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AtheroSpectrum Reveals Novel Macrophage Foam Cell Gene Signatures Associated With Atherosclerotic Cardiovascular Disease Risk.

Publication ,  Journal Article
Li, C; Qu, L; Matz, AJ; Murphy, PA; Liu, Y; Manichaikul, AW; Aguiar, D; Rich, SS; Herrington, DM; Vu, D; Johnson, WC; Rotter, JI; Post, WS ...
Published in: Circulation
January 18, 2022

BACKGROUND: Whereas several interventions can effectively lower lipid levels in people at risk for atherosclerotic cardiovascular disease (ASCVD), cardiovascular event risks remain, suggesting an unmet medical need to identify factors contributing to cardiovascular event risk. Monocytes and macrophages play central roles in atherosclerosis, but studies have yet to provide a detailed view of macrophage populations involved in increased ASCVD risk. METHODS: A novel macrophage foaming analytics tool, AtheroSpectrum, was developed using 2 quantitative indices depicting lipid metabolism and the inflammatory status of macrophages. A machine learning algorithm was developed to analyze gene expression patterns in the peripheral monocyte transcriptome of MESA participants (Multi-Ethnic Study of Atherosclerosis; set 1; n=911). A list of 30 genes was generated and integrated with traditional risk factors to create an ASCVD risk prediction model (30-gene cardiovascular disease risk score [CR-30]), which was subsequently validated in the remaining MESA participants (set 2; n=228); performance of CR-30 was also tested in 2 independent human atherosclerotic tissue transcriptome data sets (GTEx [Genotype-Tissue Expression] and GSE43292). RESULTS: Using single-cell transcriptomic profiles (GSE97310, GSE116240, GSE97941, and FR-FCM-Z23S), AtheroSpectrum detected 2 distinct programs in plaque macrophages-homeostatic foaming and inflammatory pathogenic foaming-the latter of which was positively associated with severity of atherosclerosis in multiple studies. A pool of 2209 pathogenic foaming genes was extracted and screened to select a subset of 30 genes correlated with cardiovascular event in MESA set 1. A cardiovascular disease risk score model (CR-30) was then developed by incorporating this gene set with traditional variables sensitive to cardiovascular event in MESA set 1 after cross-validation generalizability analysis. The performance of CR-30 was then tested in MESA set 2 (P=2.60×10-4; area under the receiver operating characteristic curve, 0.742) and 2 independent data sets (GTEx: P=7.32×10-17; area under the receiver operating characteristic curve, 0.664; GSE43292: P=7.04×10-2; area under the receiver operating characteristic curve, 0.633). Model sensitivity tests confirmed the contribution of the 30-gene panel to the prediction model (likelihood ratio test; df=31, P=0.03). CONCLUSIONS: Our novel computational program (AtheroSpectrum) identified a specific gene expression profile associated with inflammatory macrophage foam cells. A subset of 30 genes expressed in circulating monocytes jointly contributed to prediction of symptomatic atherosclerotic vascular disease. Incorporating a pathogenic foaming gene set with known risk factors can significantly strengthen the power to predict ASCVD risk. Our programs may facilitate both mechanistic investigations and development of therapeutic and prognostic strategies for ASCVD risk.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

January 18, 2022

Volume

145

Issue

3

Start / End Page

206 / 218

Location

United States

Related Subject Headings

  • Vascular Calcification
  • Risk
  • ROC Curve
  • Plaque, Atherosclerotic
  • Middle Aged
  • Male
  • Macrophages
  • Humans
  • Foam Cells
  • Female
 

Citation

APA
Chicago
ICMJE
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Li, C., Qu, L., Matz, A. J., Murphy, P. A., Liu, Y., Manichaikul, A. W., … Zhou, B. (2022). AtheroSpectrum Reveals Novel Macrophage Foam Cell Gene Signatures Associated With Atherosclerotic Cardiovascular Disease Risk. Circulation, 145(3), 206–218. https://doi.org/10.1161/CIRCULATIONAHA.121.054285
Li, Chuan, Lili Qu, Alyssa J. Matz, Patrick A. Murphy, Yongmei Liu, Ani W. Manichaikul, Derek Aguiar, et al. “AtheroSpectrum Reveals Novel Macrophage Foam Cell Gene Signatures Associated With Atherosclerotic Cardiovascular Disease Risk.Circulation 145, no. 3 (January 18, 2022): 206–18. https://doi.org/10.1161/CIRCULATIONAHA.121.054285.
Li C, Qu L, Matz AJ, Murphy PA, Liu Y, Manichaikul AW, et al. AtheroSpectrum Reveals Novel Macrophage Foam Cell Gene Signatures Associated With Atherosclerotic Cardiovascular Disease Risk. Circulation. 2022 Jan 18;145(3):206–18.
Li, Chuan, et al. “AtheroSpectrum Reveals Novel Macrophage Foam Cell Gene Signatures Associated With Atherosclerotic Cardiovascular Disease Risk.Circulation, vol. 145, no. 3, Jan. 2022, pp. 206–18. Pubmed, doi:10.1161/CIRCULATIONAHA.121.054285.
Li C, Qu L, Matz AJ, Murphy PA, Liu Y, Manichaikul AW, Aguiar D, Rich SS, Herrington DM, Vu D, Johnson WC, Rotter JI, Post WS, Vella AT, Rodriguez-Oquendo A, Zhou B. AtheroSpectrum Reveals Novel Macrophage Foam Cell Gene Signatures Associated With Atherosclerotic Cardiovascular Disease Risk. Circulation. 2022 Jan 18;145(3):206–218.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

January 18, 2022

Volume

145

Issue

3

Start / End Page

206 / 218

Location

United States

Related Subject Headings

  • Vascular Calcification
  • Risk
  • ROC Curve
  • Plaque, Atherosclerotic
  • Middle Aged
  • Male
  • Macrophages
  • Humans
  • Foam Cells
  • Female