title: Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma.
abstract: OBJECTIVE
  Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated.
  
  
  METHODS
  Using genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP.
  
  
  RESULTS
  We demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively). In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p<0.05). We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls.
  
  
  CONCLUSIONS
  Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. These results provide novel evidence for a role for ATG5 in childhood asthma.
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Jayanta
authors.initials: J
authors.lastname: Gupta
authors.forename: Soma S S K
authors.initials: SS
authors.lastname: Jyothula
authors.forename: Melinda
authors.initials: M
authors.lastname: Butsch Kovacic
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Biagini Myers
authors.forename: Tia L
authors.initials: TL
authors.lastname: Patterson
authors.forename: Mark B
authors.initials: MB
authors.lastname: Ericksen
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Gibson
authors.forename: Tesfaye M
authors.initials: TM
authors.lastname: Baye
authors.forename: Sushil
authors.initials: S
authors.lastname: Amirisetty
authors.forename: Anna M
authors.initials: AM
authors.lastname: Tsoras
authors.forename: Youbao
authors.initials: Y
authors.lastname: Sha
authors.forename: N Tony
authors.initials: NT
authors.lastname: Eissa
authors.forename: Gurjit K Khurana
authors.initials: GK
authors.lastname: Hershey
mesh_terms: D000293:Adolescent; D001249:Asthma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009297:Nasal Mucosa / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D049410:Luciferases, Renilla; D049409:Luciferases, Firefly; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes