CYTOKINE GENES AS GENETIC MARKERS OF CONTROLLED AND UNCONTROLLED ATOPIC BRONCHIAL ASTHMA

Abstract

Atopic bronchial asthma (ABA) is a multifactorial disease; its development is dependent on many environmental and genetic factors. Genetic risk factors can affect the clinical phenotype of ABA and the level of therapeutic control over the disease. Cytokine genes are crucially important in pathogenesis of ABA as they encode proteins participating in immune response and development of inflammation in bronchi. It was suggested that the therapeutic control of the disease is genetically mediated and depends on the presence of one or another allele in genes of mediators, participating in ABA pathogenesis. The knowledge about genetic markers will allow to predict clinical course of ABA in children. We carried out the analysis of association between genes of pro- and anti-inflammatory cytokines with the level of therapeutic control of ABA. In children with controlled and uncontrolled ABA (CABA and UABA, respectively; n = 110), and in general a population sample (n = 138), we analysed 11 polymorphisms: IL2 (rs2069762), IL4 (rs2070874 и rs2243250), IL5 (rs2069812), IL10 (rs1800872 and rs1800896), IL12B (rs3212227), TNFA (rs1800629 and rs1800630), TGFB1 (rs1800469), and IFNG (rs2069705), encoding cytokines actively participating at the development of allergic inflammation. According to results of present study, the prevalence of alleles and genotypes of the analysed loci in the East Siberia Caucasians is consistent with the data in other world Caucasian populations. We have found statistically significant differences between UABA and control groups for the prevalence of IL2 (rs2069762) polymorphism: GG genotype was more common in control group (14.1% compared to 5.9%, р = 0.03). It was shown that the IL2*T allele and ТТ genotype of the rs2069762 are associated with the increased risk of uncontrolled ABA. A comparison of the haplotypes of IL4 (rs2070874 and rs2243250) gene with correction for sex and age within an additive model revealed that the most common haplotype СC (prevalence in ABA/CABA/UABA groups is 0.75/0.76/0.74, respectively) is protective against the development of ABA (RR 0.53±0.32; p = 0.044). A comparative analysis of TNFA (rs1800629 and rs1800630) haplotypes has shown the GC haplotype to be protective against the risk of ABA (RR 0.59±0.17; р = 0.003) while the GA haplotype is positively associated with the disease (RR 2.07±0.25; р = 0.003). This was true for BA, regardless of the control over the disease (CABA GA: RR 1.93±1.2; p = 0.041; UABA GA: RR 2.43±0.31; p = 0.005). Thus, it was established that the studied cytokine genes are important for the development of ABA in children. These data were obtained for the first time for Caucasians of East Siberia. They are of interest in terms of accumulation of the data about the impact of cytokine genes polymorphism upon development of ABA and its therapeutic control in children.

Keywords

• atopy
• inflammation
• bronchial asthma
• cytokines
• gene polymorphism
• disease control