OBJECTIVE: To identify causal pathophysiological mechanisms for atherosclerosis and incident cardiovascular events using protein measurements. Approach and Results: Carotid artery atherosclerosis was assessed by ultrasound, and 86 cardiovascular-related proteins were measured using the Olink CVD-I panel in 7 Swedish prospective studies (11 754 individuals). The proteins were analyzed in relation to intima-media thickness in the common carotid artery (IMT-CCA), plaque occurrence, and incident cardiovascular events (composite end point of myocardial infarction or ischemic stroke) using a discovery/replication approach in different studies. After adjustments for traditional cardiovascular risk factors, 11 proteins remained significantly associated with IMT-CCA in the replication stage, whereas 9 proteins were replicated for plaque occurrence and 17 proteins for incident cardiovascular events. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and MMP (matrix metalloproteinase)-12 were associated with both IMT-CCA and incident events, but the overlap was considerably larger between plaque occurrence and incident events, including MMP-12, TIM-1 (T-cell immunoglobulin and mucin domain 1), GDF (growth/differentiation factor)-15, IL (interleukin)-6, U-PAR (urokinase plasminogen activator surface receptor), LOX-1 (lectin-like oxidized LDL [low-density lipoprotein] receptor 1), and TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2). Only MMP-12 was associated with IMT-CCA, plaque, and incident events with a positive and concordant direction of effect. However, a 2-sample Mendelian randomization analysis suggested that increased MMP-12 may be protective against ischemic stroke (P=5.5*10-7), which is in the opposite direction of the observational analyses.CONCLUSIONS: The present meta-analysis discovered several proteins related to carotid atherosclerosis that partly differed in their association with IMT-CCA, plaque, and incident atherosclerotic disease. Mendelian randomization analysis for the top finding, MMP-12, suggests that the increased levels of MMP-12 could be a consequence of atherosclerotic burden rather than the opposite chain of events.

Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes: Meta-Analyses and Mendelian Randomization Analyses / L. Lind, B. Gigante, Y. Borné, T. Feldreich, J. Leppert, P. Hedberg, C.J. Östgren, F.H. Nyström, J. Sundström, J. Ärnlöv, D. Baldassarre, E. Tremoli, F. Veglia, A. Hamsten, C.J. O'Donnell, N. Franceschini, M. Orho-Melander, J. Nilsson, O. Melander, G. Engström, A. Mälarstig. - In: ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY. - ISSN 1079-5642. - 41:5(2021 May 05), pp. ATVBAHA120315597.1777-ATVBAHA120315597.1788.

Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes: Meta-Analyses and Mendelian Randomization Analyses

D. Baldassarre;E. Tremoli;F. Veglia;
2021

Abstract

OBJECTIVE: To identify causal pathophysiological mechanisms for atherosclerosis and incident cardiovascular events using protein measurements. Approach and Results: Carotid artery atherosclerosis was assessed by ultrasound, and 86 cardiovascular-related proteins were measured using the Olink CVD-I panel in 7 Swedish prospective studies (11 754 individuals). The proteins were analyzed in relation to intima-media thickness in the common carotid artery (IMT-CCA), plaque occurrence, and incident cardiovascular events (composite end point of myocardial infarction or ischemic stroke) using a discovery/replication approach in different studies. After adjustments for traditional cardiovascular risk factors, 11 proteins remained significantly associated with IMT-CCA in the replication stage, whereas 9 proteins were replicated for plaque occurrence and 17 proteins for incident cardiovascular events. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and MMP (matrix metalloproteinase)-12 were associated with both IMT-CCA and incident events, but the overlap was considerably larger between plaque occurrence and incident events, including MMP-12, TIM-1 (T-cell immunoglobulin and mucin domain 1), GDF (growth/differentiation factor)-15, IL (interleukin)-6, U-PAR (urokinase plasminogen activator surface receptor), LOX-1 (lectin-like oxidized LDL [low-density lipoprotein] receptor 1), and TRAIL-R2 (TNF [tumor necrosis factor]-related apoptosis-inducing ligand receptor 2). Only MMP-12 was associated with IMT-CCA, plaque, and incident events with a positive and concordant direction of effect. However, a 2-sample Mendelian randomization analysis suggested that increased MMP-12 may be protective against ischemic stroke (P=5.5*10-7), which is in the opposite direction of the observational analyses.CONCLUSIONS: The present meta-analysis discovered several proteins related to carotid atherosclerosis that partly differed in their association with IMT-CCA, plaque, and incident atherosclerotic disease. Mendelian randomization analysis for the top finding, MMP-12, suggests that the increased levels of MMP-12 could be a consequence of atherosclerotic burden rather than the opposite chain of events.
atherosclerosis; carotid arteries; epidemiology; ischemic stroke; myocardial infarction
Settore BIO/14 - Farmacologia
4-mar-2021
https://www.ahajournals.org/doi/10.1161/ATVBAHA.120.315597?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/821186
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