Single Nucleotide Polymorphisms In EPHX1 Research Articles

Genetic variants in epoxide hydrolases modify the risk of oligozoospermia and asthenospermia in Han-Chinese population

ObjectivesEpoxide hydrolases are involved in detoxifying and excreting the environmental chemicals, which are associated with decreased semen quality and male infertility. We hypothesized that polymorphisms in epoxide hydrolases may be associated with risk of oligozoospermia and asthenospermia. Design and methodsIn this study, 468 fertile controls and 672 idiopathic male infertile patients were recruited. SNPstream and TaqMan assay were used to genotype four single nucleotide polymorphisms in EPHX1 and EPHX2. The semen analysis was performed by computer-assisted semen analysis system. ResultsOur results demonstrated that rs1042064 of EPHX2 was significantly associated with decreased risk of oligozoospermia (OR=0.65, 95% CI: 0.44–0.98) and asthenospermia (OR=0.66, 95% CI: 0.46–0.94). ConclusionsOur results provided evidence that genetic variants in epoxide hydrolases may modify the risk of oligozoospermia and asthenospermia in Han-Chinese population.

Xenobiotic‐Metabolizing gene polymorphisms and ovarian cancer risk

Because selected xenobiotic-metabolizing enzymes process pro-carcinogens that could initiate ovarian carcinogenesis, we hypothesized that single nucleotide polymorphisms (SNPs) in the genes encoding xenobiotic-metabolizing enzymes are associated with risk of ovarian cancer. Cases with invasive epithelial ovarian cancer (N = 1571 including 956 of serous sub-type) and controls (N = 2046) from three studies were genotyped at 11 SNPs in EPHX1, ADH4, ADH1A, NQO2, NAT2, GSTP1, CYP1A1, and NQO1, following an initial SNP screen in a subset of participants. Logistic regression analysis of genotypes obtained via Illumina GoldenGate and Sequenom iPlex technologies revealed the following age- and study-adjusted associations: EPHX1 rs1051740 with increased serous ovarian cancer risk [per-allele odds ratio (OR) 1.17, 95% confidence interval (95% CI) 1.04-1.32, P = 0.01), ADH4 r1042364 with decreased ovarian cancer risk (OR 0.90, 95% CI: 0.81-1.00, P = 0.05), and NQO1 rs291766 with increased ovarian cancer risk (OR 1.11, 95% CI: 1.00-1.23, P = 0.04). These findings are consistent with prior studies implicating these genes in carcinogenesis and suggest that this collection of variants is worthy of follow-up in additional studies.

Association of COPD candidate genes with computed tomography emphysema and airway phenotypes in severe COPD

The principal determining factors influencing the development of the airway disease and emphysema components of chronic obstructive pulmonary disease (COPD) have not been clearly defined. Genetic variability in COPD patients might influence the varying degrees of involvement of airway disease and emphysema. Therefore, we investigated the genetic association of single nucleotide polymorphisms (SNPs) in COPD candidate genes for association with emphysema severity and airway wall thickness phenotypes. Polymorphisms in six candidate genes were analysed in 379 subjects of the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study with quantitative chest computed tomography (CT) data. Genetic association with per cent of lung area below -950 HU (LAA950), airway wall thickness, and derived square root wall area (SRWA) of 10-mm internal perimeter airways were investigated. Three SNPs in EPHX1, five SNPs in SERPINE2 and one SNP in GSTP1 were significantly associated with LAA950. Five SNPs in TGFB1, two SNPs in EPHX1, one SNP in SERPINE2 and two SNPs in ADRB2 were associated with airway wall phenotypes in NETT. In conclusion, several COPD candidate genes showed evidence for association with airway wall thickness and emphysema severity using CT in a severe COPD population. Further investigation will be required to replicate these genetic associations for emphysema and airway wall phenotypes.

Genetic association analysis of COPD candidate genes with bronchodilator responsiveness

Airflow limitation in COPD patients is not fully reversible. However, there may be large variability in bronchodilator responsiveness (BDR) among COPD patients, and familial aggregation of BDR suggests a genetic component. Therefore, we investigated the association between six candidate genes and BDR in subjects with severe COPD. A total of 389 subjects from the National Emphysema Treatment Trial (NETT) were analyzed. Bronchodilator responsiveness to albuterol was expressed in three ways: absolute change in FEV(1), change in FEV(1) as a percent of baseline FEV(1), and change in FEV(1) as a percent of predicted FEV(1). Genotyping was completed for 122 single nucleotide polymorphisms (SNPs) in six candidate genes (EPHX1, SFTPB, TGFB1, SERPINE2, GSTP1, ADRB2). Associations between BDR phenotypes and SNP genotypes were tested using linear regression, adjusting for age, sex, pack-years of smoking, and height. Genes associated with BDR phenotypes in the NETT subjects were assessed for replication in 127 pedigrees from the Boston Early-Onset COPD (EOCOPD) Study. Three SNPs in EPHX1 (p=0.009-0.04), three SNPs in SERPINE2 (p=0.004-0.05) and two SNPs in ADRB2 (0.04-0.05) were significantly associated with BDR phenotypes in NETT subjects. One SNP in EPHX1 (rs1009668, p=0.04) was significantly replicated in EOCOPD subjects. SNPs in SFTPB, TGFB1, and GSTP1 genes were not associated with BDR. In conclusion, a polymorphism of EPHX1 was associated with bronchodilator responsiveness phenotypes in subjects with severe COPD.

Genetic Associations With Hypoxemia and Pulmonary Arterial Pressure in COPD

Hypoxemia, hypercarbia, and pulmonary arterial hypertension are known complications of advanced COPD. We sought to identify genetic polymorphisms associated with these traits in a population of patients with severe COPD from the National Emphysema Treatment Trial (NETT). In 389 participants from the NETT Genetics Ancillary Study, single-nucleotide polymorphisms (SNPs) were genotyped in five candidate genes previously associated with COPD susceptibility (EPHX1, SERPINE2, SFTPB, TGFB1, and GSTP1). Linear regression models were used to test for associations among these SNPs and three quantitative COPD-related traits (Pao(2), Paco(2), and pulmonary artery systolic pressure). Genes associated with hypoxemia were tested for replication in probands from the Boston Early-Onset COPD Study. In the NETT Genetics Ancillary Study population, SNPs in microsomal epoxide hydrolase (EPHX1) [p = 0.01 to 0.04] and serpin peptidase inhibitor, clade E, member 2 (SERPINE2) [p = 0.04 to 0.008] were associated with hypoxemia. One SNP within surfactant protein B (SFTPB) was associated with pulmonary artery systolic pressure (p = 0.01). In probands from the Boston Early-Onset COPD Study, SNPs in EPHX1 and in SERPINE2 were associated with the requirement for supplemental oxygen. In participants with severe COPD, SNPs in EPHX1 and SERPINE2 were associated with hypoxemia in two separate study populations, and SNPs from SFTPB were associated with pulmonary artery pressure in the NETT participants.

Genetic Determinants of Functional Impairment in Chronic Obstructive Pulmonary Disease

Rationale: Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions. Methods: In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test-replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study. Results: The test-replication approach identified four genes—microsomal epoxide hydrolase (EPHX1), latent transforming growth factor β binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor β-1 (TGFB1)—that were associated with COPD-related phenotypes. In all subjects, single nucleotide polymorphisms (SNPs) in EPHX1 (p ⩽ 0.03) and in LTBP4 (p ⩽ 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p ⩽ 0.05) and SFTPB (p = 0.005) were associated with six-minute walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p ⩽ 0.04). Three SNPs in TGFB1 were associated with dyspnea (p ⩽ 0.002), one of which replicated in the family study (p = 0.02). Conclusions: Polymorphisms in several genes appear to be associated with COPD-related traits other than forced expiratory volume in 1 second. These associations may identify genes in pathways important for COPD pathogenesis.

Genetic Association Analysis of Functional Impairment in Chronic Obstructive Pulmonary Disease

Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions. To identify genetic associations for COPD-related phenotypes, including measures of exercise capacity, pulmonary function, and respiratory symptoms. In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test-replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study. The test-replication approach identified four genes-microsomal epoxide hydrolase (EPHX1), latent transforming growth factor-beta binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor-beta1 (TGFB1)-that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p < or = 0.03) and in LTBP4 (p < or = 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p < or = 0.05) and SFTPB (p = 0.005) were associated with 6-min walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p < or = 0.04). Three SNPs in TGFB1 were associated with dyspnea (p < or = 0.002), one of which replicated in the family study (p = 0.02). Polymorphisms in several genes seem to be associated with COPD-related traits other than FEV(1). These associations may identify genes in pathways important for COPD pathogenesis.