Circulating miR-1246 in the Progression of Chronic Obstructive Pulmonary Disease (COPD) in Patients from the BODE Cohort

Sara Cazorla-Rivero,1,2 Glorian Mura-Escorche,1,2 Francisca Gonzalvo-Hernández,3 Delia Mayato,1 Elizabeth Córdoba-Lanús,1,2,4,* Ciro Casanova1– 3,* 1Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; 2University of La Laguna, San Cristóbal de La Laguna, Tenerife, Spain; 3Pulmonary Department, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain; 4Instituto de Enfermedades Tropicales y Salud Pública de Canarias (IUETSPC), San Cristóbal de La Laguna, Tenerife, Spain*These authors contributed equally to this workCorrespondence: Elizabeth Córdoba-LanúsUniversity of La Laguna- IUETSPC, Av. Astrofísico Francisco Sanchez. Campus Anchieta, Apartado 456, San Cristobal de la Laguna CP 38200, Tenerife, SpainEmail acordoba@ull.edu.esBackground: 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: COPD progression, miRNAs, emphysema