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Abstract
Background
COPD is characterized by a persistent inflammatory response, especially against cigarette smoke. COPD patients may develop varying degrees of emphysematous destruction of the lungs. A pathophysiological role for miRNAs in COPD has been suggested in several studies. We examined changes in microRNAs expression profile during 10 years follow-up in relation to COPD progression.
Methods
Clinical and lung function parameters were registered from every subject included in the study. miRNAs expression was determined in 14 serum samples from 7 patients in two moments (4 smokers with COPD (BODE cohort) and 3 smokers without COPD) by next generation sequencing (NGS) at baseline and after 10 years follow-up. A validation study was performed by qPCR in 20 patients with COPD (13 emphysema-diagnosed by CTscan) and 10 smoker controls at baseline and after 10 years follow-up. hsa-miRNA-20a-5p and hsa-let-7d-5p were used as endogenous controls.
Results
A total of 198 miRNAs (≥10TPM) were identified by NGS. Between these, hsa-miR-1246 was found significantly downregulated in COPD patients after 10 years when compared to baseline (p<0.0001, FDR=0.05). Seventy-five percent of these patients had an emphysema diagnose. In the validation analysis, when analyzed longitudinally, hsa-miR-1246 was significantly downregulated in COPD patients with emphysema after 10 years (p= 0.019). However, no association was found between the expression of miR-1246 and any other lung function parameters (FEV1, PaO2, DLCO, IC/TLC) within the follow-up period. GO and KEGG enrichment analysis revealed miR-1246 to be associated with target genes in several pathways involved in COPD/emphysema development.
Conclusion
Our findings suggest that hsa-miR-1246 may act as a biomarker of emphysema in COPD. Functional analysis is guaranteed to elucidate its role in COPD.
Keywords:
Acknowledgments
We will like to thank Hilaria González Acosta for her excellent technical assistance and the Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias (IUETSPC) for the use of laboratory equipment. Elizabeth Córdoba-Lanús is supported by Cabildo de Tenerife (Agustín de Betancourt programme).
Abbreviations
COPD, chronic obstructive pulmonary disease; miRNA, microRNA; hsa-miRNA, homo sapiens microRNA; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; BMI, body mass index; PaO2, partial oxygen tension; DLCO, diffusion capacity for carbon monoxide; IC/TLC, inspiratory capacity to total lung capacity ratio; 6MWD, six-minute walking distance test; CT scan, computed tomography scanner; NGS, next generation sequencing; TPM, tags per million; FDR, false discovery rate; qPCR, quantitative real time polymerase chain reaction; GLIM, general linear modelling for repeated measures test.
Data Sharing Statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as Supplemental Table 1 and Supplemental Figure 1.
Ethics Approval
Ethical approval was obtained from Hospital Universitario La Candelaria, Tenerife, Spain (PI 55/17).
Patient Consent
Written informed consent was obtained from all participants.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.
Disclosure
Sara Cazorla-Rivero, Glorian Mura-Escorche, Francisca Gonzalvo-Hernández, Delia Mayato, and Elizabeth Córdoba-Lanús, declare not to have any financial or personal conflict of interests. Ciro Casanova Macario reports grants from Astra-Zeneca, GSK, and Menarini, advisory board for Astra-Zeneca and GSK, financial support for congress from Boehringer, Novartis and Menarini, personal fees from Bial, and lectures for Novartis, outside the submitted work; and declares to have received lectures and/or scientific advice from Laboratorios Bial, Boehringer-Ingelheim, AstraZeneca, GSK, Esteve, Menarini, Novartis and Rovi in the last three years. The authors report no other potential conflicts of interest for this work.