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Comprehensive Transcriptomics Profiling of MicroRNA Reveals Plasma Circulating Biomarkers of Hypertrophic
Lusha W Liang1, Kohei Hasegawa2, Mathew S Maurer1
1Division of Cardiology, Department of Medicine (L.W.L., M.S.M., M.P.R., Y.J.S.), Columbia University Irving Medical Center, New York, NY.
Insights
Plasma microRNA (miRNA) profiling can identify biomarkers for hypertrophic cardiomyopathy (HCM). This study reveals dysregulated pathways, including Ras-MAPK, offering new insights into HCM pathogenesis.
Area of Science:
- Cardiovascular Genetics
- Molecular Biology
- Biomarker Discovery
Background:
- Hypertrophic cardiomyopathy (HCM) stems from mutations in myocardial contraction genes, but underlying signaling pathways remain unclear.
- MicroRNAs (miRNAs) are crucial gene regulators, prompting investigation into their role in HCM pathogenesis.
- This study hypothesized that plasma miRNA transcriptomics could identify circulating biomarkers and dysregulated pathways in HCM.
Purpose of the Study:
- To investigate plasma microRNA (miRNA) profiles for novel biomarkers in hypertrophic cardiomyopathy (HCM).
- To identify dysregulated signaling pathways implicated in HCM pathogenesis using transcriptomics.
- To develop and validate a transcriptomics-based model for discriminating HCM.
Main Methods:
- A multicenter case-control study involving 392 HCM cases and 163 controls.
- Plasma miRNA transcriptomics profiling was performed using RNA sequencing.
- A discrimination model was developed and validated prospectively and externally.
Main Results:
- The developed transcriptomics model demonstrated high discriminative ability (AUC 0.86-0.94).
- Pathway analysis identified dysregulation in the Ras-MAPK pathway and inflammation-related pathways in HCM.
- One thousand one hundred forty-one miRNAs were identified post-quality control.
Conclusions:
- Comprehensive transcriptomics profiling of plasma miRNAs offers valuable insights into HCM.
- Circulating miRNAs serve as potential biomarkers for HCM diagnosis and understanding disease mechanisms.
- Dysregulated Ras-MAPK and inflammation pathways are implicated in HCM pathogenesis.
Background:
Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes coding for proteins essential for myocardial contraction. However, it remains unclear through which signaling pathways these gene mutations mediate HCM pathogenesis. Growing evidence indicates that microRNAs (miRNAs) play an important role in the regulation of gene expression. We hypothesized that transcriptomics profiling of plasma miRNAs would reveal circulating biomarkers and dysregulated signaling pathways in HCM.
Methods:
We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma transcriptomics profiling of miRNAs using RNA sequencing. We developed a transcriptomics-based discrimination model using samples retrieved during the first two-thirds of the study period at one institution (training set). We prospectively tested its discriminative ability in samples collected thereafter from the same institution (prospective test set). We also externally validated the model by applying it to samples collected from the other institutions (external test set). We executed pathway analysis of dysregulated miRNAs with univariable P<0.05.
Results:
This study included 555 patients (392 cases and 163 controls). One thousand one hundred forty-one miRNAs passed our quality control filters. The area under the receiver operating characteristic curve of the transcriptomics-based model derived from the training set was 0.86 (95% CI, 0.79-0.93) in the prospective test set and 0.94 (95% CI, 0.90-0.97) in the external test set. Pathway analysis revealed dysregulation of the Ras-MAPK (mitogen-activated protein kinase) pathway and pathways related to inflammation in HCM.
Conclusions:
This study utilized comprehensive transcriptomics profiling with RNA sequencing in HCM, revealing circulating miRNA biomarkers and dysregulated pathways.
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