Asthma, a chronic and allergic respiratory illness, is caused by the combination of internal and external factors, while miRNAs may serve as critical internal factors [20, 31]. MiR-145, together with miR-138, miR-214, miR-371 and miR-544, can modulate the balance of T helper cells in asthma etiology in a combinational manner . MiR-145 has been identified as a suppressor of tumorigenesis, although its expression levels were not conclusive in certain types of cancer. Most importantly, miR-145 has been found to be significantly up-regulated in asthma . In that study, among 30 asthmatic patients and 25 healthy subjects, miR-145 was found to have lower level in the serum of healthy subjects, and may serve as a predictor for asthma . In addition, its over-expression can suppress the expression of Runx3, regulate the balance between Th1 and Th2 [31, 32]. To our surprise, there has no report on either the association of miR-145 genotypes with asthma risk or genotype-clinical correlation of miR-145 in asthma patients.
In the current study, we revealed that the genotypic proportions for TT, CT, and CC of miR-145 rs4705342 are 44.4, 43.3, and 12.3% in the control Taiwanese population (Table 2). Those of miR-145 rs4705343 are 47.0, 43.9 and 9.1% (Table 3). For the first time, the variant genotypes (CT and CC) and the C variant allele of miR-145 rs4705342 were found to be significantly associated with reduced asthma risks (Tables 2 and 4). For the first time, the present study also found that those patients with the variant genotypes (CT + CC) at miR-145 rs4705342 were at lower risks to suffer from severe symptoms than those patients with wild-type genotype (Table 5). Moreover, the genotype-phenotype correlation analysis revealed that miR-145 rs4705342 C allele is correlated with a down-regulation of miR-145 in serum from the healthy people (Fig. 1A). Our studies demonstrated that not only miR-145 rs4705342 genotypes can serve as a novel predictor for asthma risk, but a signature for asthma patients to suffer from severe symptoms. Although the detailed mechanisms of how miR-145 genotype contribute to sever symptoms remain elusive, this association may assist in predicting the prognosis of asthma patients for more precise therapy and medication.
The detailed signaling network between miR-145 and asthma etiology is remained unclear, but there are some clues. In 2015, Liu and colleagues reported that miR-145 up-regulation in airway smooth muscle cells can inhibit KLF4, and affect downstream expressions of p21, MMP-2 and MMP-9 . In 2017, miR-145 and other 4 miRNAs were confirmed to modulate the Th1/Th2 balance in asthma via regulating the expression level of Runx3 in a combinational manner . In 2019, Xiong and colleagues found that miR-145 was up-regulated in airway epithelial cells of asthmatic mice and an miR-145 antagonist can significantly improve the asthmatic symptoms . MiR-145 can promote the HDM-induced release of cytokines and epithelial barrier dysfunction via KIF3A . MiR-145-induced signaling pathways are complex and warrant more investigations. We provided evidence that the variant genotypes and alleles were associated with lower expression of miR-145 (Fig. 1A), and literature reported that miR-145 is up-regulated in asthma patient serum , therefore, it is consistent that the variant genotypes and alleles conferred reduced asthma risks by reducing the miR-145 levels.
Traditionally, there is no effective methodology for the diagnosis or prognosis of asthma. Pulmonary function examinations are not applicable if patients lose consciousness. Our results suggest that miR-145 genomic marker and/or miR-145 protein may serve as an auxiliary diagnostic indicator for asthma and used for early screening in clinical practice. The prevalence of asthma is extremely high in urban areas and there are lots of childhood or even baby asthmatic cases who may not be able to go to the hospitals readily. Detecting of miR-145 in the serum would be much more convenient and objective and can be conducive at any place even outside of the hospital, when people are suffering from epidemic burst of diseases, such as covid-19.
There are a few limitations of the current study. First, the findings were only based on genomic analysis of a single gene with a relatively moderate sample size, which needs to be validated and extended. Second, environmental factors mentioned in the introduction may all contribute to asthma etiology, however, the current study had incomplete information for those factors. Last, we measure serum miR-145 in non-asthmatic subjects for genotype-correlation analysis. It would be valuable to also measure serum miR-145 in asthma patients.