Balkan Journal of Medical Genetics

ABA, as with many other multifactorial diseases, results from the interaction between adverse environmental factors and constitutional (genetic) resistance or susceptibility. Our previous studies have shown the association between ABA in adult patients and polymorphism of the GSTM1 and GSTT1 genes [12]. 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]. GSTP1 is of particular interest in asthma because chromosome 11q13 is associated with its clinical phenotypes: atopy and bronchial hyper-responsiveness (BHR) [11].

ABA is characterized by elevated immunoglobulin E level, increase in blood eosinofil counts and BHR. The latter reflects inflammation in the asthmatic airway, a key component of which is generation of ROS [4,5]. BHR is modulated by ROS levels, possibly through their ability to regulate eicosinoid production via stimulation of arachidonic acid release. The GST genes are good candidates for participating in ABA because the enzymes they encode modulate ROS levels [9]. Data of the present study favor our earlier hypotheses that individual ability to detoxify ROS and their products, determined by polymorphism of GST genes, contribute to the development of asthma. This view is supported by studies showing that individuals with reduced antioxidant capacity are at increased risk of allergic asthma.

The GSTM1, GSTT1 and GSTP1 genes ensure synthesis of enzymes that belong to the phase II detoxification enzyme system [12,13]. The GSTM10/0 and GSTT10/0 alleles are distinguished in phenotypes as an absence of the relevant enzyme products, that are very important components of the detoxification system. The amino acid changes in the GSTP1 gene are localized in the electrophilic-binding active site of the GST-pi peptide, and as a result of these changes, the activity of the enzyme decreases [14].

Significantly higher levels of GSTM10/0 (79%) and GSTT10/0 (58%) in ABA children advocates the possible participation of these gene products in bronchial asthma pathogenesis. In contrast to GSTM1 and GSTT1 genes, polymorphisms in the pi class of GST genes in our study were not associated with asthma. Thus, it is remarkable that over 90% of the bronchial asthma patients under our supervision had a defect in at least one of the investigated genes.

The frequencies of homozygotes for the null alleles of both GST genes (GSTM1 0/0 and GSTT1 0/0) occurs in 49% of asthmatic patients, whereas this genotype comprises only 12% in the control group. Moreover, combinations of functionally impaired genotypes of all three GST genes was rarely encountered in the control group (8%), but it was rather common in the patient group (35%).

Definite correlation between GST gene genotype and the onset of ABA disease was quite obvious. Early onset asthma is less closely associated with GST null genotypes compared to late onset asthma. It is remarkable that atopic dermatitis, a common complication accompanying asthma, reveals straightforward correlation with the type of GST alleles. Ninety percent of ABA children with atopic dermatitis had the GSTM1 deficiency (0/0) versus 57% with the GSTM10/0 genotype in the group of ABA children without this complication.

Thus, the results of the present study extends our earlier findings and advocates unambiguously in favor of a clear-cut association of the GSTM1 and GSTT1 null alleles with ABA. At the moment, it is very difficult to explain the role of GST alleles in the onset and progression of asthma. Meanwhile, the application of genetic tests for GSTM1 (GSTM10/0) and GSTT1 (GSTT10/0) null homozygote identification in relevant families, or even in the population as a whole, might be useful for identifying persons at risk for ABA. The test might be of great practical value for the predictive medicine service.