© 2005 American Thoracic Society doi: 10.1164/rccm.2503006
Confirmation of GPRAA Putative Drug Target for AsthmaUniversity Medical Center Groningen, and Beatrix Children's Hospital, University of Groningen, Groningen, The Netherlands The development of asthma is determined by a complex interaction between host susceptibility and a variety of environmental exposures. Family- and population-based studies have indicated that multiple genes are likely to be involved in asthma and its intermediate phenotypes. Identification of genes through positional cloning, including ADAM-33, PHF11, DPP10, and HLA-G, represents a major breakthrough in genetic studies of atopy (1, 2). GPRA is the most recent gene characterized by this technique (3). G-protein–coupled receptors (GPCRs) are a pharmacologically important protein family, with over 800 genes identified to date (4). GPCRs have seven transmembrane domains. There are four classes of GPCR based on shared sequence motifs: classes A, B, C, and F/S (5). Many of the GPCRs are still orphan receptors and their function is unknown (6). These receptors are involved in the regulation of metabolism, embryogenesis, tissue regeneration, and cell proliferation. Pathways induced by GPCRs are targets of hundreds of drugs, including antihistamines, bronchodilators, neuroleptics, antidepressants, and antihypertensives. The majority of all prescribed drugs affect either activation of GPCRs or their downstream signals. The best-known example of a GPCR involved in asthma is the ß2-adrenergic receptor. Other examples of GPCRs relevant to asthma are adenosine, histamine, and muscarinic receptors, all located on smooth muscle cells (7). Laitinen and colleagues (3) described a GPCR gene associated with asthma and high total serum IgE levels. Positional cloning analyses found linkage on chromosome 7p in a region that harbored this particular gene in two Finnish populations and a Canadian population. In a 133-kb genomic segment, including a haplotype block with only seven alternative allelic single nucleotide polymorphism (SNP) haplotypes with frequencies above 2%, high IgE and asthma were associated with the four most closely related haplotypes in all three populations. Two genes were localized within this haplotype. The first gene has been called GPRA, for G-protein–coupled receptor for asthma susceptibility, also called GPR154 (5). Two isoforms of GPRA, named A and B, were identified. Isoform A is predominantly expressed in smooth muscle cells, whereas isoform B is overexpressed in epithelial cells of humans with asthma compared with normal control subjects. Furthermore, ovalbumin sensitization in mice induces inflammation that is associated with gpra upregulation, the mouse ortholog of human GPRA, thus supporting a role of GPRA in the pathogenesis of asthma (3). The second gene, named AAAI, is of unknown function, and it is unclear if the gene encodes a functional protein. Interestingly, the findings concerning this gene have not been replicated or refuted so far. One of the essentials in genetic research is that the role of novel genes, as found by positional cloning, is confirmed in different populations. Therefore, it was initially disappointing that the first report published after the findings of Laitinen and coworkers did not replicate their observation (8). That study was performed in 439 patients with atopic and nonatopic asthma, and in 374 control subjects of Korean origin. Shin and colleagues (8) genotyped one haplotype tagging SNP522363G>C and found a higher population frequency in Korea than in the Finnish and Canadian population (i.e., 0.478 vs. 0.333 and 0.386, respectively). They did not find significant association with the risk of asthma, atopy, total serum IgE, and log-transformed PC20 values. Factors that may explain the lack of replication include the following: (1) the number of cases and controls was relatively small; (2) the lack of association of GPRA-SNP522363G>C SNP with asthma was the result of the different genetic background among white and Asian populations, resulting in different haplotypes; and (3) certain genes may lead to the development of asthma in specific ethnic/geographic populations because of different genetic background, environmental interaction, or both. Another explanation may be that this study reported the results of one SNP, but not a complete haplotype analysis. Further studies in white populations have suggested that SNP522363G>C is not a haplotype tagging SNP and that associations of GPRA1 with asthma should be studied within a full haplotype context (9). Kormann and coworkers (9) in this issue (pp. 1358–1362) provide evidence that the GPRA gene is indeed associated with asthma and bronchial hyperresponsiveness and also, but to a lesser degree, the elevation of serum IgE in a German population. This observation is paralleled by a study from Melén and coworkers (10), which appeared in the May 15 issue of AJRCCM. It is of interest to note that the SNP546333 increased the risk for asthma (odds ratio, 1.40), and this association was even more evident when concomitant asthma and bronchial hyperresponsiveness were present (odds ratio, 2.38). This has previously also been shown to be the case when the ADAM33 gene was found to be associated with asthma (11). In that setting, the linkage increased significantly when bronchial hyperresponsiveness was added to the phenotype of a physician's diagnosis of asthma. This association shows that objective criteria for asthma are important in genetic studies and may provide better association than a clinical diagnosis alone (12). Furthermore, there is the issue of why the association with asthma is higher when bronchial hyperresponsiveness is included. This might imply that ADAM 33 is related to changes in the airways that confer susceptibility to bronchial hyperresponsiveness. Interestingly, the GPRA gene has been shown to be expressed at higher levels on airway epithelium of individuals with asthma than in control subjects (3). This could imply that GPRA isoform B plays a role in the airway epithelium. Dysfunction of the bronchial epithelium has been hypothesized to be crucial in asthma pathogenesis (13), and may contribute to bronchial hyperresponsiveness . Changes in airway structure, inflammation, and smooth muscle contractility are the principal components of bronchial hyperresponsiveness. In a recent review, Penn and colleagues (4) suggested that the airway smooth muscle contractile state can be viewed as a function of the net sum of GPCR-mediated signals that result in establishing the level of the key contractile signaling molecule, calcium, and the response of the cell's contractile machinery to calcium. Thus, GPRA could hypothetically contribute to the susceptibility of bronchial hyperresponsiveness. Signaling via GPRA isoform B may be influenced by atopic inflammation, as Kormann and colleagues (9) suggest, since there was a greater association with bronchial hyperresponsiveness in atopic asthma, than with bronchial hyperresponsiveness alone. Because the polymorphisms were associated with IgE as well, a further immunologic role cannot be ruled out. Whatever the reason, how GPRA exerts its function in the lung and how SNPs in this gene alter such mechanisms are questions still waiting to be answered. Because many GPCRs are drug targets, the confirmation of a role for this gene in asthma clearly opens important new avenues for treatment. FOOTNOTES Conflict of Interest Statement: D.S.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; G.H.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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