The <i>GSTP1</i> Gene Is a Susceptibility Gene for Childhood Asthma and the <i>GSTM1</i> Gene Is a Modifier of the <i>GSTP1</i> Gene

Abstract

Background: Bronchial asthma is a chronic airway disorder characterized by bronchial inflammation. Oxidative stress is a key component of inflammation. Glutathione S-transferase P1 (GSTP1), the abundant isoform of glutathione S-transferases (GSTs) in lung epithelium, plays a key role in cellular protection against oxidative stress. Several studies have shown that the GSTP1 geneis involved in the pathogenesis of asthma and a gene-gene interaction may occur within the GST gene superfamily. Methods: We screened single-nucleotide polymorphisms (SNPs) at the GSTP1 locus and performed an association study in the Japanese population using two independent case-control groups (group 1: 391 pediatric patients with asthma, 462 adult patients with asthma, and 639 controls, and group 2: 115 pediatric patients with asthma and 184 controls). The effect of GSTM1 null/present genotype on the association between GSTP1 Ile105Val and asthma was also investigated. Results: We identified 20 SNPs at this locus and found this region consisted of one linkage disequilibrium block represented by four SNPs (tag SNPs). The association between the Ile105Val polymorphism in the GSTP1 gene and childhood asthma was significant in both groups (p = 0.047 in group 1, and p = 0.021 in group 2). This association was only significant in patients with GSTM1-positive genotype in both groups (group 1: GSTM1 present p = 0.013 and GSTM1 null p = 0.925, and group 2: GSTM1 present p = 0.015 and GSTM1 null p = 0.362). Conclusions: These findings suggest that the GSTP1 gene is a childhood asthma susceptible gene, and the GSTM1 gene is a modifier gene of GSTP1 for the risk of childhood asthma in the Japanese population.

Association of glutathione-S-transferase polymorphisms with atopic dermatitis risk in preschool age children

“…This is consistent with our observations that GSTP1 Val105 allele carriers had an increased risk of developing AD. However, many reports have shown that the Val105 allele is associated with a decreased risk of allergic asthma (12,13), although some studies reported that the Val105 allele actually increased the risk of asthma (14,16). The GSTP1 Ile105Val polymorphism was not significantly associated with aspirin-intolerant asthma in Koreans (28).…”

“…Second, the frequencies of the Val105 allele in Asians are much lower than those of other ethnicities, which may explain the conflicting findings. For example, the Val105 allele decreased the risk of asthma in Northern Europeans for which the Val allele frequency is 47.7% (12), whereas the Val105 allele increased the risk of asthma in the Japanese population for which the Val allele frequency is 13.4% (14). Studies in Taiwanese individuals (Val allele frequencys25.3%) (15) have shown that the Ile105 homozygosity was related to an increased risk only in areas with high air pollution, and no association was found in areas with low air pollution.…”

“…Similarly, homozygous deletion of the GSTM1 and GSTT1 genes leads to the absence of the GSTM1 and GSTT1 proteins and their activity resulting in a null phenotype (11). Previous studies have reported an association between GST polymorphisms and an increased risk of inflammatory diseases such as asthma (12)(13)(14)(15)(16) and rheumatoid arthritis (17). A limited number of studies have examined the association of GST polymorphisms with risk of AD; the findings have been inconclusive (18)(19)(20).…”

DNA methylation profiling in human lung tissue identifies genes associated with COPD

“…Among these multi-site genes, 3 are of particular interest: CHRM1, as it was the top result among 10% b-diff results; ESM1, a gene mainly expressed in the endothelial cells in human lung and kidney tissues 27 ; and PITPNM1, a gene found within a linkage disequilibrium block surrounding the susceptibility gene identified in a previous association study of childhood asthma. 28 The ESM1 result provides a compelling demonstration of COPD-related gene regulation through hypermethylation in the cases, and concomitant reduction in gene expression. Although the ESM1 sites fall within the first exon for a majority of the transcripts, and this location (downstream of the transcription start site) would predict a positive correlation between gene expression and methylation, 29 other transcripts are also annotated to the 5 0 UTR, where anti-correlation could be expected.…”

Oxidative Damage and Bronchial Asthma

“…There are known two polymorphisms of GSTP1: substitution of isoleucine to valine at amino acid 105 and alanine to valine at amino acid 114, demonstrating different catalytic efficiencies due to changes in the active site (Ali-Osman et al, 1997). A number of studies suggest that GSTM1, GSTT1, GSTM1 polymorphisms increase susceptibility to asthma Hanene et al, 2007;Kamada et al, 2007;Romieu et al, 2006;Tamer et al, 2004). GSTM1 and GSTT1 deficiency may increase the risk for the asthma development of in utero and current smoke exposure .…”