title: Identification of KIF3A as a novel candidate gene for childhood asthma using RNA expression and population allelic frequencies differences.
abstract: BACKGROUND
  Asthma is a chronic inflammatory disease with a strong genetic predisposition. A major challenge for candidate gene association studies in asthma is the selection of biologically relevant genes.
  
  
  RESULTS
  Using epithelial RNA expression arrays, HapMap allele frequency variation, and the literature, we identified six possible candidate susceptibility genes for childhood asthma including ADCY2, DNAH5, KIF3A, PDE4B, PLAU, SPRR2B. To evaluate these genes, we compared the genotypes of 194 predominantly tagging SNPs in 790 asthmatic, allergic and non-allergic children. We found that SNPs in all six genes were nominally associated with asthma (p<0.05) in our discovery cohort and in three independent cohorts at either the SNP or gene level (p<0.05). Further, we determined that our selection approach was superior to random selection of genes either differentially expressed in asthmatics compared to controls (p = 0.0049) or selected based on the literature alone (p = 0.0049), substantiating the validity of our gene selection approach. Importantly, we observed that 7 of 9 SNPs in the KIF3A gene more than doubled the odds of asthma (OR = 2.3, p<0.0001) and increased the odds of allergic disease (OR = 1.8, p<0.008). Our data indicate that KIF3A rs7737031 (T-allele) has an asthma population attributable risk of 18.5%. The association between KIF3A rs7737031 and asthma was validated in 3 independent populations, further substantiating the validity of our gene selection approach.
  
  
  CONCLUSIONS
  Our study demonstrates that KIF3A, a member of the kinesin superfamily of microtubule associated motors that are important in the transport of protein complexes within cilia, is a novel candidate gene for childhood asthma. Polymorphisms in KIF3A may in part be responsible for poor mucus and/or allergen clearance from the airways. Furthermore, our study provides a promising framework for the identification and evaluation of novel candidate susceptibility genes.
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Melinda Butsch
authors.initials: MB
authors.lastname: Kovacic
authors.forename: Jocelyn M Biagini
authors.initials: JM
authors.lastname: Myers
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Mark
authors.initials: M
authors.lastname: Lindsey
authors.forename: Mark B
authors.initials: MB
authors.lastname: Ericksen
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.forename: Tia L
authors.initials: TL
authors.lastname: Patterson
authors.forename: Tesfaye M
authors.initials: TM
authors.lastname: Baye
authors.forename: Dara
authors.initials: D
authors.lastname: Torgerson
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Roth
authors.forename: Jayanta
authors.initials: J
authors.lastname: Gupta
authors.forename: Umasundari
authors.initials: U
authors.lastname: Sivaprasad
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Gibson
authors.forename: Anna M
authors.initials: AM
authors.lastname: Tsoras
authors.forename: Donglei
authors.initials: D
authors.lastname: Hu
authors.forename: Celeste
authors.initials: C
authors.lastname: Eng
authors.forename: Rocío
authors.initials: R
authors.lastname: Chapela
authors.forename: José R
authors.initials: JR
authors.lastname: Rodríguez-Santana
authors.forename: William
authors.initials: W
authors.lastname: Rodríguez-Cintrón
authors.forename: Pedro C
authors.initials: PC
authors.lastname: Avila
authors.forename: Kenneth
authors.initials: K
authors.lastname: Beckman
authors.forename: Max A
authors.initials: MA
authors.lastname: Seibold
authors.forename: Chris
authors.initials: C
authors.lastname: Gignoux
authors.forename: Salma M
authors.initials: SM
authors.lastname: Musaad
authors.forename: Weiguo
authors.initials: W
authors.lastname: Chen
authors.forename: Esteban González
authors.initials: EG
authors.lastname: Burchard
authors.forename: Gurjit K Khurana
authors.initials: GK
authors.lastname: Hershey
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency / Q000235:genetics*; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics; D016547:Kinesins / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012313:RNA / Q000235:genetics*; D015203:Reproducibility of Results
chemical_list: C087415:KIF3A protein, human; D012313:RNA; D016547:Kinesins