Spectrum of apolipoprotein ai and apolipoprotein aii proteoforms and their associations with indices of cardiometabolic health: The cardia study

John T. Wilkins, Henrique S. Seckler, Jonathan Rink, Philip D. Compton, Luca Fornelli, C. Shad Thaxton, Rich Leduc, David Jacobs, Peter F. Doubleday, Allan Sniderman, Donald M. Lloyd-Jones, Neil L. Kelleher

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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 quan-tified 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 pro-vide “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.

Original languageEnglish (US)
Article numbere019890
JournalJournal of the American Heart Association
Issue number17
StatePublished - Sep 7 2021

Bibliographical note

Funding Information:
Work performed for this study was funded by the National Institutes of Health, under grants K23 HL133601-03 (Wilkins), the American Heart Association, under grant SDG 27250022 (Wilkins), and the National Institute of General Medical Sciences, under grant P41 GM108569 (Kelleher). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The CARDIA study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201800005I & HHSN268201800007I), Northwestern University (HHSN268201800003I), University of Minnesota (HHSN268201800006I), and Kaiser Foundation Research Institute (HHSN268201800004I). This article has been reviewed by CARDIA for scientific content.

Publisher Copyright:
© 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.


  • Acylation
  • Apolipoprotein AI
  • Apolipoprotein AII
  • Post-translational modifications
  • Proteoform


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