Antioxidant Defense Enzyme Genes and Asthma Susceptibility: Gender-Specific Effects and Heterogeneity in Gene-Gene Interactions between Pathogenetic Variants of the Disease

Abstract

Oxidative stress resulting from an increased amount of reactive oxygen species and an imbalance between oxidants and antioxidants plays an important role in the pathogenesis of asthma. The present study tested the hypothesis that genetic susceptibility to allergic and nonallergic variants of asthma is determined by complex interactions between genes encoding antioxidant defense enzymes (ADE). We carried out a comprehensive analysis of the associations between adult asthma and 46 single nucleotide polymorphisms of 34 ADE genes and 12 other candidate genes of asthma in Russian population using set association analysis and multifactor dimensionality reduction approaches. We found for the first time epistatic interactions between ADE genes underlying asthma susceptibility and the genetic heterogeneity between allergic and nonallergic variants of the disease. We identified GSR (glutathione reductase) and PON2 (paraoxonase 2) as novel candidate genes for asthma susceptibility. We observed gender-specific effects of ADE genes on the risk of asthma. The results of the study demonstrate complexity and diversity of interactions between genes involved in oxidative stress underlying susceptibility to allergic and nonallergic asthma.

Joint effect of glutathione S-transferase genotypes and cigarette smoking on idiopathic male infertility

“…The distribution of null genotypes for the GSTM1 and GSTT1 genes in the case and control groups was reported in our previous study (Polonikov et al ., ). The frequencies of GST genotypes were comparable with those reported previously in our population (Polonikov et al ., , ). Associations of GST genotype combinations with risk of idiopathic male infertility are shown in Table .…”

Impact of the X Chromosome and sex on regulatory variation

“…If tested separately in each sex, this gene-SNP pair is an eQTL in males (P-value = 5.5 × 10 −3 ) but not females (P-value = 5.0 × 10 −1 ). Interestingly, PON2 does not exhibit sex-specific gene expression (P-value = 6.3 × 10 −1 , FDR 89.2%) but has been associated with sex-specific effects in oxidative stress responses (Cheng and Klaassen 2012;Giordano et al 2013;Polonikov et al 2014). …”

Impact of the X chromosome and sex on regulatory variation

“…If tested separately in each sex, this gene-SNP pair is an eQTL in males (P-value = 5.5 x 10 -3 ) but not females (P-value = 5.0 x 10 -1 ). Interestingly, PON2 does not exhibit sex-specific gene expression (P-value = 6.3 x 10 -1 , FDR 89.2%) but has been associated with sex-specific effects in oxidative stress responses (Cheng and Klaassen 2012;Giordano et al 2013;Polonikov et al 2014).…”