TY - JOUR
T1 - Integrative multiomics analysis of human atherosclerosis reveals a serum response factor-driven network associated with intraplaque hemorrhage
AU - Jin, Han
AU - Goossens, Pieter
AU - Juhasz, Peter
AU - Eijgelaar, Wouter-Jan
AU - Manca, Marco
AU - Karel, Joël
AU - Smirnov, Evgueni
AU - Sikkink, Cornelis J. J. M.
AU - Mees, Barend
AU - Waring, Olivia
AU - van Kuijk, Kim
AU - Fazzi, Gregorio
AU - Gijbels, Marion
AU - Kutmon, M.
AU - Evelo, Chris
AU - Hedin, Ulf
AU - Daemen, Mat Jap
AU - Sluimer, Judith
AU - Matic, Ljubica Perisic
AU - Biessen, Erik
PY - 2021/6/27
Y1 - 2021/6/27
N2 - Background While single-omics analyses on human atherosclerotic plaque have been very useful to map stage- or disease-related differences in expression, they only partly capture the array of changes in this tissue and suffer from scale-intrinsic limitations. In order to better identify processes associated with intraplaque hemorrhage and plaque instability, we therefore combined multiple omics into an integrated model. Methods In this study, we compared protein and gene makeup of low- versus high-risk atherosclerotic lesion segments from carotid endarterectomy patients, as judged from the absence or presence of intraplaque hemorrhage, respectively. Transcriptomic, proteomic, and peptidomic data of this plaque cohort were aggregated and analyzed by DIABLO, an integrative multivariate classification and feature selection method. Results We identified a protein-gene associated multiomics model able to segregate stable, nonhemorrhaged from vulnerable, hemorrhaged lesions at high predictive performance (AUC >0.95). The dominant component of this model correlated with alpha SMA(-)PDGFR alpha(+) fibroblast-like cell content (p = 2.4E-05) and Arg1(+) macrophage content (p = 2.2E-04) and was driven by serum response factor (SRF), possibly in a megakaryoblastic leukemia-1/2 (MKL1/2) dependent manner. Gene set overrepresentation analysis on the selected key features of this model pointed to a clear cardiovascular disease signature, with overrepresentation of extracellular matrix synthesis and organization, focal adhesion, and cholesterol metabolism terms, suggestive of the model's relevance for the plaque vulnerability. Finally, we were able to corroborate the predictive power of the selected features in several independent mRNA and proteomic plaque cohorts. Conclusions In conclusion, our integrative omics study has identified an intraplaque hemorrhage-associated cardiovascular signature that provides excellent stratification of low- from high-risk carotid artery plaques in several independent cohorts. Further study revealed suppression of an SRF-regulated disease network, controlling lesion stability, in vulnerable plaque, which can serve as a scaffold for the design of targeted intervention in plaque destabilization.
AB - Background While single-omics analyses on human atherosclerotic plaque have been very useful to map stage- or disease-related differences in expression, they only partly capture the array of changes in this tissue and suffer from scale-intrinsic limitations. In order to better identify processes associated with intraplaque hemorrhage and plaque instability, we therefore combined multiple omics into an integrated model. Methods In this study, we compared protein and gene makeup of low- versus high-risk atherosclerotic lesion segments from carotid endarterectomy patients, as judged from the absence or presence of intraplaque hemorrhage, respectively. Transcriptomic, proteomic, and peptidomic data of this plaque cohort were aggregated and analyzed by DIABLO, an integrative multivariate classification and feature selection method. Results We identified a protein-gene associated multiomics model able to segregate stable, nonhemorrhaged from vulnerable, hemorrhaged lesions at high predictive performance (AUC >0.95). The dominant component of this model correlated with alpha SMA(-)PDGFR alpha(+) fibroblast-like cell content (p = 2.4E-05) and Arg1(+) macrophage content (p = 2.2E-04) and was driven by serum response factor (SRF), possibly in a megakaryoblastic leukemia-1/2 (MKL1/2) dependent manner. Gene set overrepresentation analysis on the selected key features of this model pointed to a clear cardiovascular disease signature, with overrepresentation of extracellular matrix synthesis and organization, focal adhesion, and cholesterol metabolism terms, suggestive of the model's relevance for the plaque vulnerability. Finally, we were able to corroborate the predictive power of the selected features in several independent mRNA and proteomic plaque cohorts. Conclusions In conclusion, our integrative omics study has identified an intraplaque hemorrhage-associated cardiovascular signature that provides excellent stratification of low- from high-risk carotid artery plaques in several independent cohorts. Further study revealed suppression of an SRF-regulated disease network, controlling lesion stability, in vulnerable plaque, which can serve as a scaffold for the design of targeted intervention in plaque destabilization.
KW - CHALLENGES
KW - CLASSIFICATION
KW - GENE-EXPRESSION
KW - MACROPHAGES
KW - MUSCLE-CELL DIFFERENTIATION
KW - MYOCARDIN
KW - PARTIAL LEAST-SQUARES
KW - PLAQUES
KW - PROLIFERATION
KW - TRANSCRIPTOME
KW - carotid atherosclerosis
KW - multiomics integration
KW - proteomics
KW - transcriptomics
U2 - 10.1002/ctm2.458
DO - 10.1002/ctm2.458
M3 - Article
C2 - 34185408
SN - 2001-1326
VL - 11
JO - Clinical and Translational Medicine
JF - Clinical and Translational Medicine
IS - 6
M1 - e458
ER -