Abstract 13312: Comprehensive Sequencing of Small Non-Coding RNA Reveals Plasma Circulating Biomarkers of Hypertrophic Cardiomyopathy and Dysregulated Signaling Pathways

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes essential in normal myocardial contraction. However, it remains unclear through which signaling pathways gene mutations mediate the development of HCM. Growing evidence indicates that small non-coding RNAs (snRNAs) play important roles in post-transcriptional regulation of gene expression. Hypothesis: Comprehensive sequencing of snRNAs in plasma reveals circulating HCM biomarkers and differentially regulated signaling pathways. Methods: We conducted a multicenter case-control study of cases with HCM and age-, sex-, and body mass index-matched controls with hypertensive left ventricular hypertrophy. We carried out RNA-seq of 3293 snRNAs in plasma. We performed a sparse partial least squares discriminant analysis to develop snRNA-based discrimination model using samples retrieved during the first two-thirds of the study period (the training set). We prospectively tested the discriminative ability in independent samples that were collected thereafter (the test set). We also identified signaling pathways associated with snRNAs that were significantly dysregulated in HCM with Bonferroni-adjusted P<0.05. Results: The study included 324 patients (165 cases and 159 controls; n=224 in the training set, n=100 in the test set). Using the transcriptomics-based model derived from the training set, the area under the receiver-operating-characteristic curve in the test set was 0.89 (95%CI 0.81-0.96; Figure ). Pathway analysis revealed that the Ras-MAPK pathway was upregulated in HCM (false discovery rate [FDR]=0.000002). Pathways involved in inflammation and fibrosis - e.g., TNF (FDR=0.000003) and TGF-β (FDR=0.002) - were also upregulated. Conclusions: This study serves as the largest-scale investigation to reveal circulating snRNA biomarkers of HCM and exhibits both novel (e.g., Ras-MAPK) and known (e.g., TNF, TGF-β) pathways that are differentially regulated in HCM.