Allergy Asthma Immunol Res.  2017 May;9(3):247-256. 10.4168/aair.2017.9.3.247.

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

• Fodor LE
• Gézsi A
• Ungvári L
• Semsei AF
• Gál Z
• Nagy A
• Gálffy G
• Tamási L
• Kiss A
• Antal P
• Szalai C

• KMID: 2371725
• DOI: http://doi.org/10.4168/aair.2017.9.3.247

Abstract

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.

Keyword

Asthma; genetics; rhinitis; YAP1

MeSH Terms

Asthma*
Asthma, Exercise-Induced
Blotting, Western
Epithelial Cells
Gene Expression
Genetic Variation
Genetics
Genotype
Haplotypes
Hypersensitivity*
Multilevel Analysis
Phenotype
Polymorphism, Single Nucleotide
Rhinitis
Rhinitis, Allergic
RNA, Messenger
Sputum
RNA, Messenger

Figure

• 

  Fig. 1 Examples of signals and pathways regulating YAP1 activity.25262728

• 

  Fig. 2 (A) YAP1 mRNA levels in the induced sputum of asthmatic patients (n=18) and controls (n=10). (B) Relationship between YAP1 mRNA and bronchial epithelial cell levels. The mRNA levels were normalized and expressed according to the delta delta Ct method. The Mann-Whitney U test (A) and Spearmann's non-parametric correlation (B) were used.

• 

  Fig. 3 DAG of the most likely relations of variants and targets. The directed edges represent only probabilistic relationships between the variables which are not necessary causal. DAG, directed acyclic graph.

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