title: Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function.
abstract: BACKGROUND
  Asthma commonly originates in early life in association with impaired lung function, which tracks to adulthood.
  
  
  OBJECTIVE
  Within the context of a prospective birth cohort study, we investigated the association between single nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene and early-life lung function.
  
  
  METHODS
  Children were genotyped for 17 SNPs in ADAM33. Lung function at age 3 (n = 285) and 5 years (n = 470) was assessed using plethysmographic measurement of specific airway resistance (sRaw). At age 5, we also measured FEV(1). SNPs were analyzed individually using logistic regression, followed by linkage disequilibrium mapping to identify the causal locus.
  
  
  RESULTS
  Carriers of the rare allele of F+1 SNP had reduced lung function at age 3 years (p = 0.003). When the recessive model was considered, four SNPs (F+1, S1, ST+5, V4) showed association with sRaw at age 5 years (p < 0.04). Using linkage disequilibrium mapping, we found evidence of a significant causal location between BC+1 and F1 SNPs, at the 5' end of the gene. Four SNPs were associated with lower FEV(1) (F+1, M+1, T1, and T2; p < or = 0.04). The risk of transient early wheezing more than doubled among children homozygous for the A allele of F+1 (odds ratio, 2.39; 95% confidence intervals, 1.18-4.86; p = 0.02), but there was no association between any SNP and allergic sensitization or physician-diagnosed asthma.
  
  
  CONCLUSIONS
  Polymorphisms in ADAM33 predict impaired early-life lung function. The functionally relevant polymorphism is likely to be at the 5' end of the gene.
authors.affiliation: North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK. asimpson@fs1.with.man.ac.uk
authors.forename: Angela
authors.initials: A
authors.lastname: Simpson
authors.forename: Nikolas
authors.initials: N
authors.lastname: Maniatis
authors.forename: Francine
authors.initials: F
authors.lastname: Jury
authors.forename: Julie A
authors.initials: JA
authors.lastname: Cakebread
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Lowe
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Holgate
authors.forename: Ashley
authors.initials: A
authors.lastname: Woodcock
authors.forename: William E R
authors.initials: WE
authors.lastname: Ollier
authors.forename: Andrew
authors.initials: A
authors.lastname: Collins
authors.forename: Adnan
authors.initials: A
authors.lastname: Custovic
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.forename: Sally L
authors.initials: SL
authors.lastname: John
mesh_terms: D051722:ADAM Proteins; D001249:Asthma / Q000235:genetics* / Q000503:physiopathology; D002675:Child, Preschool; D015331:Cohort Studies; D019483:Disintegrins / Q000235:genetics*; D005260:Female; D005333:Fetus; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008666:Metalloendopeptidases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011247:Pregnancy; D011379:Prognosis; D011446:Prospective Studies; D012129:Respiratory Function Tests / Q000379:methods; D018709:Statistics, Nonparametric; D011795:Surveys and Questionnaires
chemical_list: D019483:Disintegrins; D051722:ADAM Proteins; C450441:ADAM33 protein, human; D008666:Metalloendopeptidases