Abstract
Introduction.
The development of postinfectious airway hyperresponsiveness in children remains a major challenge in pediatric pulmonology. Despite the accumulated clinical and functional data, molecular genetic predictors of this condition are still insufficiently studied.
Aim.
To investigate the frequency distribution of genotypes and alleles of the polymorphic loci of TRPV2 (rs1129235, rs3813769, rs7217735), TRPV4 (rs6606743), and TRPM8 (rs11562975) genes in children with various patterns of post-infectious airway reactivity to a hypoosmolar stimulus.
Materials and methods.
A total of 105 children aged 10 [8, 12] years were examined during the recovery phase of respiratory diseases. The mean height of the children was 148.7 ± 1.5 cm, body weight was 40 [30, 53] kg, and body mass index (BMI) was 17.4 [15.7, 20.4] kg/m
2
. Airway response to a hypoosmolar stimulus was assessed using a bronchial provocation test with ultrasonic inhalation of distilled water (IDW). Genotyping of the polymorphic loci in TRPV2, TRPV4, and TRPM8 genes was performed by real-time polymerase chain reaction (qPCR) in peripheral blood leukocytes, followed by high-resolution melting (HRM) curve analysis. The mRNA expression levels of target genes in nasal epithelial cells were determined by quantitative reverse transcription PCR (RT-qPCR) in real-time.
Results.
Based on the results of the bronchial provocation test with IDW, the patients were divided into two groups: children with altered responsiveness to IDW (Group 1, n = 59) and children with no reaction to the stimulus (Group 2, n = 40). In Group 1 patients, airway dysfunction was verified at all levels of the bronchial tree, affecting the entire spectrum of expiratory flow parameters. Molecular genetic analysis revealed a highly significant protective effect of the overdominant inheritance model for the synonymous locus rs6606743 of the TRPV4 gene. It was established that the heterozygous AG genotype was associated with a 4-fold reduction in the odds of developing hypoosmolar bronchospasm in children (OR = 0.25; 95 % CI: 0.10–0.61; p = 0.002). According to the linear regression analysis performed on the entire cohort, the minor A allele of the rs6606743 SNP in the TRPV4 gene was associated with a statistically significant decrease in the degree of FEV
1
decline in response to IDW (β = +3.66 %, R
2
= 0.075, p = 0.0149). No statistically significant associations with the risk of pathology were found for the loci of the TRPM8 and TRPV2 genes.
Conclusion.
The data obtained confirm the contribution of genetic factors to the formation of post-infectious airway reactivity in children. The heterozygous AG genotype of the rs6606743 locus in the TRPV4 gene serves as an independent protective factor that reduces the odds of developing hypoosmolar bronchospasm, whereas the carriage of the minor A allele is associated with a stepwise decrease in the severity of bronchoconstriction. This polymorphism can be considered a prognostic marker for assessing the course of the post-infectious period of respiratory pathology in pediatric practice.