A haplotype for SOD2 (OR=2.91 and p=0.0491) compared with those with the other pair of haplotypes for each gene. Furthermore, the risk score composed of 4 risky pair of haplotypes showed interactive effect with BPA on abnormal liver function (p=0.0057). Our study results suggest that genetic polymorphisms of COX2, EPHX1, CAT, and SOD2 modify the association of BPA with liver function.

Exploration of association between EPHX1 and chronic obstructive pulmonary disease on the basis of combined data mining.

Chronic obstructive pulmonary disease (COPD) is an important respiratory disease with high mortality. Although smoking is the major environmental risk factor for the development of COPD, only 10% of heavy smokers develop symptomatic disease, suggesting association between genetic susceptibilities and environmental influences. In recent years, as one of the most widely studied genes including tests for associations between a genetic variant and COPD, epoxide hydrolase 1 (EPHX1) was found to be involved in the metabolism of tobacco smoke, an important risk factor of COPD. However, genetic associations with COPD identified in studies on EPHX1 are controversial. To address this issue, except for performing the meta-analysis, which specially added our current study on two polymorphisms (T337C and A416G) of EPHX1, we performed combined data mining based on functional prediction algorithms of nonsynonymous single-nucleotide polymorphisms and gene-based variable threshold testing. Genetic variations in EPHX1 did not affect COPD in Caucasian and Eastern Asian population, which is supported by recent evidence. We found no association between EPHX1 and COPD; however, a minor effect of EPHX1 on COPD risk was not completely excluded; further replication studies with large samples are needed to confirm our findings.