Abstract
Asthma is a global health problem with increasing prevalence. The airway epithelium is the initial barrier against inhaled noxious agents or aeroallergens. In asthma, the airway epithelium suffers from structural and functional abnormalities and as such, is more susceptible to normally innocuous environmental stimuli. The epithelial structural and functional impairments are now recognised as a significant contributing factor to asthma pathogenesis. Both genetic and environmental risk factors play important roles in the development of asthma with an increasing number of genes associated with asthma susceptibility being expressed in airway epithelium. Epigenetic factors that regulate airway epithelial structure and function are also an attractive area for assessment of susceptibility to asthma. In this review we provide a comprehensive discussion on genetic factors; from using linkage designs and candidate gene association studies to genome-wide association studies and whole genome sequencing, and epigenetic factors; DNA methylation, histone modifications, and non-coding RNAs (especially microRNAs), in airway epithelial cells that are functionally associated with asthma pathogenesis. Our aims were to introduce potential predictors or therapeutic targets for asthma in airway epithelium. Overall, we found very small overlap in asthma susceptibility genes identified with different technologies. Some potential biomarkers are IRAKM, PCDH1, ORMDL3/GSDMB, IL-33, CDHR3 and CST1 in airway epithelial cells. Recent studies on epigenetic regulatory factors have further provided novel insights to the field, particularly their effect on regulation of some of the asthma susceptibility genes (e.g. methylation of ADAM33). Among the epigenetic regulatory mechanisms, microRNA networks have been shown to regulate a major portion of post-transcriptional gene regulation. Particularly, miR-19a may have some therapeutic potential.
Highlights
Asthma affects people of all ethnicities and ages and there has been a substantial increase in the prevalence of asthma over the past few decades, with current estimates of approximately 300 million people suffering from the disease worldwide [1]
Among susceptibility genes detected by positional cloning (Table 1), IL-1 receptor associated kinase-M (IRAKM) may represent a potential biomarker for early onset of asthma [26] whereas PCDH1 may be a potential biomarker in both children and adults [22]
A disintegrin and metalloprotease 33 (ADAM33) protein increases in epithelium of asthmatics, it is not related to severity of disease [18]
Summary
Asthma affects people of all ethnicities and ages and there has been a substantial increase in the prevalence of asthma over the past few decades, with current estimates of approximately 300 million people suffering from the disease worldwide [1]. The epithelial abnormalities are associated with increased susceptibility to oxidant-induced stress, aberrant cytokine and ECM release [6], mitotic dyssynchrony [7] and a deficient innate immune response [8,9,10]. These abnormalities affect epithelial repair and regeneration processes after injury, leading to defective maintenance of the epithelial barrier and its normal function [2, 11, 12]
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