Microsomal epoxide hydrolase, glutathione S-transferase P1, traffic and childhood asthma

Abstract

Background: Microsomal epoxide hydrolase (EPHX1) metabolises xenobiotics including polyaromatic hydrocarbons (PAHs). Functional variants at this locus have been associated with respiratory diseases. The effects of EPHX1 variants may depend upon exposures from tobacco smoke and traffic emissions that contain PAHs as well as variants in other enzymes in the PAH metabolic pathway such as glutathione S-transferase (GST) genes. A study was undertaken to investigate associations of variants in EPHX1, GSTM1, GSTP1 and GSTT1 with asthma and the relationships between asthma, EPHX1 metabolic phenotypes and exposure to sources of PAHs. Methods: Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate the associations of genetic variants and exposures with asthma phenotypes using data from 3124 children from the Children's Health Study. Results: High EPHX1 activity was associated with an increased risk for lifetime asthma (OR 1.51, 95% CI 1.14 to 1.98) which varied by GSTP1 Ile105Val genotype and by residential proximity to major roads (p for interaction = 0.006 and 0.03, respectively). Among children with GSTP1 105Val/Val genotype, those who had high EPHX1 phenotype had a fourfold (95% CI 1.97 to 8.16) increased risk of lifetime asthma than children with low/intermediate EPHX1 phenotype. Among children living within 75 metres of a major road, those with high EPHX1 activity had a 3.2-fold (95% CI 1.75 to 6.00) higher lifetime asthma risk than those with low/intermediate activity. The results were similar for current, early persistent and late onset asthma. Children with high EPHX1 phenotype, GSTP1 Val/Val genotype who lived ,75 metres from a major road were at the highest asthma risk. Conclusion: EPHX1 and GSTP1 variants contribute to the occurrence of childhood asthma and increase asthma susceptibility to exposures from major roads.

EPHX1 polymorphisms, COPD and asthma in 47,000 individuals and in meta-analysis

“…Genetic variations in xenobioticmetabolising enzymes such as EPHX1 have been found to modify asthma susceptibility [39,40]. SALAM et al [40] report that high activity phenotypes of EPHX1 predisposes for asthma.…”

“…Genetic variations in xenobioticmetabolising enzymes such as EPHX1 have been found to modify asthma susceptibility [39,40]. SALAM et al [40] report that high activity phenotypes of EPHX1 predisposes for asthma. This is in contrast to the findings of DUAN et al [41] who hypothesise that EPHX1 may have a dual effect on susceptibility to asthma.…”

Gene by Environment Interaction in Asthma

“…In the context of this article, for a single nucleotide polymorphism such as CD14-159C/T, there are three possible genotypes, CC, CT, TT asthma or related phenotypes ( Table 2) (3,8,15,16,30,36,39,46,51,68,69,72,90). The number of different genes studied in relation to environmental tobacco smoke and ambient air pollution is relatively small.…”

A bioinformatics strategy for detecting the complexity of Chronic Obstructive Pulmonary Disease in Northern Chinese Han Population

“…When we used PLINK software to explore their epitasis interactions, these interactions were also found to be significant: rs1051740 (EPHX1) × rs1138272 (GSTP1) (p = 0.015), and rs6712954 (SERPINE2) × rs1051740 (EPHX1) (p = 0.035). It has been reported that high EPHX1 activity was associated with an increased risk for lifetime asthma which varied by GSTP1 Ile105Val genotype (Salam et al, 2007). In addition, some SNPs showing more interactions with other SNPs in BN2 and BN4 can be explained by LD on one hand, and on the other hand, these interactions approved by epitasis interactions might be potential interactions between genes, such as rs975278 (SERPINE2) × rs41266229 (EPHX1) (p = 0.011).…”