Association of single-nucleotide variants of the orsomucoid-1-like protein 3 gene with phenotypes of atopic march in children

Abstract

Background. The problem of atopic march (AM), namely its progression from monoorganic phenotypes of atopic dermatitis (AD), allergic rhinitis/rhinoconjunctivitis (AR/ARC), bronchial asthma (BA) to their multiorgan combinations, is one of the biggest in the modern pediatrics. One of the most important causes for the development of these pathologies are single nucleotide variants (SNV) of the causative genes, orsomucoid-1-like protein 3 (ORMDL3), in particular rs_7216389 ORMDL3. The roles of T- and C-alleles in relation to monoorganic and polyorganic AM phenotypes have not been sufficiently studied. The objective was to study associations of the SNVs rs_7216389 ORMDL3 in the development of different AM phenotypes in children. Materials and methods. There were 293 children recruited into the main group and 105 controls aged 3 to 18 years. Children of the main group had monoorganic and polyorganic phenotypes of AM: AD, AR/ARC, BA, AD+AR/ARC, BA+AR/ARC, AD+AR/ARC+BA. Children of the control group suffered from organic and functional digestive pathology without clinical or paraclinical signs of AM. All children were genotyped for C/C, T/T, C/T variants of SNV rs_7216389 ORMDL3 by allelic discrimination method based on real time polymerase chain reaction with restriction fragment length polymorphism of the buccal swab obtained from each patient. Spearman’s correlation coefficient (rs) was used to determine associations; risks and protective effects were determined using logistic regression analysis by calculating odds ratios (OR) and 95% confidence intervals (CI). The results obtained were significant at p < 0.05 according to the Student’s test. Results. Risks and associations for the monoorganic AR/ARC phenotype: C/C SNV rs_7216389 ­ORMDL3: rs = 0.197, OR = 0.33 (95% CI 0.14–0.78, p < 0.05); T/T SNV rs_7216389 ORMDL3: rs = 0.246, OR = 3.21 (95% CI 1.57–6.59, p < 0.05). For the monoorganic BA phenotype: T/T SNV rs_7216389 ORMDL3: rs = 0.192, CI = 2.97 (95% CI 1.08–8.14, p < 0.05). For the polyorganic AD+AR/ARC phenotype: C/C SNV rs_7216389 ORMDL3: rs = 0.146, OR = 0.42 (95% CI 0.16–1.11, p = 0.05–0.1); T/T SNV rs_7216389 ­ORMDL3: rs = 0.265, OR = 3.64 (95% CI 1.62–8.18, p < 0.05). For the polyorganic BA+AR/ARC phenotype: C/C SNV rs_7216389 ORMDL3: rs = 0.163, OR = 0.42 (95% CI 0.19–0.93, p < 0.05); T/T SNV rs_7216389 ORMDL3: rs = 0.255, OR = 3.34 (95% CI 1.63–6.82, p < 0.01). The C/T SNV rs7216389 ORMDL3 genotype did not reveal significant associations or impact on the development of any AM phenotypes in children. Conclusions. The T-allele SNV rs7216389 ORMDL3 has an inductive impact on the development of AM in children — the homozygous T/T genotype of SNV rs7216389 ORMDL3 is significantly associated with and increases the risk of developing the monoorganic AR/ARC and BA phenotypes, as well as polyorganic AD+AR/ARC and BA+AR/ARC phenotypes. The C-allele SNV rs7216389 ORMDL3 has a protective impact on the development of AM in children — the homozygous genotype C/C of SNV rs7216389 ORMDL3 is significantly associated with and reduces the risk of developing the monoorganic AR/AR phenotype, as well as polyorganic AD+AR/AR and BA+AR/ARC phenotypes.