Multi-level transcriptome sequencing identifies COL1A1 as a candidate marker in human heart failure progression

Xiumeng Hua,Yuan Chang,Songqing Lai,Yin-Ying Wang,Jiangping Song,Yiqing Hu,Zhongming Zhao,Yong Xu,Qing Xiong,Peilin Jia

doi:10.1186/s12916-019-1469-4

Abstract

BackgroundHeart failure (HF) has been recognized as a global pandemic with a high rate of hospitalization, morbidity, and mortality. Although numerous advances have been made, its representative molecular signatures remain largely unknown, especially the role of genes in HF progression. The aim of the present prospective follow-up study was to reveal potential biomarkers associated with the progression of heart failure.MethodsWe generated multi-level transcriptomic data from a cohort of left ventricular heart tissue collected from 21 HF patients and 9 healthy donors. By using Masson staining to calculate the fibrosis percentage for each sample, we applied lasso regression model to identify the genes associated with fibrosis as well as progression. The genes were further validated by immunohistochemistry (IHC) staining in the same cohort and qRT-PCR using another independent cohort (20 HF and 9 healthy donors). Enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma level in a validation cohort (139 HF patients) for predicting HF progression.ResultsBased on the multi-level transcriptomic data, we examined differentially expressed genes [mRNAs, microRNAs, and long non-coding RNAs (lncRNAs)] in the study cohort. The follow-up functional annotation and regulatory network analyses revealed their potential roles in regulating extracellular matrix. We further identified several genes that were associated with fibrosis. By using the survival time before transplantation, COL1A1 was identified as a potential biomarker for HF progression and its upregulation was confirmed by both IHC and qRT-PCR. Furthermore, COL1A1 content ≥ 256.5 ng/ml in plasma was found to be associated with poor survival within 1 year of heart transplantation from heart failure [hazard ratio (HR) 7.4, 95% confidence interval (CI) 3.5 to 15.8, Log-rank p value < 1.0 × 10− 4].ConclusionsOur results suggested that COL1A1 might be a plasma biomarker of HF and associated with HF progression, especially to predict the 1-year survival from HF onset to transplantation.

Highlights

Heart failure (HF) has been recognized as a global pandemic with a high rate of hospitalization, morbidity, and mortality
We identified 126 mRNAs, 16 long non-coding RNA (lncRNA), and 42 miRNAs that were differentially expressed in HF versus control samples by requiring the absolute log2-transformed fold change (FC) > 1 and adjusted p value < 0.05 by the BH method
With the survival rate and gene expression data in this study, we identified a fibrosis-associated gene, COL1A1, that was significantly associated with HF progression

Summary

Introduction

Heart failure (HF) has been recognized as a global pandemic with a high rate of hospitalization, morbidity, and mortality. Studies have reported that several mRNAs (e.g., CORIN, CTGF, and POSTIN), miRNAs (e.g., miR-1, miR-133 and miR423-5p), and lnRNAs (e.g., H19 and HOTAIR) might play roles in the pathogenic mechanisms leading to HF [7,8,9,10,11]. These studies have reported many promising findings, a systematic investigation of multiple types of expression and their regulation in HF will likely reveal more dynamic and regulatory signatures related to fibrosis in HF, helping us better understand the development and progression of HF

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Conclusion