{
  "abstract": "Background Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial regulator of cholesterol metabolism. Loss-of-function variants in PCSK9 are associated with lower levels of circulating low-density lipoprotein cholesterol (LDL-C) and reduced cardiovascular disease (CVD) risk, while gain-of-function variants correlate with elevated LDL-C concentrations and increased CVD risk. This study investigated whether genetically determined LDL-C levels, proxied by four PCSK9 genetic variants, influence common carotid artery atherosclerosis.Methods The analysis included 3040 European participants (mean age 64.2±5.4 years; 45.8% men) at high cardiovascular risk from the IMPROVE Study, alongside 49 088 individuals of white British ancestry (mean age 55.2±7.6 years; 47.9% men) from the UK Biobank (UKB). Ultrasonographic measurements of common carotid intima-media thickness (CC-IMTmean, CC-IMTmax, CC-IMTmean-max) were obtained. Four lipid-level affecting genetic variants in the PCSK9 locus were selected for analysis, both individually and in a standardised Lipid-Lowering Allelic Score (LLAS), to assess their effects on LDL-C and PCSK9 levels in the IMPROVE cohort and on ultrasonographic measures in both IMPROVE and UKB.Results In the IMPROVE cohort, PCSK9 variants (rs11206510, rs2479409, rs11591147, rs11583680) exhibited expected effect directions, although not all statistically significant, on LDL-C and PCSK9 levels. The LLAS was negatively correlated with CC-IMTmean, CC-IMTmax and CC-IMTmean-max among women in IMPROVE, and among men and overall in UKB (all p<0.05). Effect sizes were comparable between cohorts.Conclusions Genetic variants in the PCSK9 locus influence LDL-C levels and CC-IMT, in keeping with proven benefits of PCSK9 inhibitors on atherosclerotic cardiovascular events.",
  "authors": [
    {
      "affiliations": [
        "Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Lombardy, Italy"
      ],
      "name": "Daniela Coggi"
    },
    {
      "affiliations": [
        "Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK"
      ],
      "name": "Joey Ward"
    },
    {
      "affiliations": [
        "Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy"
      ],
      "name": "Chiara Macchi"
    },
    {
      "affiliations": [
        "Cardiovascular Epidemiology, IMM, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Bruna Gigante"
    },
    {
      "affiliations": [
        "Centro Cardiologico Monzino, Milano, Italy"
      ],
      "name": "Mauro Amato"
    },
    {
      "affiliations": [
        "University of Glasgow, Glasgow, UK"
      ],
      "name": "Donald M Lyall"
    },
    {
      "affiliations": [
        "Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Lombardy, Italy"
      ],
      "name": "Beatrice Frigerio"
    },
    {
      "affiliations": [
        "Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Lombardy, Italy"
      ],
      "name": "Alessio Ravani"
    },
    {
      "affiliations": [
        "Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Lombardy, Italy"
      ],
      "name": "Daniela Sansaro"
    },
    {
      "affiliations": [
        "Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Lombardy, Italy"
      ],
      "name": "Nicola Ferri"
    },
    {
      "affiliations": [
        "Dipartimento di Medicina, Università degli Studi di Padova, Padua, Italy"
      ],
      "name": "Maria Giovanna Lupo"
    },
    {
      "affiliations": [
        "Università degli Studi di Milano, Milano, Italy"
      ],
      "name": "Massimiliano Ruscica"
    },
    {
      "affiliations": [
        "Maria Cecilia Hospital, Cotignola, Italy"
      ],
      "name": "Fabrizio Veglia"
    },
    {
      "affiliations": [
        "Dipartimento di Medicina, Università degli Studi di Padova, Padua, Italy"
      ],
      "name": "Nicolo Capra"
    },
    {
      "affiliations": [
        "IHU-ICAN, Paris, France",
        "Department of Nutrition, Hôpital Pitié-Salpêtrière, Paris, France"
      ],
      "name": "Antonio Gallo"
    },
    {
      "affiliations": [
        "Internal Medicine Department of Medicine and Surgery, University of Perugia, Perugia, Italy"
      ],
      "name": "Matteo Pirro"
    },
    {
      "affiliations": [
        "Department of Clinical Physiology and Nuclear Medicine, University of Eastern Finland, Kuopio, Finland",
        "Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland"
      ],
      "name": "Kai Savonen"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University of Groningen, Groningen, Netherlands"
      ],
      "name": "Douwe J Mulder"
    },
    {
      "affiliations": [
        "Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Lombardy, Italy"
      ],
      "name": "Roberta Baetta"
    },
    {
      "affiliations": [
        "Maria Cecilia Hospital, Cotignola, Italy"
      ],
      "name": "Elena Tremoli"
    },
    {
      "affiliations": [
        "Section of Public Health and Health Policy, University of Glasgow, Glasgow, UK"
      ],
      "name": "Jill P. Pell"
    },
    {
      "affiliations": [
        "BHF GCRC, University of Glasgow, Glasgow, UK"
      ],
      "name": "Paul Welsh"
    },
    {
      "affiliations": [
        "British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK"
      ],
      "name": "Naveed Sattar"
    },
    {
      "affiliations": [
        "Centro Cardiologico Monzino, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Lombardy, Italy",
        "Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy"
      ],
      "name": "Damiano Baldassarre"
    },
    {
      "affiliations": [
        "University of Glasgow, Glasgow, UK",
        "Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Rona J Strawbridge"
    }
  ],
  "title": "PCSK9 genetic variants, carotid atherosclerosis and vascular remodelling",
  "uid": "5fdbf2b5-8220-5de1-8b2a-70f962a10ce2"
}