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.

Figure 1

The results of statistical modeling of gene-gene interactions in allergic asthma using set association approach. Significance level of S _n statistic as a function of the number n of SNPs in different genes which are included at each step for gene-gene interactions analysis. The smallest significance level, P _min⁡, occurs with 5 SNPs in males and with 3 SNPs in females. The interacting genes in the models are circled in red.

Figure 2

The results of statistical modeling of gene-gene interactions in nonallergic asthma using set association approach. Significance level of S _n statistic as a function of the number n of SNPs in different genes which are included at each step for gene-gene interactions analysis. The smallest significance level, P _min⁡, occurs with 5 SNPs in males and with 2 SNPs in females. The interacting genes in the models are circled in red.

Figure 3

Dendrograms of gene-gene interactions in the pathogenetic variants of asthma (MDR method). Dendrograms show both complexity and diversity of interactions between polymorphic genes of antioxidant defense enzymes in allergic and nonallergic asthma (dendrograms are stratified by gender). Each dendrogram comprises a spectrum of lines representing a continuum from synergy (black) to redundancy (gray) of gene-gene interactions. The lines range from bold black, representing a high degree of synergy (positive information gain), thin black, representing a lesser degree, and dotted line representing the midway point between synergy and redundancy. On the redundancy end of the spectrum, the highest degree is represented by bold gray (negative information gain) with a lesser degree represented by thin gray.