Abstract
BackgroundSmall non-coding RNAs (microRNAs) have been evolved to master numerous cellular processes. Genetic variants within microRNA seed region might influence microRNA biogenesis and function. The study aimed at determining the role of microRNA-499 (MIR-499) gene family polymorphism as a marker for susceptibility and progression of bronchial asthma and to analyze the structural and functional impact of rs3746444 within the seed region.MethodsGenotyping for 192 participants (96 patients and 96 controls) in the discovery phase and 319 subjects (115 patients and 204 controls) in the replication phase was performed via Real Time-Polymerase Chain Reaction technology. Patients underwent the methacholine challenge test and biochemical analysis. Gene structural and functional analysis, target prediction, annotation clustering, and pathway enrichment analysis were executed. Predicted functional effect of rs37464443 SNP was analyzed.ResultsmiR-499 gene family is highly implicated in inflammation-related signaling pathways. Rs374644 (A > G) in MIR499A and MIR499B within the seed region could disrupt target genes and create new genes. The G variant was associated with high risk of developing asthma under all genetic association models (G versus A: OR = 3.27, 95% CI = 2.53–4.22; GG versus AA: OR = 9.52, 95% CI = 5.61–16.5; AG versus AA: OR = 2.13, 95% CI = 1.24–3.46; GG + AG versus AA: OR = 4.43, 95% CI = 2.88–6.82). GG genotype was associated with poor pre-bronchodilator FEV1 (p = 0.047) and the worst bronchodilator response after Salbutamol inhalation, represented in low peaked expiratory flow rate (p = 0.035).ConclusionsmiR-499 rs3746444 (A > G) polymorphism was associated with asthma susceptibility and bronchodilator response in Egyptian children and adolescents. Further functional analysis is warranted to develop more specific theranostic agents for selecting targeted therapy.
Highlights
Small non-coding RNAs have been evolved to master numerous cellular processes
Similar orthologs are present in other species; mouse MIR-499 was mapped to intron 19 of the Myh7b gene on chromosome 2 (Mus musculus; 2:155,622,880–155,622,958 (+); GRCm38)
Multiple sequence alignment showed miR-499a gene (MIR499A) gene to display a high level of conservation throughout 17 mammalian species (Fig. 3)
Summary
Small non-coding RNAs (microRNAs) have been evolved to master numerous cellular processes. In early 90’s, the presence of small non-coding RNAs (ncRNAs) was discovered in the mammalian genome [7] These microRNAs are transcriped via specific cellular machinery to form short single-stranded mature RNAs of 19–24 nucleotides long. They function by complementary base pairing with mRNA targets, leading to its degradation or translational repression [8]. They are estimated to modulate gene expression of 60% of protein-coding genes, and to regulate many cellular processes; including proliferation, apoptosis, immunomodulation, stress response, and angiogenesis [9]. Over-expressed microRNAs in human diseases can be sequestered by anti-miRNA oligonucleotides, miRNA sponges, miRNA masking and small molecule inhibitors [8]
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