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

doi:10.1161/JAHA.120.019890

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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 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 language	English (US)
Article number	e019890
Journal	Journal of the American Heart Association
Volume	10
Issue number	17
DOIs	https://doi.org/10.1161/JAHA.120.019890
State	Published - Sep 7 2021

Funding

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.

Keywords

Acylation
Apolipoprotein AI
Apolipoprotein AII
Post-translational modifications
Proteoform

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1161/JAHA.120.019890

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Wilkins, J. T., Seckler, H. S., Rink, J., Compton, P. D., Fornelli, L., Thaxton, C. S., Leduc, R., Jacobs, D., Doubleday, P. F., Sniderman, A., Lloyd-Jones, D. M., & Kelleher, N. L. (2021). Spectrum of apolipoprotein ai and apolipoprotein aii proteoforms and their associations with indices of cardiometabolic health: The cardia study. Journal of the American Heart Association, 10(17), Article e019890. https://doi.org/10.1161/JAHA.120.019890

@article{7c478c6c622b43b785eb639a0bea70f8,

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

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 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.",

keywords = "Acylation, Apolipoprotein AI, Apolipoprotein AII, Post-translational modifications, Proteoform",

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

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.",

year = "2021",

month = sep,

day = "7",

doi = "10.1161/JAHA.120.019890",

language = "English (US)",

volume = "10",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

publisher = "American Heart Association Inc.",

number = "17",

}

Wilkins, JT, Seckler, HS, Rink, J, Compton, PD, Fornelli, L, Thaxton, CS, Leduc, R, Jacobs, D, Doubleday, PF, Sniderman, A, Lloyd-Jones, DM & Kelleher, NL 2021, 'Spectrum of apolipoprotein ai and apolipoprotein aii proteoforms and their associations with indices of cardiometabolic health: The cardia study', Journal of the American Heart Association, vol. 10, no. 17, e019890. https://doi.org/10.1161/JAHA.120.019890

TY - JOUR

T1 - Spectrum of apolipoprotein ai and apolipoprotein aii proteoforms and their associations with indices of cardiometabolic health

T2 - The cardia study

AU - Wilkins, John T.

AU - Seckler, Henrique S.

AU - Rink, Jonathan

AU - Compton, Philip D.

AU - Fornelli, Luca

AU - Thaxton, C. Shad

AU - Leduc, Rich

AU - Jacobs, David

AU - Doubleday, Peter F.

AU - Sniderman, Allan

AU - Lloyd-Jones, Donald M.

AU - Kelleher, Neil L.

PY - 2021/9/7

Y1 - 2021/9/7

N2 - 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.

AB - 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.

KW - Acylation

KW - Apolipoprotein AI

KW - Apolipoprotein AII

KW - Post-translational modifications

KW - Proteoform

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U2 - 10.1161/JAHA.120.019890

DO - 10.1161/JAHA.120.019890

M3 - Article

C2 - 34472376

AN - SCOPUS:85116014034

SN - 2047-9980

VL - 10

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

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ER -

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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