Open Access Open Badges Research article

Mechanistic role of a disease-associated genetic variant within the ADAM33 asthma susceptibility gene

Richard G Del Mastro1*, Laura Turenne2, Heidi Giese1, Tim P Keith3, Paul Van Eerdewegh3, Klaus JW May4 and Randall D Little3

Author Affiliations

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

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BMC Medical Genetics 2007, 8:46  doi:10.1186/1471-2350-8-46

Published: 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.