Department of neonatology, General Hospital of Northern Theater Command, Shenyang, 110016, Liaoning, People's Republic of China.
Post-graduate College, Jinzhou Medical University, Jinzhou, 121000, Liaoning, People's Republic of China.
BMC Pulm Med. 2023 Dec 6;23(1):493. doi: 10.1186/s12890-023-02790-0.
Asthma is a polygenic disease that may onset during childhood. Inhaled corticosteroids (ICS) are the main therapy in asthma, although their efficacy varies among individuals. Nuclear factor κB (NF-κB) is an important target of ICS treatment of asthma. Recent research has reported that GRB2 associated binding protein 1 (GAB1) gene may participate in the pathogenesis of asthma by regulating the NF-κB pathway. Therefore, we used the technique of an improved multiplex ligation detection reaction to sequence GAB1 gene and investigated the involvement of Single-nucleotide variants (SNVs) in GAB1 gene in asthma and ICS efficacy in asthmatic children. We found no differences between asthma cases and controls in allele or genotype frequencies of GAB1. Haplotype analysis showed an increased tendency for AGGAGC frequency in asthma patients compared with controls (OR = 2.69, p = 0.018). The percentage of EOS and genotype distribution of rs1397527 were associated (p = 0.007). The EOS percentage was higher in GT genotype when compared to the GG genotype (5.50 vs 3.00, Bonferroni adjusted p = 0.005). After 12-weeks ICS treatment, GAB1 rs1397527 TT and GT genotype carriers had a smaller change in forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) than GG carriers (p = 0.009), and rs3805236 GG and AG genotype carriers also had a smaller change in FEV1/FVC than AA carriers (p = 0.025). For ICS response, the frequency of GG genotype of rs1397527 was significantly higher in good responders (p = 0.038). The generalized multifactor dimensionality reduction (GMDR) analysis showed a best significant four-order model (rs1397527, allergen exposure, environmental tobacco smoke exposure, and pet exposure) involving gene-environment interactions (p = 0.001). In summary, we found that GAB1 SNVs were not associated with asthma susceptibility. Haplotype AGGAGC was a risk factor for asthma. GAB1 variants were associated with eosinophils and ICS response in asthmatics. Furthermore, gene-environment interaction was observed.
哮喘是一种多基因疾病，可能在儿童时期发病。吸入性皮质类固醇（ICS）是哮喘的主要治疗方法，尽管其疗效在个体之间有所不同。核因子 kappa B（NF-κB）是 ICS 治疗哮喘的重要靶点。最近的研究表明，GRB2 相关结合蛋白 1（GAB1）基因可能通过调节 NF-κB 途径参与哮喘的发病机制。因此，我们使用改良多重连接检测反应技术对 GAB1 基因进行测序，并研究 GAB1 基因中的单核苷酸变异（SNVs）在哮喘和哮喘儿童 ICS 疗效中的作用。我们发现哮喘病例和对照组之间 GAB1 等位基因或基因型频率无差异。单体型分析显示哮喘患者中 AGGAGC 频率呈增加趋势，与对照组相比（OR=2.69，p=0.018）。EOS 百分比和 rs1397527 基因型分布相关（p=0.007）。与 GG 基因型相比，GT 基因型的 EOS 百分比更高（5.50 比 3.00，Bonferroni 校正 p=0.005）。ICS 治疗 12 周后，GAB1 rs1397527 TT 和 GT 基因型携带者的用力呼气量 1 秒/用力肺活量（FEV1/FVC）变化小于 GG 携带者（p=0.009），rs3805236 GG 和 AG 基因型携带者的 FEV1/FVC 变化也小于 AA 携带者（p=0.025）。对于 ICS 反应，rs1397527 GG 基因型的良好反应者频率明显较高（p=0.038）。广义多因素维度缩减（GMDR）分析显示，基因-环境相互作用的最佳显著四阶模型（rs1397527、过敏原暴露、环境烟草烟雾暴露和宠物暴露）（p=0.001）。综上所述，我们发现 GAB1 SNVs 与哮喘易感性无关。单体型 AGGAGC 是哮喘的危险因素。GAB1 变体与哮喘患者的嗜酸性粒细胞和 ICS 反应有关。此外，还观察到基因-环境相互作用。
