ADAM33, the first asthma candidate gene identified by positional cloning, may be associated with childhood asthma, lung function decline and bronchial hyperresponsiveness.
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.
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.
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.
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.
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 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.
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.
Three genes in a distal region (zinc finger RNA binding protein [ZFR], natriuretic peptide receptor C, and a disintegrin and metalloproteinase domain with thrombospondin type 1 motif [ADAMTS12]) were associated with BHR, whereas 4 genes in a proximal region (prolactin receptor, IL-7 receptor [IL7R], leukemia inhibitory factor receptor [LIFR], and prostaglandin E4 receptor [PTGER4]) were associated with asthma symptoms in the Hutterites.
The Arg16/Gln27 beta(2)AR haplotype is important in COPD, asthma and BHR, and may be associated with more severe respiratory symptoms in middle-aged and older adults.
However, given the importance of beta2AR in modulating lung function, studies have been carried out to determine if polymorphic forms may play roles in promoting asthmatic phenotypes, establishing bronchial hyperreactivity, or influencing the response to acute or chronic beta-agonist therapy.
In contrast, asthma phenotypes, such as asthma severity and bronchial hyperresponsiveness, have been associated with beta(2)-adrenoceptor polymorphisms.
Asthma models show increased ASM G(alphai) expression, considered the basis for the proasthmatic phenotypes of enhanced bronchial hyperreactivity to contraction mediated by M(3)-muscarinic receptors and diminished relaxation mediated by beta(2)-adrenergic receptors (beta(2)ARs).
This observation suggests therefore that ADRB2 gene can confer genetic susceptibility to BHR, rather than having only a disease-modifying effect in asthma.
We performed a retrospective analysis of our database (n = 487) of patients with asthma with the aim first, to compare methacholine and AMP challenge as screening tools, and second, to identify any relationships between BHR and disease severity markers or beta(2)-adrenoceptor genotype.
B2AR polymorphisms may play an important role in the expression of nocturnal cough in atopic subjects but not in the expression of atopy and bronchial hyperresponsiveness in a general population.