Plasma microRNAs as biomarkers for Lamin A/C-related dilated cardiomyopathy
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Lamin A/C gene (LMNA)-related familial dilated cardiomyopathy (fDCM) is an aggressive heart disease that often leads to transplantation and sudden death. The aim of our study was to evaluate the circulating microRNA (miRNA) profiles of patients with LMNA pathogenic mutations. The study population (N = 75) included (i) patients with pathogenic LMNA mutations responsible for fDCM (LMNAMUT), (ii) age- and sex-matched LMNA wild-type controls (LMNAWT control), and (iii) LMNA wild-type idiopathic DCM (iDCM) patients (LMNAWT iDCM). Detailed clinical information was obtained from each participant. A panel of 179 plasma miRNAs was evaluated using RT-qPCR. An initial screening study was performed in LMNAMUT carriers and age-matched LMNAWT controls (N = 16). Forty-four miRNAs were specifically deregulated in LMNAMUT carriers. Ten miRNA candidates were selected for subsequent validation after coexpression analyses and filtered for expression levels and statistical significance. Among the candidates, let-7a-5p, miR-142-3p, miR-145-5p and miR-454-3p levels were significantly increased in LMNAMUT carriers compared to LMNAWT controls and iDCM patients (P < 0.050). These circulating miRNAs, and their combination, were also associated with the presence of pathogenic mutations in regression and ROC analyses. This signature also discriminates between LMNAWT healthy subjects and LMNAMUT carriers who are phenotypically negative for DCM and between LMNAWT iDCM and LMNA-related DCM patients. Correlation and functional enrichment analyses supported their association with the pathophysiology of the disease. We demonstrated for the first time that a specific miRNA signature could serve as a novel non-invasive tool to assist in the diagnosis of patients with fDCM caused by LMNA pathogenic mutations.
Let-7a-5p, miR-142-3p, miR-145-5p and miR-454-3p are differentially expressed in LMNAMUT carriers.
A composite score based on these miRNAs is a biomarker of mutations in the LMNA gene.
This miRNA signature can be associated with the pathophysiology of familial DCM.
The circulating miRNA profile can assist in the diagnosis of familial DCM.
KeywordsDilated cardiomyopathy Lamin A/C (LMNA) Circulating microRNAs Biomarkers
This work was supported by the Fundación Pública Andaluza Progreso y Salud para la Financiación de la I+i Biomédica y en Ciencias de las Salud en Andalucia (PI-0011/2014) and a grant in the framework of the Integrated Territorial Initiative (ITI)2014-2020 for the province of Cádiz by the Ministry of Health and the European Regional Developement Fund (ERDF) PI0048-2017 (project co-finantiated 80% by funds from the ERDF operational program of Andalusia 2014-2020) (ITI 0048-2017). This work was also supported by FIS PI14/01729 from the Instituto Salud Carlos III, co-financed by the European Fund for Regional Development (E.F.R.D.), Fundació Marató TV3 (201521 10), and Fundació “La Caixa.” CIBER Cardiovascular (CB16/11/00403) is an Instituto de Salud Carlos III Project. DdG-C was a recipient of a Juan de la Cierva-Incorporación grant from the Ministerio de Economía y Competitividad (IJCI-2016-29393).
Compliance with ethical standards
Our ethics committee (Comité de Ética de la Investigación de Cádiz) approved the study protocol, following the Helsinki II declaration. The genetic study was approved by the Ethics Committee of the Hospital Josep Trueta (Girona, Spain), also following the Helsinki II declaration. All subjects gave their written informed consent before participating in the study.
Conflict of interest
The authors declare that they have no conflicts of interest.
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