The role of CYP3A4 polymorphic variants in the development of increased epithelial permeability in children with cow milk allergy: results of the observational cross-sectional study

Background. The continuing increase in the prevalence and severity of allergic diseases determines the relevance of the search for new approaches to their treatment and prevention. One of the leading areas is the study of the epithelial permeability role, including disorders in the cytochrome system that contribute to the formation of increased epithelial permeability and the development of allergies. Aims — to determine the role of the CYP3A4 gene polymorphism (rs2740574) in the development of increased epithelial permeability in children with food allergy to cow’s milk (CMA). Methods. Observational cross-sectional study of infants with a verified diagnosis of food allergy to cow’s milk (main group, n = 30). The study period was from 01.12.2023 to 30.12.2024. The target indicator of the study was the CYP3A4*1B polymorphism (rs2740574; c.-392C>T) of the CYP3A4 gene (rs2740574) in children with CMA in blood lymphocytes and the level of cytochrome P450 3A4 (CYP3A4) in the serum. Additional indicators were the intestinal permeability marker zonulin in the blood serum and feces. Statistical analysis of the results - the difference in the distributions of polymorphic variants between the samples using Fisher’s exact test. Pairwise comparison of genotype and allele frequencies in the groups of patients and healthy people was performed using the chi-square test for contingency tables with Yates’ correction for continuity. The data of the variables are presented as the median and quartiles (Me (Q₁; Q₃)), the nonparametric Mann–Whitney test (U) was calculated to compare quantitative indicators. Differences are significant at p < 0.05. Correlation analysis was performed to determine linear relationships between quantitative and between quantitative and qualitative binary indicators. Results. A statistically significant increase in the frequency of the pathological allele G in patients of the main group by 2.47 times was obtained (χ² = 6.173; p = 0.001). Serum zonulin levels did not show statistically significant differences in patients with CMA compared to the group of healthy children (U = 0.065), but were statistically significantly higher in the group of children with skin manifestations of CMA compared to patients with isolated gastrointestinal manifestations (144.33 ng/ml (Q₁–Q₃: 126.32–151.78) and 118.78 ng/ml (Q₁–Q₃: 108.67–136.24) respectively; p < 0.05). The fecal zonulin level in our study was significantly 1.9 times higher than in the group of healthy children, U = 0.0025, regardless of the clinical phenotype of CMA (1.39 ng/ml (Q₁–Q₃: 1.18–1.61) and 1.45 ng/ml (Q₁–Q₃: 1.14–1.58) respectively; p > 0.05). There were no statistically significant (p = 0.071) differences in the CYP3A4 content in the serum of PA patients (Me = 0.18 ng/ml; Q₁–Q₃: 0.13–0.33) and children in the control group (Me = 0.17 ng/ml; Q₁–Q₃: 0.12–0.20). The conducted correlation analysis showed a significant association of the 392G allele of the CYP3A41B gene with changes in the level of all determined indicators. Conclusions. The results indicate the contribution of cytochrome system disorders in children with increased epithelial permeability. Understanding the molecular mechanism responsible for epithelial barrier defects is important in developing new treatments for food allergies and allergopathology.