ADAM 33: just another asthma gene or a breakthrough in understanding the origins of bronchial hyperresponsiveness?
- Southampton General Hospital, Southampton, UK
- Correspondence to:
Professor S T Holgate, Southampton General Hospital, Southampton, UK;
s.holgate{at}soton.ac.uk
ADAM 33, the latest of the ADAM proteins to be described, has been identified as a major susceptibility gene in asthma linked to bronchial hyperresponsiveness. It provides an important breakthrough in our understanding of this complex disorder and its variable clinical and physiological presentations.
Asthma is a disorder of the conducting airways in which Th2 mediated inflammation interacts with structural changes to cause variable airflow obstruction. Fundamental to disordered function is the concept of bronchial hyperresponsiveness (BHR) in which the airways constrict too much and too easily. In chronic severe asthma the inflammation and structural changes both become more intense1 and are paralleled by an increase in BHR that is only partially or non-responsive to treatment with corticosteroids.2 Explanations for BHR include mucosal and adventitial swelling causing a disproportionate reduction in airway calibre for a given degree of airways smooth muscle (ASM) shortening,3 excessive ASM shortening,4 an increase in ASM mass causing greater force generation,5 and an excessive velocity of contraction linked to altered crossbridge cycling.6 Morphometric studies have shown a graded increase in ASM mass in proportion to disease severity, and computer modelling has revealed that this and altered contractility are the most plausible explanations for BHR.5,7
IDENTIFICATION OF A NEW ASTHMA RELATED GENE
Asthma has a high heritability of up to 79%,8 involving a few genes with moderate effects rather than many genes with small effects.9 We have recently reported the first novel asthma related gene identified by positional cloning.10 A genome wide screen was undertaken using phenotypic data and DNA from 362 families in Wessex and 98 in the USA with at least two siblings with asthma. Using 401 microsatellite markers at a density of 9 cM and multipoint linkage analysis, suggestive evidence for linkage (maximum lod score (MLS) 2.24) was found on …
