Investigation of the Possible Role of the Hippo/YAP1 Pathway in Asthma and Allergy

PURPOSE: Several lines of evidence indicate that the Hippo/Yes-associated protein 1 (YAP1) pathways might play a role in the pathogenesis of asthma. To investigate the possible role of the Hippo/YAP1 pathway in the pathogenesis of asthma or its phenotypes. METHODS: The levels of gene expressions of the members of the Hippo/YAP1 were compared. The presence of the proteins of the YAP1 and FRMD6 were analyzed with Western blot in induced sputum of 18 asthmatic subjects and 10 control subjects. Fourteen single nucleotide polymorphisms (SNPs) in the YAP1 gene were genotyped in 522 asthmatic subjects and 711 healthy controls. The results were evaluated with traditional frequentist methods and with Bayesian network-based Bayesian multilevel analysis of relevance (BN-BMLA). RESULTS: The mRNA of all the members of the Hippo/YAP1 pathway could be detected in the induced sputum of both controls and cases. A correlation was found between YAP1 mRNA levels and sputum bronchial epithelial cells (r=0.575, P=0.003). The signal for the FRMD6 protein could be detected in all sputum samples while the YAP1 protein could not be detected in the sputum samples, of the healthy controls and severe asthmatics, but it was detectable in mild asthmatics. The rs2846836 SNP of the YAP1 gene was significantly associated with exercise-induced asthma (odds ratio [OR]=2.1 [1.3-3.4]; P=0.004). The distribution of genotypes of rs11225138 and certain haplotypes of the YAP1 gene showed significant differences between different asthma severity statuses. With BN-BMLA, 2 SNPs, genetic variations in the FRMD6 gene proved to be the most relevant to exercise-induced asthma and allergic rhinitis. These 2 SNPs through allergic rhinitis and exercise-induced asthma were in epistatic interaction with each other. CONCLUSIONS: Our results provided additional evidence that the FRMD6/Hippo/YAP1 pathway plays a role in the pathogenesis of asthma. If additional studies can confirm these findings, this pathway can be a potential novel therapeutic target in asthma and other inflammatory airway diseases.

Novel genes in Human Asthma Based on a Mouse Model of Allergic Airway Inflammation and Human Investigations

PURPOSE: Based on a previous gene expression study in a mouse model of asthma, we selected 60 candidate genes and investigated their possible roles in human asthma. METHODS: In these candidate genes, 90 SNPs were genotyped using MassARRAY technology from 311 asthmatic children and 360 healthy controls of the Hungarian (Caucasian) population. Moreover, gene expression levels were measured by RT PCR in the induced sputum of 13 asthmatics and 10 control individuals. t-tests, chi-square tests, and logistic regression were carried out in order to assess associations of SNP frequency and expression level with asthma. Permutation tests were performed to account for multiple hypothesis testing. RESULTS: The frequency of 4 SNPs in 2 genes differed significantly between asthmatic and control subjects: SNPs rs2240572, rs2240571, rs3735222 in gene SCIN, and rs32588 in gene PPARGC1B. Carriers of the minor alleles had reduced risk of asthma with an odds ratio of 0.64 (0.51-0.80; P=7x10(-5)) in SCIN and 0.56 (0.42-0.76; P=1.2x10(-4)) in PPARGC1B. The expression levels of SCIN, PPARGC1B and ITLN1 genes were significantly lower in the sputum of asthmatics. CONCLUSIONS: Three potentially novel asthma-associated genes were identified based on mouse experiments and human studies.