Van Eerdewegh P, Little RD, Dupuis J, et al. Nature. 2002;418:426–430
Purpose of the Study.
To identify novel genetic polymorphisms associated with bronchial hyperresponsiveness (BHR) in asthma.
Four hundred sixty white affected sib-pair families from the United States and the United Kingdom with current asthma.
A genetic linkage analysis was performed for current asthma and BHR. Case-control, transmission disequilibrium, and haplotype analyses were conducted to identify the gene(s) most commonly associated with asthma. Novel genes of interest were identified by a combination of public data mining, complementary DNA (cDNA) library screening, direct cDNA selection, and reverse transcriptase-polymerase chain reaction (RT-PCR).
Positional cloning revealed a novel genomic region of interest on chromosome 20p13. Ultimately, polymorphisms in the ADAM33 gene were linked to asthma and BHR. ADAM 33 is a complex metalloproteinase with numerous diverse functions that is expressed in lung fibroblasts and bronchial smooth muscle, but not bronchial epithelial cells. The alleles in ADAM 33 that were associated with an increased susceptibility to asthma were common, ranging from 20% to 95%.
Allelic variation in the ADAM33 gene may underlie lower airways dysfunction in asthma, including BHR and airway remodeling.
What are the genetic predispositions to asthma? In this study, current asthma and BHR were linked to a new category of molecules. ADAM proteins are a subfamily of matrix metalloproteinases. They have diverse posttranslational cellular functions, capable of regulating myogenic fusion, proteolysis, cell adhesion, and cell signaling. Their proteolytic functions include the shedding of cell-surface cytokine and cytokine receptors that are involved in inflammation, cell proliferation, and cell death. How the linkage of the ADAM33 gene to asthma and BHR and its expression in human lung fibroblasts and bronchial smooth muscle relates to asthma is not clear. It is speculated that ADAM33 expression may be a primary cause of fibroblast proliferation, and their differentiation into myofibroblasts and smooth muscle, leading to subepithelial fibrosis, smooth muscle hyperplasia and increased matrix deposition, underlying BHR, and airway remodeling. For more information on this subject, please see a brief editorial, titled “Inherit the Wheeze” by Drazen and Weiss, that accompanies this article on pages 383–384 of the same issue, and a review article, titled “ADAM-33 Surfaces as an Asthma Gene,” by Shapiro and Owen in the New England Journal of Medicine (2002;347:936–938).