Laitinen T, Polvi A, Rydman P, et al. Science. 2004;304(5668):300–304
Purpose of the Study.
Susceptibility to asthma is known to be hereditary, but the specific genes that determine the risk for asthma are not understood completely.
The initial studies were conducted on a geographically isolated cohort in northern Finland, and the genetic associations were then confirmed in a separate cohort from Quebec. Finally, a mouse model of ovalbumin-induced lung inflammation was used to address mechanistic questions.
Methods and Results.
Positional cloning was used to identify a 133-kilobase segment containing 2 genes that were associated with asthma risk and high IgE. One of these genes coded for a G protein-coupled receptor named G protein-coupled receptor for asthma susceptibility (GPRA); the B isoform of this protein was found to be elevated in bronchial biopsies and smooth muscle from asthmatic individuals. Lung tissue of sensitized mice also expressed higher levels of GPRA mRNA.
Together, these data implicate GPRA in the pathogenesis of atopy and asthma and provide a novel therapeutic target for these disorders.
Although positional cloning is labor intensive and requires a large number of study subjects, this approach has the distinct advantage of being able to identify genes for which there is no previous mechanistic information linking them to asthma. Using the technique, this group of investigators were able to identify a gene associated with asthma and demonstrated that the protein product is in fact overexpressed in airway tissues in asthma and in the mouse lung in response to allergen challenge. Similar to the recent identification of chitinase by Jack Elias and colleagues at Yale, this discovery should shed new light on inflammatory mechanisms and provide new initiatives for asthma therapy. The GPRA protein is especially interesting in that it is also highly expressed in epithelium of the skin and gastrointestinal tracks: could it also be involved in atopic dermatitis and food allergy? Stay tuned!