Integrative proteomic analyses across common cardiac diseases yield mechanistic insights and enhanced prediction

Art Schuermans; Ashley B Pournamdari; Jiwoo Lee; Rohan Bhukar; Shriienidhie Ganesh; Nicholas Darosa; Aeron M Small; Zhi Yu; Whitney Hornsby; Satoshi Koyama; Charles Kooperberg; Alexander P Reiner; James L Januzzi; Michael C Honigberg; Pradeep Natarajan

doi:10.1038/s44161-024-00567-0

Integrative proteomic analyses across common cardiac diseases yield mechanistic insights and enhanced prediction

Nat Cardiovasc Res. 2024 Nov 21. doi: 10.1038/s44161-024-00567-0. Online ahead of print.

Authors

Art Schuermans^#^{1

2

3}, Ashley B Pournamdari^#^{1

4}, Jiwoo Lee^{1

2}, Rohan Bhukar^{1

2}, Shriienidhie Ganesh^{1

2}, Nicholas Darosa^{1

2}, Aeron M Small^{1

5}, Zhi Yu^{1

2

6}, Whitney Hornsby^{1

2}, Satoshi Koyama^{1

2}, Charles Kooperberg⁷, Alexander P Reiner⁷, James L Januzzi^{8

9

10}, Michael C Honigberg^{11

12

13

14}, Pradeep Natarajan^{15

16

17

18}

Affiliations

¹ Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
² Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
³ Faculty of Medicine, KU Leuven, Leuven, Belgium.
⁴ Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁵ Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁶ Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁷ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁸ Baim Institute for Clinical Research, Boston, MA, USA.
⁹ Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹¹ Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA. mhonigberg@mgh.harvard.edu.
¹² Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. mhonigberg@mgh.harvard.edu.
¹³ Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA. mhonigberg@mgh.harvard.edu.
¹⁴ Department of Medicine, Harvard Medical School, Boston, MA, USA. mhonigberg@mgh.harvard.edu.
¹⁵ Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA. pnatarajan@mgh.harvard.edu.
¹⁶ Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. pnatarajan@mgh.harvard.edu.
¹⁷ Division of Cardiology, Massachusetts General Hospital, Boston, MA, USA. pnatarajan@mgh.harvard.edu.
¹⁸ Department of Medicine, Harvard Medical School, Boston, MA, USA. pnatarajan@mgh.harvard.edu.

^# Contributed equally.

PMID: 39572695
DOI: 10.1038/s44161-024-00567-0

Abstract

Cardiac diseases represent common highly morbid conditions for which molecular mechanisms remain incompletely understood. Here we report the analysis of 1,459 protein measurements in 44,313 UK Biobank participants to characterize the circulating proteome associated with incident coronary artery disease, heart failure, atrial fibrillation and aortic stenosis. Multivariable-adjusted Cox regression identified 820 protein-disease associations-including 441 proteins-at Bonferroni-adjusted P < 8.6 × 10^-6. Cis-Mendelian randomization suggested causal roles aligning with epidemiological findings for 4% of proteins identified in primary analyses, prioritizing therapeutic targets across cardiac diseases (for example, spondin-1 for atrial fibrillation and the Kunitz-type protease inhibitor 1 for coronary artery disease). Interaction analyses identified seven protein-disease associations that differed Bonferroni-significantly by sex. Models incorporating proteomic data (versus clinical risk factors alone) improved prediction for coronary artery disease, heart failure and atrial fibrillation. These results lay a foundation for future investigations to uncover disease mechanisms and assess the utility of protein-based prevention strategies for cardiac diseases.

Abstract

Grants and funding