Currently, the association studies between genetic variations and asthma susceptibility in population of Chinese children are still limited. To the best of our knowledge, this is the first study that confirmed the rs2236674 SNP in STIP1 gene is significantly associated with the risk of Chinese asthmatic children. We also report here that GLCCI1 rs37969, rs37972, and rs37973 were associated with the response to ICS treatment in Chinese children with asthma.
An Arab study has indicated that the STIP1 rs2236647 C allele can be used as an asthma marker for adult . In our study, C is the major allele of rs2236647 polymorphism and the frequency of wild-type homozygote (CC) in asthmatics was lower than controls. After adjusting the gender and age, we found CC homozygote children had an increased risk of asthma compared with CT/TT genotype. The previous studies were focused on adult asthma and there were no similar results have been reported in childhood asthma. Our finding demonstrated that CC homozygotes of STIP1 rs2236647 polymorphism might be an asthma susceptibility marker in Chinese childhood asthma. However, no relationship was found between rs2236647 polymorphism and onset age of asthma.
Moreover, a white adult asthma study identified that STIP1 rs2236647 was associated with change in lung function after ICS treatment for 4 weeks . But in our study, there was no association between STIP1 rs2236647 and the change of lung function after ICS treatment for 3 months in Chinese children. Therefore, we speculate that the difference may be related to regions and ages and more studies are needed to explore the reasons.
In a Saudi Arabian study, 2 GLCCI1 SNPs, (rs37972 and rs37973), were found to be unrelated to adult asthma susceptibility . Similarly, we found GLCCI1 rs37969, rs37972, and rs37973 polymorphisms were all irrelevant to the risk of childhood asthma in the current study. However, GLCCI1 rs37969 was found to be associated with onset age of asthma. Compared with wild-type homozygote (GG), TT/GT genotypes in asthmatic children were related to the increased risk of early onset asthma. This result indicated that GLCCI1 rs37969 polymorphism might be used to predict the onset age of asthma. And it is necessary that combining rs37969 and the SNPs that are associated with the risk of childhood asthma to predict the occurrence and development of asthma in children.
In 2011, Tantisira et al. discovered that the GLCCI1 SNPs, (rs37972 and rs37973), was associated with change in lung function after ICS treatment in 1,053 asthmatic patients . Then, GLCCI1 rs37972 and rs37973 variant genotypes were found to be related to less improvement in the FEV1 after ICS treatment for 12 weeks in Chinese patients . Similar results were replicated in another Chinese study . Associations also were found between GLCCI1 rs37973 and ICS response in Japanese adult asthmatics . However, a non-Hispanic white study discovered that rs37973 was not associated with the change in FEV1 after treatment with ICS . Negative results were showed in a Saudi Arabian study and a recent GWAS study [21, 25]. Most of the above studies were conducted on adult asthma. In our study, we found there were no associations between GLCCI1 polymorphisms and the improvement in FEV1/pre and FEV1/FVC after ICS treatment in childhood asthma. However, GLCCI1 rs37969, rs37972, and rs37973 mutant genotypes were found to be related to less improvement of the MMEF after ICS treatment. MMEF may be more sensitive than FEV1 when assessing the lung function of asthmatics [26, 27]. Therefore, we support that GLCCI1 can be considered as a predictor of ICS response in Chinese Han childhood asthma, and MMEF deserves more attention after ICS treatment.
It is especially noticed that asthmatic children with GLCCI1 rs37969 mutant genotypes have increased risk of early onset asthma and lower ICS response compared with the wild-gene homozygote in our study. Rs37969 is located in the intron region of GLCCI1 (https://www.ncbi.nlm.nih.gov/snp/). The current data on GLCCI1 rs37969 is extremely lacking, especially in childhood asthma. More basic experimental studies are needed to confirm whether the mutation affects the expression of GLCCI1.
There are still several limitations in this study. First, the follow-up for asthmatic children in this study was only 3 months. The follow-up period could be extended in the future. Second, the number of participants was small for a genetic study, especially in the follow-up group. Third, this study focuses on the effect of single SNPs on childhood asthma. Gene-gene interaction, epigenetics, and environment need to be considered in the future [28, 29].