Association between polymorphisms of microsomal epoxide hydrolase and COPD: Results from meta‐analyses

Abstract

Association between polymorphisms of microsomal epoxide hydrolase and COPD: Results from meta-analyses HU G, SHI Z, HU J, ZOU G, PENG G, RAN P. Respirology 2008; 13: 837-850 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 c 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 metaanalysis 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 HardyWeinberg 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.

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

“…One study found an association of the 113C allele with functional impairment in COPD [35]. Some studies indicate a protective effect of the putative fast 139G allele [1,28]; however, many studies find no effect at all of either polymorphism [7,22,36]. Similar disparities are found in studies investigating association of COPD with EPHX1 phenotype [7,21,22,36].…”

Genetic Implications in COPD. The Current Knowledge

“…But still the treatment tools, available to date, are insufficient to perform panacea of the disease. Studies that have been implicated the oxidative stress as a crucial impact factor in lung inflammatory pathways and COPD concluded that several antioxidant genes such as gst (gstm1, gstt1 and gstp1), microsomal epoxide hydrolase 1 (mephx1) [15][16][17][18] and Klotho gene [52] exert an important role regarding the rapid decline in pulmonary function. However, some inconclusive results drawn out from previous studies are due to diversities in population that have been studied.…”

“…Hu G. et al in a study reviewing meta analysis results concerning the association of antioxidant genes in pathogenesis of COPD, concluded that EPHX1 113 and EPHX1 139 are both genetically relative factors for susceptibility of COPD in Asian population, especially the fast activity phenotype EPHX1.This observation did not appeared in Caucasians who are more susceptible in the risk for developing COPD concerning the slow activity phenotype of the EPHX 1 in contrast to the Asians. These facts underline that the susceptibility in COPD depends upon the diverse ethnic gene-environment interactions [17]. Analyses the same aspect of the oxidative stress and the plausible role of the EPHX 1 as a protective mechanism against it Lakhdar R. et al in an association study concluded in weak association of the EPHX 1 113His genotype and no association with the EPHX 139His genotype in Tunisians, when adjusted on the basis of phenotypical appearance of the disease [18].…”

A Case of Multiple Genetic Lesions in Different Systems of the Lung Defense

“…Затем, в процессе 2 й фазы, эти про межуточные метаболиты с помощью ферментов семейств глутатионтрансфераз, УДФ глюкуронсуль фотрансфераз, N ацетилтрансфераз превращаются в водорастворимые нетоксичные продукты и выво дятся из организма. Известны 2 функционально зна чимых полиморфизма гена EPHX1 в 3 м (Т 337С) и 4 м (A 415G) экзонах, приводящие к аминокис лотным заменам Y113H (T>C) и H139R (A>G) соот ветственно, что изменяет свойства фермента [13]. По лиморфизм Т 337С ответственен за снижение активности фермента на 50 % ("медленный" аллель), а полиморфизм A 415G -за повышение активности примерно на 25 % ("быстрый" аллель).…”

“…Можно полагать, что факторами, способ ствующими развитию токсического гепатита, явились комбинированная антибактериальная терапия, нали чие тяжелой респираторной вирусной инфекции, на личие гепатита А в анамнезе, а также полиморфизм в гене микросомальной эпоксидгидролазы (EPHX1 Y113H TC). Как известно, данный полиморфизм спо собен нарушать процесс биотрансформации ксено биотиков (в т. ч. антибактериальных препаратов), что может усиливать их токсическое действие [13].…”