Genetic polymorphism of epoxide hydrolase and glutathione S-transferase in COPD

Abstract

Genetic susceptibility to the development of chronic obstructive pulmonary disease (COPD) might depend on variation in the activities of enzymes that detoxify cigarette smoke products, such as microsomal epoxide hydrolase (mEPHX) and glutathione S-transferase (GST). It was investigated whether polymorphisms in these genes had any association with susceptibility to COPD and COPD severity.The genotypes of 184 patients with COPD and 212 control subjects were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis of the mEPHX, GSTM1, GSTT1 and GSTP1 genes. All subjects were smokers or exsmokers.The proportion of GSTM1-null genotypes was significantly higher in patients with COPD than in control subjects (61.4 versus 42.5%). No differences were observed in the frequency of polymorphic genotypes for mEPHX, GSTT1 and GSTP1. During combined analysis of genetic polymorphisms for mEPHX, GSTM1 and GSTP1, it was found that there are strong indicators for susceptibility to COPD (genotype combination with at least one mutant mEPHX exon-3 allele (histidine 113), GSTM1 null and homozygous for the GSTP1 isoleucine 105 allele). The frequencies of homozygous mutant alleles of mEPHX exon 3 and the GSTM1-null genotype were significantly higher in patients with severe COPD (forced expiratory volume in one second of v35% of the predicted value).It is proposed that the combination of genetic variants including at least one mutant microsomal epoxide hydrolase exon-3 allele and glutathione S-transferase M1-null and homozygous isoleucine 105 glutathione S-transferase P1 genotypes are significant indicators of susceptibility to chronic obstructive pulmonary disease in the Taiwanese population. In addition, the homozygous variant of microsomal epoxide hydrolase exon 3 and the glutathione S-transferase M1-null genotype are independent risk factors for developing severe chronic obstructive pulmonary disease.

The role of gene polymorphisms in the pathogenesis of chronic obstructive pulmonary disease

“…This deletion allele was demonstrated to occur in a higher frequency in patients with emphysema and lung cancer . Cheng et al (2004) demonstrated that the GSTM1 null genotype is a risk factor for developing COPD in a Taiwanese population (Table 2). A different study in a Caucasian population indicated that the presence of at least one active allele in the GSTM1 locus had a protective effect against the development of COPD in smokers with non-small-cell lung cancer (Tkacova et al 2004).…”

“…Rodriguez et al (2002) found a significantly higher proportion of individuals homozygous for mutant exon 3 among COPD patients than control subjects whereas Xiao et al (2003) reported similar results for mEPHX exon 3 heterozygotes. In addition, a comparison of patients with severe COPD to those with mild-to-moderate disease revealed that the frequency of the homozygous His113His mEPHX exon 3 variant was significantly higher in severe COPD (Cheng et al 2004). In the study by Park et al (2005), a significantly increased risk for COPD was observed for subjects with the mEPHX (His113His) genotypes.…”

“…Most of the studies reported significant associations between low mEPHX activity genotypes and the risk for COPD Sandford et al 2001;Rodriguez et al 2002;Xiao et al 2003;Cheng et al 2004;Park et al 2005). In the study by Sandford et al (2001), a combination of a family history of COPD together with a homozygosity for the His 113 /His 139 haplotype in the mEPHX gene was associated with rapid decline of lung function.…”

“…The GSTT1*0 mutant has also been suggested as a risk factor for human lung disease (Cheng et al 2004). In Caucasians, homozygotes for the null allele are present with 20% frequency (Hayes & Strange 2000).…”

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

“…These studies included 9 Caucasian populations (Rodriguez et al, 2002;Korytina et al, 2003;Hersh et al, 2005;Park et al, 2005;Brøgger et al, 2006;Chappell et al, 2008;Židzik et al, 2008;Penyige et al, 2010;Lee et al, 2011) and 10 Eastern Asian populations (Takeyabu et al, 2000;Yim et al, 2000;Yoshikawa et al, 2000;Zhang et al, 2002;Budhi et al, 2003;Park et al, 2003;Cheng et al, 2004;Xiao et al, 2004;Fu et al, 2007;Hua et al, 2012) ( Table 1). The total number of samples in the Caucasian and Eastern Asian populations were 47,048 (6471 cases vs 40,577 controls) and 2586 (1228 cases vs 1358 controls), respectively.…”