Effects of cigarette smoking on cardiovascular-related protein profiles in two community-based cohort studies

  • Biying Huang
    Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94304, USA

    Department of Medicine, Solna, Karolinska Institutet, 17176 Stockholm, Sweden
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  • Per Svensson
    Department of Medicine, Solna, Karolinska Institutet, 17176 Stockholm, Sweden
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  • Johan Ärnlöv
    Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, 75185 Uppsala, Sweden

    School of Health and Social Studies, Dalarna University, 79188 Falun, Sweden
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  • Johan Sundström
    Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, 75185 Uppsala, Sweden
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  • Lars Lind
    Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, 75185 Uppsala, Sweden
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  • Erik Ingelsson
    Corresponding author. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94304, USA.
    Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94304, USA

    Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, 75185 Uppsala University, Uppsala, Sweden
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      • Ten cardiovascular-related biomarkers were significantly associated with smoking.
      • The associations were similar in men and women.
      • Associations were consistent in individuals without cardiovascular diseases.
      • Our findings highlight the role of smoking in processes leading to atherosclerosis.


      Background and aims

      Cardiovascular diseases account for the largest fraction of smoking-induced deaths. Studies of smoking in relation to cardiovascular-related protein markers can provide novel insights into the biological effects of smoking. We investigated the associations between cigarette smoking and 80 protein markers known to be related to cardiovascular diseases in two community-based cohorts, the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS, n = 969, 50% women, all aged 70 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 717, all men aged 77 years).


      Smoking status was self-reported and defined as current smoker, former smoker or never-smoker. Levels of the 80 proteins were measured using the proximity extension assay, a novel PCR-based proteomics technique.


      We found 30 proteins to be significantly associated with current cigarette smoking in PIVUS (FDR<5%); and ten were replicated in ULSAM (p < 0.05). Matrix metalloproteinase-12 (MMP-12), growth/differentiation factor 15 (GDF-15), urokinase plasminogen activator surface receptor (uPAR), TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), lectin-like oxidized LDL receptor 1 (LOX-1), hepatocyte growth factor (HGF), matrix metalloproteinase-10 (MMP-10) and matrix metalloproteinase-1 (MMP-1) were positively associated, while endothelial cell-specific molecule 1 (ESM-1) and interleukin-27 subunit alpha (IL27-A) showed inverse associations. All of them remained significant in a subset of individuals without manifest cardiovascular disease.


      The findings of the present study suggest that cigarette smoking may interfere with several essential parts of the atherosclerosis process, as evidenced by associations with protein markers representing endothelial dysfunction, inflammation, neointimal formation, foam cell formation and plaque instability.



      CVD (cardiovascular disease), COPD (chronic obstructive pulmonary disease), PEA (proximity extension assay), PIVUS (Prospective Study of the Vasculature in Uppsala Seniors), ULSAM (Uppsala Longitudinal Study of Adult Men), CRP (C-reactive protein), FDR (false discovery rate), MMP-12 (matrix metalloproteinase-12), GDF-15 (growth/differentiation factor 15), UPAR (urokinase plasminogen activator surface receptor), TRAIL-R2 (TNF-related apoptosis-inducing ligand receptor 2), LOX-1 (Lectin-like oxidized LDL receptor 1), HGF (hepatocyte growth factor), MMP-10 (matrix metalloproteinase-10), MMP-1 (matrix metalloproteinase-1), ESM-1 (endothelial cell-specific molecule 1), IL27-A (interleukin-27 subunit alpha), PAD (peripheral artery disease), VSMC (vascular smooth muscle cell), ECM (extracellular matrix)
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