Association of Polymorphic Variants of HHIP, ADRB2 and IL-33 Genes with Clinical Manifestations of Bronchial Asthma in Children

Studying the contribution of genetic mechanisms to the development of bronchial asthma (BA) is to look for associations of the disease and its phenotypes with polymorphic markers of candidate genes. Objective To investigate the association of polymorphic variants of HHIP, ADRB2 and IL-33 genes with the phenotypes of clinical course of BA in children and the effectiveness of therapy of the disease Patients and methods A cohort single-center study of 90 bronchial asthma patients aged 5 to 17 years with an established diagnosis of bronchial asthma of varying degree of severity and control was conducted. The allele and genotype frequencies of polymorphic loci of the following genes were studied: rs12551256-A and rs146597587-G of IL-33 gene; rs12504628 of HHIP gene and ARG16GLY rs1042713 of ADRB2 gene in 90 BA patients with regard to the severity and control of the disease. In children with severe BA, as well as in children with poorly controlled/uncontrolled asthma (n=26), sequencing of the entire coding sequence of the IL-33 gene located on the 9th chromosome in the 9p24.1 region was additionally performed (search for mutations in 9 exons). Results Comparison of genetic markers in patients with severe BA (tBA) and non-severe BA (nBA) revealed a reduced risk of severe disease realization among those carrying the TT genotype (OR=0.221 (95% CI: 0.059-0.828; χ2=5.759; p=0.056)) and the T allele (OR=0.491 (95% CI: 0.190-1.269; χ2=4.270; p=0.039)) of the studied genetic variant rs12504628 (T>C) of the HHIP gene, the frequency of the CC genotype in severe BA was 64%, versus 28% in nonsevere BA, and the C allele 77% versus 52%.Comparison of genetic markers in patients with a combination of atopic dermatitis (AtD) and bronchial asthma (BA+AtD) and BA without AtD (BA without AtD) revealed an increased risk of combining asthma and dermatitis among individuals carrying the TT genotype (OR=2.875 (95% CI: 1.130-7.316; χ2=5.751; p=0.056)) of genetic variant rs12504628 (T>C) of the HHIP gene. Sequencing and exome analysis of the IL-33 gene showed a statistically significant positive association between the frequency of lesions in exons 4 (r=0.417; p=0.034) and 6 (r=0.593; p=0.001) on the one hand and the severity of BA on the other. Nucleotide substitutions in these exons were found to be more frequently associated with the severe course of bronchial asthma. Conclusion It was shown that TT genotype of genetic variant rs12504628 (T>C) of HHIP gene reduces the risk of severe BA, but increases the risk of atopic dermatitis combined with BA by 2.8 times. The CC+ST genotype of the HHIP gene increases the risk of drug allergy against the background of BA by 2.9 times. Polymorphic variants in exons 4 and 6 of the IL-33 gene are more often combined with moderate and severe asthma, and nucleotide substitutions in exons 4 and 6 are associated with a severe course of BA. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was supported by a joint grant from the Israel Ministry of Science and Technology (MOST, 3-16500), the Russian Centre for Scientific Information (RFBR) (Joint Research Project 19-515-06001) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted in accordance with the principles of the World Medical Association Declaration of Helsinki. Informed consent was obtained in writing from the child's legal representative in accordance with local laws and regulations before the child was included in the study. Conclusion of the local ethical committee at E.A.Wagner Perm State Medical University No. 5/20 dated 4 August 2020. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors