A study of families containing asthma sufferers has led to the discovery of a gene that is associated with the disease. The finding brings the biological basis of asthma into sharper focus.
Asthma — a condition that afflicts hundreds of millions of people worldwide — has been recognized by physicians and lay people for more than two millennia. One would think that after all this time, and with so many affected people, we would understand the root causes of the disease. We don't; but we do know a little. Pathologically, asthma is characterized by infiltration of the airways with two specific types of immune cells. Physiologically, the disease features both the asthma attack itself (episodic obstruction of the airways) and bronchial hyperresponsiveness — the tendency of the airways to narrow when exposed to a stimulus, such as cold, dry air, that would be innocuous in a normal person. Genetically, asthma is known to be a heritable, complex disorder (although the underlying genes have not been pinpointed) that requires exposure to certain environmental factors before it is fully expressed.
With all of this understanding, however, we still can't answer the simple question, 'What causes asthma?'. But in a paper on page 426 of this issue, Van Eerdewegh and colleagues1 describe how they exploited the heritability of asthma to get closer to the solution.
Van Eerdewegh et al. have succeeded in identifying a gene that is associated with susceptibility to asthma. The authors initially studied 460 Caucasian families in which there were at least two siblings who were diagnosed as asthmatic by a physician, and who were using medications for their condition. The authors screened the genomes of all the members of these families by using a set of highly variable DNA markers. With this approach — known as linkage analysis — they found that a specific DNA 'signature' on the short arm of chromosome 20 occurred about 1,000 times more often in pairs of affected siblings than would be expected by chance. When Van Eerdewegh et al. repeated the analysis using a more restricted definition of asthma (that noted above plus the presence of bronchial hyperresponsiveness), they increased the statistical significance by a factor of ten and narrowed the region of interest to one that contained 23 genes, as defined by the Human Genome Project.
To figure out which of these genes was responsible for the linkage signature, the group identified single nucleotides within the genes that varied from person to person. They then carried out two case–control association analyses, in which they investigated whether a particular sequence variant occurred more frequently in the asthma patients than in nationality-matched controls in US and UK populations. By assessing linkage disequilibrium (the non-random association of genes across the genome) and haplotypes (combinations of single nucleotide variations on one chromosome that tend to be inherited together), Van Eerdewegh et al. narrowed the region further and implicated one gene as most commonly associated with asthma. This is the ADAM33 gene, which encodes a protein-processing enzyme known as a metalloprotease2.
Finally, the authors wanted to be sure that the identification of ADAM33 in the case–control studies was not confounded by different ethnic mixes between cases and controls. So they carried out another family-based study, called the transmission-disequilibrium test, in which the observed frequency of gene variants transmitted from healthy parents to children with asthma was compared to the frequency that would be observed if the gene distribution occurred purely by chance. The results again showed that variations in ADAM33 are significantly associated with asthma.
Further support for the importance of this gene came from an earlier study3 of the genetics of bronchial hyperresponsiveness in mice. This study pinpointed a region on mouse chromosome 2 that is close to the region containing a mouse counterpart of ADAM33. This striking body of data is strong evidence that ADAM33 is indeed an asthma-associated gene. It is now up to the community of asthma investigators to determine whether the finding is broadly replicable, and to define the functional implications of this association.
What do we learn from the identification of ADAM33 as an 'asthma gene'? First, this study would seem to confirm that these genetic techniques can be used to unlock the riddle of complex inherited traits. Second, the results suggest that although asthma and allergy are closely related conditions, they have at least some distinct genetic determinants. In Van Eerdewegh et al.'s analysis, linkage was not improved when high levels of the IgE antibody in blood serum — a defining feature of allergy — were included in the definition of asthma. Worldwide, the prevalence of allergy far exceeds that of asthma. So the newly discovered variations in ADAM33 may be the first genetic clue to what turns the runny nose of a person with allergies into an asthma-related wheezy chest. Third, if the results are replicable, the haplotype defined could be used to identify uniform populations of asthma patients for clinical studies.
Fourth, the most tempting mechanistic interpretation of Van Eerdewegh et al.'s data is that the metalloprotease encoded by ADAM33 has a regulatory role, perhaps in processing proteins that influence fibroblast cells and airway smooth-muscle cells — both of which are known to be activated in asthma. It also seems reasonable to speculate that ADAM33 could be important in other airway-obstructing diseases, such as chronic obstructive pulmonary disease. But definitive insights await a full functional analysis of normal ADAM33 and its genetic variants.
We still can't answer the question, 'What causes asthma?'. But we are closer to understanding this complex disease. The study by Van Eerdewegh et al.1 teaches us that there are probably fundamental differences in the airway walls of unaffected people and asthma sufferers. The results broaden the horizons of asthma biologists and physicians beyond a purely immunological interpretation of the disease. This improved understanding is just one benefit derived from the Human Genome Project.
Van Eerdewegh, P. et al. Nature 418, 426–430 (2002); advance online publication, 10 July 2002 (doi:10.1038/nature00878).
Yoshinaka, T. et al. Gene 282, 227–236 (2002).
De Sanctis, G. T. et al. Nature Genet. 11, 150–154 (1995).
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