title: Mechanistic role of a disease-associated genetic variant within the ADAM33 asthma susceptibility gene.
abstract: BACKGROUND
  ADAM33 has been identified as an asthma-associated gene in an out-bred population. Genetic studies suggested that the functional role of this metalloprotease was in airway remodeling. However, the mechanistic roles of the disease-associated SNPs have yet to be elucidated especially in the context of the pathophysiology of asthma. One disease-associated SNP, BC+1, which resides in intron BC toward the 5' end of ADAM33, is highly associated with the disease.
  
  
  METHODS
  The region surrounding this genetic variant was cloned into a model system to determine if there is a regulatory element within this intron that influences transcription.
  
  
  RESULTS
  The BC+1 protective allele did not impose any affect on the transcription of the reporter gene. However, the at-risk allele enforced such a repressive affect on the promoter that no protein product from the reporter gene was detected. These results indicated that there exists within intron BC a regulatory element that acts as a repressor for gene expression. Moreover, since SNP BC+1 is a common genetic variant, this region may interact with other undefined regulatory elements within ADAM33 to provide a rheostat effect, which modulates pre-mRNA processing. Thus, SNP BC+1 may have an important role in the modulation of ADAM33 gene expression.
  
  
  CONCLUSIONS
  These data provide for the first time a functional role for a disease-associated SNP in ADAM33 and begin to shed light on the deregulation of this gene in the pathophysiology of asthma.
authors.affiliation: Molecular Therapeutics Division, AmberGen Incorporated, Waltham, Massachusetts 02453, USA. rdm@ambergen.com
authors.forename: Richard G
authors.initials: RG
authors.lastname: Del Mastro
authors.forename: Laura
authors.initials: L
authors.lastname: Turenne
authors.forename: Heidi
authors.initials: H
authors.lastname: Giese
authors.forename: Tim P
authors.initials: TP
authors.lastname: Keith
authors.forename: Paul
authors.initials: P
authors.lastname: Van Eerdewegh
authors.forename: Klaus J W
authors.initials: KJ
authors.lastname: May
authors.forename: Randall D
authors.initials: RD
authors.lastname: Little
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D001249:Asthma / Q000235:genetics*; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
chemical_list: D051722:ADAM Proteins; C450441:ADAM33 protein, human