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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Lars Lind
  • Bruna Gigante
  • Tobias Feldreich
  • Jerzy Leppert
  • Pär Hedberg
  • Carl Johan Östgren
  • Fredrik H Nyström
  • Johan Sundström
  • Johan Ärnlöv
  • Damiano Baldassarre
  • Elena Tremoli
  • Fabrizio Veglia
  • Anders Hamsten
  • Christopher J O'Donnell
  • Nora Franceschini
  • Anders Mälarstig
Organisations
External organisations
  • Dalarna University
  • Boston University
  • Uppsala University
  • Västmanland Hospital
  • Linköping University
  • University of New South Wales
  • University of Milan
  • University of North Carolina
  • Karolinska Institutet
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems
Original languageEnglish
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Publication statusPublished - 2021 Mar 4
Publication categoryResearch
Peer-reviewedYes