Plasma Protein Profile of Carotid Artery Atherosclerosis and Atherosclerotic Outcomes : Meta-Analyses and Mendelian Randomization Analyses
(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.
(Less)
- author
- organization
-
- Nutrition Epidemiology (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- EpiHealth: Epidemiology for Health
- Diabetes - Cardiovascular Disease (research group)
- Hepato-Pancreato-Biliary Surgery (research group)
- Surgery (Lund)
- Cardiovascular Research - Hypertension (research group)
- Cardiovascular Research - Epidemiology (research group)
- publishing date
- 2021-03-04
- 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
- 2025-01-24 07:53:18
@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}}, }