4.6 Article

Comprehensive Proteomics Profiling Reveals Circulating Biomarkers of Hypertrophic Cardiomyopathy

期刊

CIRCULATION-HEART FAILURE
卷 14, 期 7, 页码 777-787

出版社

LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCHEARTFAILURE.120.007849

关键词

biomarkers; cardiomyopathies; hypertrophy; mutation; proteomics

资金

  1. National Institutes of Health (NIH) [R01 HL157216]
  2. American Heart Association National Clinical and Population Research Awards
  3. American Heart Association Career Development Award
  4. Korea Institute of Oriental Medicine
  5. Columbia University Irving Medical Center Irving Institute for Clinical and Translational Research Precision Medicine Pilot Award
  6. NIH [UL1 TR001873, K24 HL107643, K24 AG036778]

向作者/读者索取更多资源

This study identified plasma protein biomarkers of HCM and revealed upregulated molecular pathways, such as the Ras-MAPK and TGF-beta pathways, in HCM patients. This investigation represents the largest-scale proteomics profiling in HCM, highlighting both novel and known pathways differentially regulated in the disease.
Background: Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes coding for proteins essential in normal myocardial contraction. However, it remains unclear through which molecular pathways gene mutations mediate the development of HCM. The objectives were to determine plasma protein biomarkers of HCM and to reveal molecular pathways differentially regulated in HCM. Methods: We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma proteomics profiling of 1681 proteins. We performed a sparse partial least squares discriminant analysis to develop a proteomics-based discrimination model with data from 1 institution (ie, the training set). We tested the discriminative ability in independent samples from the other institution (ie, the test set). As an exploratory analysis, we executed pathway analysis of significantly dysregulated proteins. Pathways with false discovery rate Results: The study included 266 cases and 167 controls (n=308 in the training set; n=125 in the test set). Using the proteomics-based model derived from the training set, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.83-0.94) in the test set. Pathway analysis revealed that the Ras-MAPK (mitogen-activated protein kinase) pathway, along with its upstream and downstream pathways, was upregulated in HCM. Pathways involved in inflammation and fibrosis-for example, the TGF (transforming growth factor)-beta pathway-were also upregulated. Conclusions: This study serves as the largest-scale investigation with the most comprehensive proteomics profiling in HCM, revealing circulating biomarkers and exhibiting both novel (eg, Ras-MAPK) and known (eg, TGF-beta) pathways differentially regulated in HCM.

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