P1586Plasma microRNAs for identification of patients with Lamin A/C gene mutation causing familial dilated cardiomyopathy

Abstract

Background: Mutations in the Lamin A/C (LMNA) gene are one of the most common genetic causes of familial dilated cardiomyopathy (fDCM). LMNA-related DCM is an aggressive disease often leading to heart transplantation and sudden cardiac death (SCD). Effective therapeutic strategies have been developed for the clinical management of individuals with LMNA-related DCM. However, diagnosis and risk stratification of LMNA mutation carriers remains challenging. We and others have previously demonstrated the potential of circulating microRNAs (miRNAs) as diagnostic biomarkers of cardiac conditions. Purpose: The purpose of current study was to explore the circulating miRNA signature of LMNA mutation carriers. Methods: Plasma samples were collected from 25 subjects with a LMNA mutation considered to be pathogenic (from four different families) and 40 subjects without LMNA pathogenic variant: 20 healthy subjects and 20 patients with idiopathic DCM (iDCM). Detailed clinical and echocardiographic information was obtained for each participant. The levels of 21 miRNAs previously associated with fDCM by our group were measured using quantitative reverse transcriptionpolymerase chain reaction (RT-qPCR). Results: Plasma levels of all miRNAs were upregulated in LMNA mutation carriers compared to healthy controls and iDCM patients (P<0.050). Differences remain statistically significant even after adjusting for age, sex and body mass index. Additional sub-analyses were performed to explore the potential of circulating miRNAs as biomarkers. Circulating levels of let-7a-5p, miR-142-3p and miR-145- 5p were upregulated in LMNA mutation carriers with established DCM compared to patients with iDCM (P<0.050). Levels of all miRNAs were higher in asymptomatic LMNA mutation carriers compared to healthy controls (P<0.050). In all comparisons, the mean concentration of the conventional parameter currently used in clinical practice NT-proBNP was similar in all study groups (P>0.050). Similar expression levels were observed between LMNA mutation carriers with established and non-established DCM (P>0.050). Conclusions: The analysis of the circulating miRNA signature is a novel tool for the identification of LMNA mutation carriers. Future studies should validate the potential application of circulating miRNAs for the clinical management of LMNArelated DCM.