Personalized genotype-associated diagnosis of the progression of atopic march in children

Abstract

Background. Atopic march (AM) is the progression of atopic lesions (AL) from monoorganic phenotypes (MOPh), usually atopic dermatitis (AD), to a combination with allergic rhinitis/rhinoconjunctivitis (AR/ARC) and bronchial asthma (BA) in the full-scope polyorganic phenotype (POPh) AD + AR/ARC + BA. At the same time, AD is the initial and basic AM MOPh. The basis of AL and AM is the human genotype, in particular, single nucleotide variants (SNV) of genes that predispose to the development of AL phenotypes. Namely, these are SNV of thymic stromal lymphopoietin (TSLP) and orоsomucoid-1-like protein 3 (ORMDL3): SNV rs_11466749 TSLP and rs_7216389 ORMDL3. The purpose of this study was to detect the associations and risks of developing AM POPh AD + AR/ARC and AD + AR/ARC + BA related to baseline MOPh AD and to each other in children with different SNV rs_11466749 TSLP and rs_7216389 ORMDL3 genotypes. Materials and methods. Two hundred and thirty-two children aged 3 to 18 years took part in the study. The main group consisted of 127 patients with 3 studied AM phenotypes: one MOPh AD (n = 58) and two POPh: AD + AR/ARC (n = 43) and AD + AR/ARC + BA (n = 26). The control group included 105 children without AL, suffering from gastrointestinal diseases. All children in the study groups underwent a buccal swab of the DNA material, which then was studied using the real-time polymerase chain reaction with restriction fragment length polymorphism to determine the genotypes of SNV candidates: A/A, A/G, G/G rs_11466749 TSLP and C/C, C/T, T/T rs_7216389 ORMDL3. Pearson’s χ2 criterion and Fisher’s exact test, Bravais-Pearson contingency coefficient (r), logistic regression analysis with determination of odds ratio (OR) with 95% confidence interval (95% CI), receiver operating characteristic (ROC) analysis with calculation of the area under the ROC curve with a 95% CI and operating characteristics — sensitivity and specificity were used for statistical processing. The critical level of statistical significance of the results during testing of all hypotheses was p < 0.05, the tendency to probability was determined at p = 0.05–0.1. Results. The following statistically significant differences were detected in the occurrence of genotypes related to the control group: for POPh AD + AR/ARC: SNV rs_7216389 ORMDL3: C/C — 14.0 %, T/T — 39.5 to 27.6 and 15.2 %, respectively (p = 0.08 and p < 0.05); for POPh AD + AR/ARC + BA: SNV rs_11466749 TSLP: A/A — 77.0 %, A/G — 11.5 to 50.5 and 45.7 %, respectively (p < 0.05 and p < 0.01). Among the phenotypes of the main group, the following statistically significant differences in the genotypes incidence had been detected: AD + AR/ARC related to AD: G/G rs_11466749 TSLP — 9.3 to 1.7 % (p = 0.08), T/T rs_7216389 ORMDL3 — 39.5 to 19.0 % (p < 0.05); AD + AR/ARC + BA related to AD: SNV rs_11466749 TSLP: A/A — 77.0 to 55.2 % (p = 0.06), A/G — 11.5 to 43.1 % (p < 0.01), G/G — 11.5 to 1.7 % (p = 0.09). The following associations were found between POPh AM and MOPh AD: AD + AR/ARC related to AD: G/G rs_11466749 TSLP, r = 0.173 (p = 0.08), T/T rs_7216389 ORMDL3, r = 0.227 (p < 0.05); AD + AR/ARC + BA related to AD: SNV rs_11466749 TSLP: A/A, r = 0.207 (p = 0.06), A/G, r = –0.310 (p < 0.01), G/G, r = 0.213 (p = 0.09). The following statistically significant risks of developing POPh AM were determined related to MOPh AD: AD + AR/ARC: G/G rs_11466749 TSLP, OR = 5.85 (95% CI 0.63–54.31, p = 0.08), T/T rs_7216389 ORMDL3, OR = 2.79 (95% CI 1.14–6.85, p < 0.05); AD + AR/ARC + BA related to AD: SNV rs_11466749 TSLP: A/A, OR = 2.71 (95% CI 0.95–7.73, p = 0.06), A/G, OR = 0.17 (95% CI 0.05–0.64, p < 0.01), G/G, OR = 7.43 (95% CI 0.73–75.23, p = 0.09). Conclusions. Carriers of the G/G rs_11466749 TSLP genotype with a tendency toward probability have a direct association and a 5.85-fold increased risk of developing POPh AD + AR/ARC relative to MOPh AD. Carriers of the T/T rs_7216389 ORMDL3 genotype have a significant direct association and an increased risk (by up to 2.79 times) of developing POPh AD + AR/ARC related to MOPh AD. The risk of developing the complete POPh of AD + AR/ARC + BA related to the basic MOPh AD is determined by different types of SNV rs_11466749 TSLP: A/A and G/G with a trend to significance have direct low associations and increase this risk by up to 2.71 and 7.43 times, respectively, and A/G has significant direct low association and reduces this risk to up to 0.17 times.