title: Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population.
abstract: BACKGROUND
  It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering.
  
  
  OBJECTIVE
  To identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure.
  
  
  METHODS
  We performed a GWAS by genotyping a total of 480 098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP-gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues.
  
  
  RESULTS
  In the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P = 1.43 × 10(-7) ). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P = 0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P = 7.92 × 10(-9) ). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung.
  
  
  CONCLUSIONS
  Our study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.
authors.affiliation: Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yatagai
authors.forename: T
authors.initials: T
authors.lastname: Sakamoto
authors.forename: H
authors.initials: H
authors.lastname: Yamada
authors.forename: H
authors.initials: H
authors.lastname: Masuko
authors.forename: Y
authors.initials: Y
authors.lastname: Kaneko
authors.forename: H
authors.initials: H
authors.lastname: Iijima
authors.forename: T
authors.initials: T
authors.lastname: Naito
authors.forename: E
authors.initials: E
authors.lastname: Noguchi
authors.forename: T
authors.initials: T
authors.lastname: Hirota
authors.forename: M
authors.initials: M
authors.lastname: Tamari
authors.forename: S
authors.initials: S
authors.lastname: Konno
authors.forename: M
authors.initials: M
authors.lastname: Nishimura
authors.forename: N
authors.initials: N
authors.lastname: Hizawa
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D001249:Asthma / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D002898:Chromosomes, Human, Pair 8; D008192:Deception; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000076002:Hyaluronan Synthases; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors
chemical_list: D012333:RNA, Messenger; D014453:Glucuronosyltransferase; C101754:HAS2 protein, human; D000076002:Hyaluronan Synthases
keywords: asthma; genomewide association study; hyaluronan; hyaluronan synthase 2