Characteristics of cytokine gene polymorphisms in children with different phenotypes of bronchial asthma

BACKGROUND: Bronchial asthma is a chronic inflammatory disease of the airways, the development of which is based on genetic predictors associated with the differentiation and functioning of T-helper (Th) cells. Polymorphisms in the genes of cytokines involved in the regulation of the direction of the Th cell-mediated immune response are risk factors for the development of the disease and the realization of various phenotypes of bronchial asthma.

AIM: To study of the structure and frequency of occurrence of single nucleotide polymorphisms of cytokine genes with an assessment of the risk of various phenotypes of bronchial asthma in children.

MATERIALS AND METHODS: In this case–control study, 250 children were examined, including 150 children with a verified diagnosis of bronchial asthma (including 75 children with virus-induced and 75 children with allergen-induced disease phenotypes) and 100 sexually comparable healthy peers. The children underwent a comprehensive general clinical and allergological examination, genotyping, structure analysis, frequency of occurrence of cytokine gene polymorphisms, and calculation of the odds ratio of the risk of developing different bronchial asthma phenotypes. DNA samples isolated from peripheral venous blood were used as material for molecular genetic analysis. The following mutation points were selected: IFN-γ (T-874A), IL-4 (C-589T), IL-6 (C-174G), IL-17A (G-197A), and TNF-α (G-308A).

When processing digital data, we used the methods of descriptive, parametric, and nonparametric statistics of the Statistica 10 program, comparison of unrelated groups by qualitative characteristics, and assessment of the correspondence of the distributions of genotypes to the expected values at the Hardy–Weinberg equilibrium. The frequency distributions of genotypes and alleles in two subpopulations were analyzed using the chi-square test (χ2).

RESULTS: A comparative analysis of the frequencies of alleles and genotypes of cytokines of various Th profiles with the definition of features in allergen-induced and virus-induced phenotypes of the disease revealed the predominance of homozygous genotypes IFN-γ (A-874A), IL-4 (T-589T), IL-6 (G-174G), IL-17A (A-197A), and TNF-α (A-308A) in children with bronchial asthma, and in healthy peers, IFN-γ (T-874T), IL-4 (C-589C), IL-6 (C-174C), IL-17A (G-197G), and TNF-α G-308G were prevalent. Heterozygous genotypes IL-4 (C-589T), IL-6 (G-174C), IL-17A (G-197A), and TNF-α (G-308A) were found in children with bronchial asthma more often than in healthy peers, with the exception of the IFN-γ genotype (T-874A). In children with the virus-induced bronchial asthma phenotype, the presence of the IL-4 (C-589T) mutant allele was found in 30.67% of cases with an odds ratio of 19.3 (95% CI, 11.23–33.31). When carrying the mutant A-genotype IFN-γ (T-874A), the odds ratio of the risk of developing the disease reflected a high degree of probability of the virus-induced bronchial asthma phenotype (OR, 5.11; 95% CI, 3.18–8.23). Carriage of homozygous genotypes IL-6 (G-174G) and IL-17A (A-197A) determined an increased risk of developing allergen-induced bronchial asthma (OR, 2.71; 95% CI, 1.73–4.18, and OR, 0.51; 95% CI, 0.32–0.71, respectively). Among children with bronchial asthma, a statistically significant increase was noted in the incidence of the functionally unfavorable genotype A308A of the TNF-α gene, and the odds ratio reflects a 2.6-fold increase in the risk of developing a virus-induced bronchial asthma phenotype (χ²=18.66; p=0.017; OR, 2.60; 95% CI, 1.67–4.01).

CONCLUSIONS: As a result of the study, significant differences were determined in the structure and frequency of occurrence of cytokine gene polymorphisms in children with allergen and virus-induced bronchial asthma, depending on the realized phenotype of the disease. Carriage of mutant alleles IFN-γ (A-874A), IL-4 (T-589T), IL-6 (G-174G), IL-17A (A-197A), and TNF-α (A-308A) can be characterized as genetic predictors of bronchial asthma, for the implementation of the virus-induced phenotype, and the odds ratio is higher in the presence of mutant alleles IFN-γ (A-874A), IL-4 (T-589T), and TNF-α (A-308A), for the allergen-induced phenotype of the disease — IL-6 (G-174G) and IL-17A (A-197A).