Biobank-Scale Plasma Proteomics Identifies Novel Biomarkers in Hypertrophic Cardiomyopathy

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by substantial heterogeneity in both clinical phenotype and risk of adverse outcomes, including heart failure and sudden cardiac death. This highlights the need for robust biomarkers for risk stratification, and while previous studies have identified the role of select plasma proteins, comprehensive large-scale proteomic analyses have been limited in HCM. METHODS: We performed a case-control analysis of 2922 plasma proteins in 49 588 UK Biobank participants (100 HCM cases) to identify proteins associated with HCM. External replication analyses were performed in the deCODE Genetics Icelandic study (51 cases/38 904 controls) and All of Us (546 cases/41 049 controls) data sets. Associations with adverse clinical outcomes and cardiac endophenotypes of disease severity were further identified, and causal relationships were evaluated using Mendelian randomization. Relative biomarker importance was also assessed by joint modeling via machine learning. RESULTS: We identified novel associations of ANGPT2 (angiopoietin-2) and LTBP2 (latent transforming growth factor-beta binding protein 2) with HCM, with both also showing prognostic utility for heart failure-related outcomes in HCM cases. We also confirmed the associations of established biomarkers (eg, NT-proBNP [N-terminal pro-B-type natriuretic peptide], troponins I and T) with HCM cases, cardiac imaging markers of disease severity, and adverse outcomes. Mendelian randomization analyses supported a causal effect of HCM on increasing NT-proBNP and troponin T levels. CONCLUSIONS: This biobank-scale plasma proteomic study in HCM identified ANGPT2 and LTBP2 as novel HCM biomarkers with potential diagnostic and prognostic utility. These findings highlight the potential for plasma proteomics to improve risk prediction and provide insight into HCM pathobiology.

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Journal
Circulation Genomic and Precision Medicine
Published
2026-04-22
DOI
https://doi.org/10.1161/circgen.125.005325
Primary Topic
Cardiomyopathy and Myosin Studies
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article
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article

Biobank-Scale Plasma Proteomics Identifies Novel Biomarkers in Hypertrophic Cardiomyopathy

Carolyn Yung Ho, Dana Dawson, Bette Kim, NANCY GELLER et al.
Circulation Genomic and Precision Medicine
Cardiomyopathy and Myosin Studies
article

Biobank-Scale Plasma Proteomics Identifies Novel Biomarkers in Hypertrophic Cardiomyopathy

Carolyn Yung Ho, Dana Dawson, Bette Kim, NANCY GELLER, Eleanor Elstein, Camillo Autore, William Bradlow, Betty Raman, Jeff Geske, Paul Kolm, Hugh Watkins, Christopher M. Kramer, Amedeo Chiribiri, Robert Clarke, Heiko Mahrholdt, Anuj Goel, Christopher Madias, Michael Salerno, Daniel Jacoby, Evan Appelbaum, Christopher Grace, Stefan Neubauer, Masliza Mahmod, Mark Link, Lubna Choudhury, Chiara Bucciarelli‐Ducci, Sven Plein, Eli V. Gelfand, Jonathan Chan, Éric Larose, AK Nightingale, Tjeerd Germans, Mohsen Mazidi, Anna Woo, Matthias Friedrich, Han Kim, Allison Hays, Adam Helms, Albert van Rossum, James White, Theodore Abraham, Saidi Mohiddin, Sanjay Sharma, John DiMarco, William Weintraub, Colin Berry, Martin Maron, Anjali Owens, Gary Francis, Mark Sherrid, Sherif Nagueh, Jeanette Schulz-Menger, Barry Greenberg, Michelle Michels, Elena Biagini, Eric Williamson, Steven Heitner, Raymond Y. Kwong, Gerry P. McCann, Andrew Flett, F. Pierre Mongeon, Milind Desai, Ornella Rimoldi, Sanjay Prasad, John DiMarc, Iacopo Olivotto, Lauren Baldassarre, Ahmad Masri, David Newby, Patrice Desvigne-Nickens, Andrew Crean, Jonathan Weinsaft, Florian Andre, Lisa Anderson, Dong-Yun Kim
article en

Abstract

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by substantial heterogeneity in both clinical phenotype and risk of adverse outcomes, including heart failure and sudden cardiac death. This highlights the need for robust biomarkers for risk stratification, and while previous studies have identified the role of select plasma proteins, comprehensive large-scale proteomic analyses have been limited in HCM. METHODS: We performed a case-control analysis of 2922 plasma proteins in 49 588 UK Biobank participants (100 HCM cases) to identify proteins associated with HCM. External replication analyses were performed in the deCODE Genetics Icelandic study (51 cases/38 904 controls) and All of Us (546 cases/41 049 controls) data sets. Associations with adverse clinical outcomes and cardiac endophenotypes of disease severity were further identified, and causal relationships were evaluated using Mendelian randomization. Relative biomarker importance was also assessed by joint modeling via machine learning. RESULTS: We identified novel associations of ANGPT2 (angiopoietin-2) and LTBP2 (latent transforming growth factor-beta binding protein 2) with HCM, with both also showing prognostic utility for heart failure-related outcomes in HCM cases. We also confirmed the associations of established biomarkers (eg, NT-proBNP [N-terminal pro-B-type natriuretic peptide], troponins I and T) with HCM cases, cardiac imaging markers of disease severity, and adverse outcomes. Mendelian randomization analyses supported a causal effect of HCM on increasing NT-proBNP and troponin T levels. CONCLUSIONS: This biobank-scale plasma proteomic study in HCM identified ANGPT2 and LTBP2 as novel HCM biomarkers with potential diagnostic and prognostic utility. These findings highlight the potential for plasma proteomics to improve risk prediction and provide insight into HCM pathobiology.

Circulation Genomic and Precision Medicine
Brigham and Women's Hospital (US), University of Virginia Health System (US), John Radcliffe Hospital (GB), Centre For Human Genetics (IN), Nuffield Health (GB)
Openalex Percentile: Top 18%
Cardiomyopathy and Myosin Studies
DOIOpen Access PDFOpenAlex
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