Pollen — a common trigger for asthma.

Asthma is characterized by chronic inflammation of the airways that results in breathing difficulties, coughing and wheezing. So far, there have been reports of linkage to at least nine chromosomes, and a paper by Keith and colleagues in Nature now reports linkage to a tenth. So, why should we get excited? Keith and colleagues show that, through careful and thorough work, it was possible to locate a novel asthma susceptibility gene — in this case, one that has a plausible role in the disease and so might encode a therapeutic target.

In this study, the authors carried out a multipoint linkage analysis on Caucasian families from both the United States and the United Kingdom. Definition of the 'asthma' phenotype is crucial, and, in this study, cases had to be diagnosed by a physician and to need asthma medication. Unexpectedly, the strongest linkage signal was to 20p13, a region not previously implicated by most large-scale asthma studies. However, the region on mouse chromosome 2 that is syntenic to human 20p13 is linked to bronchial hyperresponsiveness (BHR), which often occurs in asthma patients. Indeed, when the authors only considered the cases of asthma with BHR, the linkage signal in 20p13 got even stronger. So, the group constructed a physical map of the 2.5-Mb region with the strongest signal.

To find the right gene, the authors reanalysed the cases for association to SNPs and haplotypes (SNP combinations) in the 20p13 interval using a case–control study design. The strongest associations occurred in the ADAM33 gene. The authors then went on to analyse some of their SNP markers in ADAM33 in a family-based test for association, the TDT. Certain ADAM33 alleles were significantly over-transmitted to asthmatic compared with non-affected offspring, especially when the tested phenotype was restricted to asthma with BHR. So, using several approaches, Keith and colleagues seem to have pinpointed quite robustly a novel susceptibility gene for asthma.

So, what does ADAM33 have to do with asthma? The gene encodes a zinc-dependent metalloprotease, which the authors show is expressed in lung tissues. Such proteins could be important for remodelling the airway in response to injury, and it is conceivable that variation in the amount of functional ADAM33 product leads to impaired remodelling and therefore chronic inflammation. No causative mutations in the gene have been reported, and we don't know whether variation in the abundance or activity of the ADAM33 protein is altered in the lungs of asthma patients. But, in the search for therapies to aid the ∼5% of humans affected with asthma, we can use all the targets we can find.