The ADAM33 (a disintegrin and metalloprotease domain-containing protein 33) gene, discovered through positional cloning, is the first to be associated with asthma and bronchial hyperresponsiveness.
ADAM33, a disintegrin and metalloproteinase 33 gene, has been identified as a risk factor for asthma and bronchial hyperresponsiveness and has been postulated as a gene for airway remodeling.
ADAM33, the first asthma candidate gene identified by positional cloning, may be associated with childhood asthma, lung function decline and bronchial hyperresponsiveness.
Subsequent genetic studies have now provided evidence that ADAM33 may be involved in determining lung function throughout life, associated with early life lung function as well as increased decline therapeutic intervention in asthma and future work will focus on the mechanisms by which it alters lung function and bronchial hyperresponsiveness.
It has been previously suggested that ADAM33, which is a member of a gene family that encodes membrane-anchored proteins with a disintegrin and a metalloprotease domain, is primarily expressed in lung fibroblasts and bronchial smooth muscle cells and has been associated with airway remodelling and bronchial hyperresponsiveness.
The ADAM33 gene has recently been identified as being a potentially important asthma candidate gene, and polymorphisms in this gene have been shown to be associated with asthma and bronchial hyperresponsiveness in Caucasian individuals from several populations.
Several ADAM33 protein isoforms occur in adult bronchial smooth muscle and in human embryonic bronchi and surrounding mesenchyme, strongly suggesting its importance in smooth muscle development and/or function, which could explain its genetic association with bronchial hyperresponsiveness.
The potential for therapeutic intervention with ADAM 33 is extremely attractive and further work will not only focus on the specific domains of ADAM 33, but also the mechanisms by which they lead to bronchial hyperreactivity.
The identification of ADAM33 as a major risk factor involved in the pathogenesis of BHR and airway wall remodelling provides insight into the pathogenesis of asthma and represents a novel therapeutic target.
IL4 and IL13 strongly influence bronchial hyperreactivity in response to allergen, airway remodeling, airway inflammation and airway smooth muscle proliferation.
In addition, there appears to be a synergistic effect between the TNF-alpha promoter polymorphism and an IL-13 coding region polymorphism in terms of asthma susceptibility and BHR in this population.