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

Lind, Lars ; Gigante, Bruna ; Borné, Yan LU ; Feldreich, Tobias ; Leppert, Jerzy ; Hedberg, Pär ; Östgren, Carl Johan LU ; Nyström, Fredrik H ; Sundström, Johan and Ärnlöv, Johan , et al. (2021) In Arteriosclerosis, Thrombosis, and Vascular Biology 41(5).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Arteriosclerosis, Thrombosis, and Vascular Biology
volume
41
issue
5
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:33657885
  • scopus:85104725883
ISSN
1524-4636
DOI
10.1161/ATVBAHA.120.315597
language
English
LU publication?
yes
id
0b1c8a9f-dc67-49cc-b0ca-c2baa7b2b177
date added to LUP
2021-03-10 13:14:00
date last changed
2024-04-18 03:14:37
@article{0b1c8a9f-dc67-49cc-b0ca-c2baa7b2b177,
  abstract     = {{<p>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.</p><p>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.</p>}},
  author       = {{Lind, Lars and Gigante, Bruna and Borné, Yan and Feldreich, Tobias and Leppert, Jerzy and Hedberg, Pär and Östgren, Carl Johan and Nyström, Fredrik H and Sundström, Johan and Ärnlöv, Johan and Baldassarre, Damiano and Tremoli, Elena and Veglia, Fabrizio and Hamsten, Anders and O'Donnell, Christopher J and Franceschini, Nora and Orho-Melander, Marju and Nilsson, Jan and Melander, Olle and Engström, Gunnar and Mälarstig, Anders}},
  issn         = {{1524-4636}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{5}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Arteriosclerosis, Thrombosis, and Vascular Biology}},
  title        = {{Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes : Meta-Analyses and Mendelian Randomization Analyses}},
  url          = {{http://dx.doi.org/10.1161/ATVBAHA.120.315597}},
  doi          = {{10.1161/ATVBAHA.120.315597}},
  volume       = {{41}},
  year         = {{2021}},
}