2. Academic Validation
  3. Spectrum of Apolipoprotein AI and Apolipoprotein AII Proteoforms and Their Associations With Indices of Cardiometabolic Health: The CARDIA Study

Spectrum of Apolipoprotein AI and Apolipoprotein AII Proteoforms and Their Associations With Indices of Cardiometabolic Health: The CARDIA Study

  • J Am Heart Assoc. 2021 Sep 7;10(17):e019890. doi: 10.1161/JAHA.120.019890.
John T Wilkins 1,  Henrique S Seckler 2,  Jonathan Rink 3,  Philip D Compton 2,  Luca Fornelli 4,  C Shad Thaxton 3,  Rich LeDuc 2,  David Jacobs 5,  Peter F Doubleday 2,  Allan Sniderman 6,  Donald M Lloyd-Jones 1,  Neil L Kelleher 2
Affiliations

Affiliations

  • 1 Department of Medicine (Cardiology) and Department of Preventive Medicine Northwestern University Chicago IL.
  • 2 Department of Chemistry Chemistry of Life Processes Institute and Proteomics Center of Excellence Northwestern University Evanston IL.
  • 3 Department of Medicine (Urology) Northwestern University Chicago IL.
  • 4 Department of Molecular Biology University of Oklahoma Norman OK.
  • 5 Division of Epidemiology and Community Health School of Public Health University of Minnesota Minneapolis MN.
  • 6 Mike and Valeria Rosenbloom Centre for Cardiovascular Prevention Department of Medicine McGill University Health Centre Montreal Quebec Canada.
PMID: 34472376 DOI: 10.1161/JAHA.120.019890
Abstract

Background ApoAI (apolipoproteins AI) and apoAII (Apolipoprotein AII) are structural and functional proteins of high-density lipoproteins (HDL) which undergo post-translational modifications at specific residues, creating distinct proteoforms. While specific post-translational modifications have been reported to alter Apolipoprotein function, the full spectrum of apoAI and apoAII proteoforms and their associations with cardiometabolic phenotype remains unknown. Herein, we comprehensively characterize apoAI and apoAII proteoforms detectable in serum and their post-translational modifications and quantify their associations with cardiometabolic health indices. Methods and Results Using top-down proteomics (mass-spectrometric analysis of intact proteins), we analyzed paired serum samples from 150 CARDIA (Coronary Artery Risk Development in Young Adults) study participants from year 20 and 25 exams. Measuring 15 apoAI and 9 apoAII proteoforms, 6 of which carried novel post-translational modifications, we quantified associations between percent proteoform abundance and key cardiometabolic indices. Canonical (unmodified) apoAI had inverse associations with HDL Cholesterol and HDL-cholesterol efflux, and positive associations with obesity indices (body mass index, waist circumference), and triglycerides, whereas glycated apoAI showed positive associations with serum glucose and diabetes mellitus. Fatty-acid‒modified ApoAI proteoforms had positive associations with HDL Cholesterol and efflux, and inverse associations with obesity indices and triglycerides. Truncated and dimerized proteoforms of apoAII were associated with HDL Cholesterol (positively) and obesity indices (inversely). Several proteoforms had no significant associations with phenotype. Conclusions Associations between apoAI and AII and cardiometabolic indices are proteoform-specific. These results provide "proof-of-concept" that precise chemical characterization of human apolipoproteins will yield improved insights into the complex pathways through which proteins signify and mediate health and disease.

Keywords

acylation; apolipoprotein AI; apolipoprotein AII; post‐translational modifications; proteoform.

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