Association of GAB1 gene with asthma susceptibility and the efficacy of inhaled corticosteroids in children

Abstract

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.

Keywords: Childhood asthma; Environment; GAB1; Inhaled corticosteroids; Interaction; Variant.

Fig. 1

Linkage disequilibrium diagram. (A) coefficient of LD (D′). The D′ value is displayed in gradients from red (strong linkage) to green (weak linkage). (B) correlation coefficient (r²). The r² value is displayed in gradients from black (strong linkage) to gray (weak linkage)

Fig. 2

Changes in FEV1/FVC for the rs1397527 genotypes after treatment. The letters a and b appear separately to indicate differences between groups and there is no difference between groups with same letter

Fig. 3

Analysis of the three-order model. Each cell represents an interaction combination; highrisk cells are denoted by a dark color, lowrisk cells are denoted by a light tint. The more positive the score in the cell, the higher the risk of asthma in the combo

Fig. 4

Analysis of the four-order model. Each cell represents an interaction combination; high-risk cells are denoted by a dark color, low-risk cells are denoted by a light tint. The more positive the score in the cell, the higher the risk of asthma in the combo

Fig. 5

Main findings of the current study