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Development and Validation of Apolipoprotein AI-Associated Lipoprotein Proteome Panel for the Prediction of Cholesterol Efflux Capacity and Coronary Artery Disease

Jin, Z; Collier, TS; Dai, DLY; Chen, V; Hollander, Z; Ng, RT; McManus, BM; ... Bystrom, C; + view all (2019) Development and Validation of Apolipoprotein AI-Associated Lipoprotein Proteome Panel for the Prediction of Cholesterol Efflux Capacity and Coronary Artery Disease. Clinical Chemistry , 65 (2) 10.1373/clinchem.2018.291922. (In press).

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Abstract

BACKGROUND: Cholesterol efflux capacity (CEC) is a measure of HDL function that, in cell-based studies, has demonstrated an inverse association with cardiovascular disease. The cell-based measure of CEC is complex and low-throughput. We hypothesized that assessment of the lipoprotein proteome would allow for precise, high-throughput CEC prediction. METHODS: After isolating lipoprotein particles from serum, we used LC-MS/MS to quantify 21 lipoprotein-associated proteins. A bioinformatic pipeline was used to identify proteins with univariate correlation to cell-based CEC measurements and generate a multivariate algorithm for CEC prediction (pCE). Using logistic regression, protein coefficients in the pCE model were reweighted to yield a new algorithm predicting coronary artery disease (pCAD). RESULTS: Discovery using targeted LC-MS/MS analysis of 105 training and test samples yielded a pCE model comprising 5 proteins (Spearman r = 0.86). Evaluation of pCE in a case-control study of 231 specimens from healthy individuals and patients with coronary artery disease revealed lower pCE in cases (P = 0.03). Derived within this same study, the pCAD model significantly improved classification (P < 0.0001). Following analytical validation of the multiplexed proteomic method, we conducted a case-control study of myocardial infarction in 137 postmenopausal women that confirmed significant separation of specimen cohorts in both the pCE (P = 0.015) and pCAD (P = 0.001) models. CONCLUSIONS: Development of a proteomic pCE provides a reproducible high-throughput alternative to traditional cell-based CEC assays. The pCAD model improves stratification of case and control cohorts and, with further studies to establish clinical validity, presents a new opportunity for the assessment of cardiovascular health.

Type: Article
Title: Development and Validation of Apolipoprotein AI-Associated Lipoprotein Proteome Panel for the Prediction of Cholesterol Efflux Capacity and Coronary Artery Disease
Location: United States
DOI: 10.1373/clinchem.2018.291922
Publisher version: https://doi.org/10.1373/clinchem.2018.291922
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: http://discovery.ucl.ac.uk/id/eprint/10063291
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