Genetic effects of multiple asthma loci identified by genomewide association studies on asthma and spirometric indices

Background: Genomewide association study (GWAS) published by GABRIEL consortium identified 10 asthma-associated loci. However, their relationship with lung functions is unclear. This study investigated the association between asthma traits and single-nucleotide polymorphisms (SNPs) of these GWAS loci. Methods: Rs3894194 and rs9273349 were not genotyped due to unavailable TaqMan assays. Genetic associations of remaining eight SNPs were investigated in 903 school-age asthmatics and 1205 non-allergic controls. Four significant SNPs were then replicated in 479 adult asthmatics and 746 adult controls, and 1341 Chinese preschool children. Meta-analyses were performed by combining data from school-age children and adults. Generalized multifactor dimensionality reduction (GMDR) was used to analyze their interactions for asthma traits. Results: Childhood asthma was associated with GSDMB_rs2305480 (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.57-0.83). IL13_rs1295686 was associated with all asthma (OR 1.64, 95% CI 1.16-2.32) and early-onset asthma (OR 1.92, 95% CI 1.20-3.06) in adults, whereas GSDMB_rs2305480 was only associated with early-onset asthma (OR 0.69, 95% CI 0.49-0.96). According to meta-analyses, the minor allele of rs2305480 was inversely associated with FEV₁, FVC, and FEV₁/FVC (p < 0.01). GMDR analyses revealed 2-locus models of SLC22A5 with SMAD3 to modulate FEV_t/FVC in both preschool children and adults, with IL13 to determine FVC in both school-age children and adults, and with IL2RB to modulate FEV₁/FVC in school-age children. Conclusions: IL13 and GSDMB are replicated as asthma genes. Rs2305480 of GSDMB is also associated with low FEV₁, FVC, and FEV₁/FVC among asthmatics. Moreover, SLC22A5, IL13, SMAD3, and GSDMB interact to modulate spirometric indices.