Frequency and impact of glutathione-S-transferase gene polymorphisms on lung function and bronchial asthma susceptibility in Moldovan children

Abstract

Asthma is a highly prevalent chronic inflammatory disease of the respiratory tract with genetic predisposition. However, the complex mechanisms of its inheritance, from the genetic predisposition of atopy to allergic diseases, are still not completely understood. Recent data suggest that the pathogenesis of atopic diseases is complex and might be caused by gene-gene and/or gene-environmental interactions. Polymorphisms of the glutathione-S-transferase (GST) genes are known risk factors for some environmentally related diseases. The aim of the present study was to investigate the frequency of polymorphisms in the GSTT1, GSTM1, GSTP1 and NAT2 genes in the population groups of healthy Moldovans and children with asthma, and to analyze their role on lung function. The studied population included 180 subjects – 90 children with asthma, aged 5 to 17 years (mean ± VEM age of 10,9 ± 0,4 years) and 90 healthy controls who showed no signs or history of allergic diseases (mean age 13,5 ± 0,2 years). The asthma group included 51 males and 39 females, who were randomly selected from asthmatic children referred by the Allergy Clinic of the Research Institute for Maternal and Child Healthcare, Chisinau, Moldova, during 2009-2010. Asthma was defined according to the criteria of the Global Initiative for Asthma (GINA). A complete clinical history, physical examination, and pulmonary function test (PFT) were performed for all the subjects in accordance with standards. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured using a portable spirometer (Spirobank G, Mir, Italy). Genes coding for the xenobiotic-metabolizing enzymes (GSTT1, GSTM1, GSTP1 and NAT2) were evaluated by polymerase chain reaction (PCR). Analysis of the xenobiotic-metabolizing enzyme genes’ frequency in the studied population showed an equally distributed prevalence of GST genes genotypes in the patient group in comparison with the controls. However, the heterozygous genotype of the GSTP1 341 C>T Ala114Val polymorphism was found significantly more frequent in healthy subjects (14,4±9,7% in patients vs 26,7±9,0% in controls; χ2 = 3,4, gl = 1, p=0,06). The GSTM1 null genotype was overrepresented in asthmatic males in comparison with controls (54,9±9,4% vs 35,3±11,3%; χ2 = 3,21, gl=1, p=0,07). The GSTT1 null genotype was associated with a significant decrease in the FEV1/FVC% ratio when compared with the GSTT1 wild genotype (89,3±3,4 vs 95,8±1,3, respectively, p<0,05) and the homozygous GSTP1 Val105Val genotype was associated with the decrease of FEV1 (64,4±8,2 vs 87,3±2,5 in patients with GSTP1 Ile105/x genotypes, p<0,001) and the FEV1/FVC% ratio (82,6±5,7 vs 95,8±1,2 in patients with GSTP1 Ile105/x genotypes, p<0,01). However, there was no association between GSTM1 polymorphism and lung function tests. Our results suggest that GST gene polymorphisms may play an important role in asthma susceptibility in Moldovan children. Also GST gene polymorphisms may affect asthma pathogenesis as polymorphisms influence lung functioning in asthmatic children. These findings suggest a potentially raised susceptibility to negative environmental influences and predisposition to respiratory morbidity in this particular group.