Mechanistic role of a disease-associated genetic variant within the ADAM33 asthma susceptibility gene
1 Molecular Therapeutics Division, AmberGen Incorporated, Waltham, Massachusetts 02453, USA
2 Cambridge, MA 02139, USA
3 Genomatix Software GmbH, D-80335 Munich, Germany
4 Genizon BioSciences, Quebec, H4T 2C7, Canada
BMC Medical Genetics 2007, 8:46 doi:10.1186/1471-2350-8-46Published: 17 July 2007
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.
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.
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.
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.