Cytokinegene polymorphisms and asthma susceptibility, severity and associated allergic manifestations in Moldovan children

Abstract

Introduction: Asthma is a complex inflammatory disease, caused by the interaction of genetic and environmental factors, and its management requires understanding of its various pathogenesis and control mechanisms. Cytokines and other inflammatory mediators are important factors in asthma pathophysiology. The reported racial and/or ethnic differences in asthma-related loci define the importance of the candidate gene research in ethnically diverse populations. The study was aimed to investigate the association between cytokine gene polymorphisms asthma in a sample of Moldovan patients and controls. Methods: The sample comprised 90 individuals with asthma, aged from 5 to 17 years (mean ±SEM age of 10,9±0,4 years), 51 males and 39 females, who were randomly selected from a group of asthmatic children referred to the Allergy Clinic of the Research Institute for Maternal and Child Healthcare, Chisinau, Moldova, during the years 2009-2010. The control group included 90 healthy children, matched by sex and age with patients’ group (mean age 13,5±0,2), without respiratory symptoms or history of asthma and allergy. 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) in a standard fashion were performed for all the subjects. TNF-a G-308A, IL-4 C-590T and IL-4Ra Arg55lGln polymorphisms were evaluated by polymerase chain reaction. Results: The genotypes frequency for TNF-ct, IL-4, and IL-4Ra were equally distributed in the patient group in comparison with the controls. However, there were significant differences for IL-4 C-590T gene between the subgroups of asthmatics with different degree of the disease severity. Thus, IL-4 CT+TT at position -590 was significantly overrepresented in children with severe asthma in comparison with those with the moderate one (53,8% in severe asthma vs 25,0% in moderate asthma; x2=2,7; gl=l; p=0,086). The same difference was found for the T allele (minor allele): 34,6% in severe asthma vs 12,5% in patients with moderate asthma (x2=5,3; gl=l; p<0,05). The study showed that the homozygous genotype TNF-a GG at position -308 has a protective role, being significantly more frequently identified in children with solitary form of asthma compared with those with allergic triad (86,2% vs 60,0%, respectively; x2—3,88; gl=l; p<0,05). Functionally compromised genotypes TNF-a GA+AA at position -308 were found more frequently in children with asthma associated with other allergic symptoms (40,0% in allergic triad and 55,6% in asthma cases associated with atopic dermatitis vs 13,8% solitary asthma, p<0,05). Conclusions: The results of our study suggested an association between the IL-4 polymorphism at position -590 and asthma severity, and the association of the functionally compromised genotypes of the TNF-a polymorphism at position -308 with different clinical phenotypes of asthma in Moldovan children.