AIM: To investigate the clinical role of T-cell transcription factor (TBX21) and adenylate cyclase 9 antibody (ADCY9) gene polymorphisms in the development of childhood asthma. METHODS: Two hundred Han Chinese wheezing children aged 5 years and younger in Henan region from July  2016 to January 2017 were selected as the study group, and another 100 Han Chinese healthy children aged 5 years and younger in the same period were selected as the control group. Oral mucosal exfoliated cells were collected from both groups, and the genotypes of TBX21 gene rs2240017 polymorphic locus and ADCY9 gene rs2230739 polymorphic locus were detected by real-time fluorescence quantitative polymerase chain reaction (PCR) tech- nique, and the risk level of asthma was assessed based on the test results. The children in the low-risk and high-risk groups were compared in terms of serum immunoglobulin E (IgE) levels, API positivity rate and allergic disease incidence, and the correlation between the risk level of asthma-related genetic polymorphisms and serum IgE levels, API and allergic disease incidence was analyzed. All children were followed up until 6 years of age to confirm the diagnosis of asthma, and the incidence of asthma was compared between the low-risk and high-risk groups. Children with asthma were treat- ed with inhaled glucocorticoids and leukotriene receptor antagonists for 3 months, and the control of asthma and the impairment of lung function were compared between the low-risk and high-risk groups. RESULTS: The genotype detection results of rs2240017 polymorphic locus of TBX21 gene and rs2230739 polymorphic locus of ADCY9 gene in the study group compared with those in the control group were statistically significant (P<0.001). The percentages of CC, CT, and TT genotypes of rs2240017 polymorphic locus of TBX21 gene were 19.50%, 56.00%, and 24.50%, respectively, and the percentages of CC, CG, and GG genotypes of rs2230739 polymorphic locus of ADCY9 gene were 86.00%, 10.00%, and 4.00%, respectively, in 200 children with wheezing; serum IgE level, API positiv- ity rate and allergic disease incidence were higher in the high-risk group than in the low-risk group (P< 0.001, <0.001, 0.021, respectively). The degree of risk of asthma-related gene polymorphisms in children with wheezing was positively correlated with serum IgE levels, API positivity, and the incidence of allergic diseases (P<0.001); the incidence of asthma (81.48%) and impaired lung function (74.07%) were higher in the high-risk group than in the low-risk group (4.90%, 3.50%) (P<0.001). There was no statistically significant difference between the asthma control rate of children with asthma in the high-risk group (79.55%) compared with the asthma control rate of children with asthma in the low-risk group (100.00%) (P=0.433). CONCLUSION: Gene polymorphisms at rs2240017 locus of TBX21 gene and rs2230739 locus of ADCY9 gene are closely associated with asthma development and impaired lung function in children with wheezing.