title: Genetic effects of multiple asthma loci identified by genomewide association studies on asthma and spirometric indices.
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.
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Man Fung
authors.initials: MF
authors.lastname: Tang
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Hing Yee
authors.initials: HY
authors.lastname: Sy
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Alice Pik-shan
authors.initials: AP
authors.lastname: Kong
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Fanny Wai-san
authors.initials: FW
authors.lastname: Ko
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Susan Shuxin
authors.initials: SS
authors.lastname: Wang
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Tak Chi
authors.initials: TC
authors.lastname: Liu
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Wa Cheong
authors.initials: WC
authors.lastname: Chan
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Gary Wing-kin
authors.initials: GW
authors.lastname: Wong
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Kam Lun
authors.initials: KL
authors.lastname: Hon
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Juliana Chung-ngor
authors.initials: JC
authors.lastname: Chan
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: David Shu-cheong
authors.initials: DS
authors.lastname: Hui
authors.affiliation: Department of Paediatrics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Ting Fan
authors.initials: TF
authors.lastname: Leung
mesh_terms: D000293:Adolescent; D000328:Adult; D001249:Asthma / Q000235:genetics*; D002648:Child; D004843:Epistasis, Genetic; D056426:Genetic Loci / Q000276:immunology; D055106:Genome-Wide Association Study; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D013147:Spirometry; D000094524:Gasdermins
chemical_list: D018793:Interleukin-13; D009363:Neoplasm Proteins; C485887:GSDMA protein, human; D000094524:Gasdermins
keywords: asthma; epistasis; gene-gene interaction; genomewide association study; lung function