Balkan Journal of Medical Genetics

The prevalence of asthma, allergic rhinitis and atopic dermatitis has dramatically increased over the past few decades. These atopy-related disease are the common chronic disorders of childhood. Asthma is a complex polygenic disorder, most probably caused by an interaction of multiple disease susceptibility genes with poorly identified environmental factors. The search for the genes participating in the origin and progression of asthma has already led to the identification of several loci on chromosomes 5, 11 and 12 [1-3]. The number of genes involved in this complex disorder have not yet been fully determined. The severity of the disease phenotype varies between individuals, and it is likely that some unique combinations of certain polymorphisms of particular genes constitute the inherited background of asthma severity.

Asthma is characterized by airway inflammation, a critical component of which is oxidative stress. Oxidative stress, with the formation of reaction oxygen species (ROS), is a key component of inflammation [4,5]. Although host antioxidant defenses should detoxify ROS, individuals differ in their ability to deal with an oxidant burden, and such differences are, in part, genetically determined [5]. Inability to detoxify ROS should perpetuate the inflammatory process, activate broncho-constrictor mechanisms, and potentiate asthmatic symptoms.

The high population prevalence of asthma substantiated the investigation on possible participation of the detoxification system genes such as mEPHX and NAT2 in the pathogenesis of this disease [6,7]. It was shown that a polymorphism of the GSTP1 gene, responsible for the enzyme of phase II of detoxification, is strongly associated with asthma, and provides an alternative explanation for the genetic linkage of atopy with chromosome locus 11q13 [8].

We hypothesized that the GST super-gene family is an attractive candidate, associated with asthma. The enzymes encoded by the members of the mu, theta, and pi class GST families can utilize as substrates a wide variety of products of oxidative stress, and are thus critical in the protection of cells from ROS [9].

The enzymes encoded by different GST gene classes preferentially metabolize different ROS products. For example, quinone metabolites of catecholamines (dopachrome) are utilized by mu GST but not by GSTP1 or GSTT1. Mu and theta, but not pi, GST genes demonstrate preferential activity against phospholipid hydroperoxide.

These GST genes may also influence the synthesis of eicosanoids (critical mediators in the asthmatic response) via modulation of ROS level [9]. Furthermore, the products are essential for mobilization of arachidonic acid, with subsequent production of pro-inflammatory eicosanoids.

So far, common allelic variants have been identified in the mu (GSTM10/0), the theta (GSTT10/0), and the pi (GSTP1 B, GSTP1 C) class genes. We have examined the hypothesis that polymorphisms of the GSTM1, GSTT1, and GSTP1 genes are associated with asthma.