ABSTRACT
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 FEVt /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.
Subject(s)
Asthma/genetics , Interleukin-13/genetics , Neoplasm Proteins/genetics , Adolescent , Adult , Child , Epistasis, Genetic , Genetic Loci/immunology , Genome-Wide Association Study , Humans , Polymorphism, Genetic , SpirometryABSTRACT
BACKGROUND: Childhood asthma is caused by both genetic and environmental factors. The first genomewide association study (GWAS) for asthma revealed putative candidates on nine chromosomal regions in Caucasians, with 17q21 locus being the most widely replicated one. However, there was no replication study for the other loci. This study investigated genetic associations between childhood asthma and autosomal single nucleotide polymorphisms (SNPs) on eight loci reported in the first GWAS among Hong Kong Chinese. METHODS: 510 asthmatic children and 510 non-allergic controls were recruited. 110 tagging SNPs selected based on r(2 ) ≥ 0.80 and minor allele frequency ≥0.05 for Han Chinese among all SNPs located 50-kb upstream and downstream of significant autosomal SNPs were genotyped by TaqMan allelic discrimination assays. Transcription factor binding of SNPs was determined by electrophoretic mobility shift assay (EMSA). RESULTS: Asthma was significantly associated with SNPs on 17q21 and 2q14 loci. Twelve SNPs on 17q21 were associated with asthma, with rs6503527 being the most significant SNP. Five SNPs of protein C gene (PROC) on 2q14 were associated with asthma, with rs6755028 being the most significant SNP. Plasma protein C concentrations were higher in asthmatic patients than controls, and five PROC SNPs were associated with plasma protein C concentrations. EMSA showed specific differential binding of rs878461 to nuclear extracts from bronchial epithelial and hepatocarcinoma cell lines. CONCLUSIONS: Our findings identify PROC on 2q14 as a novel candidate for childhood asthma and replicate the genetic association for 17q21 locus. Rs878461 of PROC may increase asthma susceptibility by altering transcription factor binding.