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CME Evaluation

Oral Communication Session

Diagnostics, OMICs and Advanced Technologies

Session: Omics-based clinical discoveries for thrombosis and hemostasis

OC 08.2 - Genome-wide meta-analyses and integrative multi-omics analysis of endogenous thrombin generation potential in the CROSSLINK consortium

Saturday, June 22, 2024
13:15 – 13:30 ICT
Room: 211 A-D

    Presenting Author(s)

  • Vincent Ten Cate, MSc, PhD

    Group leader
    Clinical Epidemiology and Systems Medicine, University Medical Center of the Johannes Gutenberg University Mainz
    Mainz, Rheinland-Pfalz, Germany

    • Co-Author(s)

  • Jihee Han

    PhD student
    Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
    Leiden, Zuid-Holland, Netherlands

  • AP

    Alejandro Pallares Robles

    PhD student
    Clinical Epidemiology and Systems Medicine,University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
    Mainz, Rheinland-Pfalz, Germany

  • MG

    Marine Germain

    Research Scientist
    University of Bordeaux
    Bordeaux, Aquitaine, France

  • Ruifang Li-Gao

    Postdoc
    Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
    Leiden, Zuid-Holland, Netherlands

  • GW

    Gonneke Willemsen

    Professor
    Department of Biological Psychology, Vrije Universiteit (VU), Amsterdam, the Netherlands
    Amsterdam, Noord-Holland, Netherlands

  • FR

    Frits R Rosendaal

    Professor at Leiden University Medical Center and Chairman of the Clinical Epidemiology Department
    Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
    Leiden, Zuid-Holland, Netherlands

  • Henri M.H Spronk, PhD

    Professor of Biochemistry of Atherothrombosis
    Maastricht University
    Maastricht, Limburg, Netherlands

  • Tilman M. Hackeng, PhD

    Professor
    Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University
    Maastricht, Netherlands

  • DB

    Dorret Boomsma

    Professor
    Department of Biological Psychology, Vrije Universiteit (VU), Amsterdam, the Netherlands
    Amsterdam, Noord-Holland, Netherlands

  • David-Alexandre Trégouët

    Senior Investigator
    Bordeaux Population Health research Center, Inserm U1219, Bordeaux University
    Bordeaux, Aquitaine, France

  • Pierre Morange, MD, PhD

    Aix-Marseille University, France

  • JH

    Jouke Jan Hottenga

    Senior researcher
    Department of Biological Psychology, Vrije Universiteit (VU), Amsterdam, the Netherlands
    Amsterdam, Noord-Holland, Netherlands

  • Hugo ten Cate, MD, PHD

    MD, PhD
    Departments of Internal Medicine and Biochemistry, Maastricht University Medical Center+, Maastricht, The Netherlands
    Maastricht, Limburg, Netherlands

  • Astrid van Hylckama Vlieg

    Associate professor
    Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
    Leiden, Zuid-Holland, Netherlands

  • PW

    Philipp S. Wild

    Professor
    Clinical Epidemiology and Systems Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
    Mainz, Rheinland-Pfalz, Germany

Background: The genetic regulation of thrombin generation (TG) and its mechanistic links to downstream phenotypes remain incompletely understood.

Aims: To characterize the genetic architecture of TG and to elucidate links to downstream phenotypes, including mRNA and protein levels, subclinical disease development and clinical endpoints.

Methods: A genome-wide meta-analysis of six European cohorts of the CROSSLINK consortium with imputed genotyping data and TG measurements was performed (N=19,159; Figure 1). TG was measured in platelet-poor plasma by calibrated automated thrombography, using effective low (1-2.5 pM) and high (≥5 pM) concentrations of tissue factor (TF). Population-based cohort studies (GHS, NEO, NTR) were analysed for the discovery with the GWAMA software. Genome-wide significant (p < 5×10-8) variants underwent conditional analysis using the GCTA-COJO software. Replication meta-analysis of conditionally independent variants was conducted in clinical cohort studies (MyoVasc, MEGA, MARTHA). Whole blood and monocyte gene expression (eQTL) and plasma protein quantitative trait loci (pQTL) were identified by linear regression. Downstream analyses relating resulting variants to coagulation factor assays, cardiovascular organ damage markers and clinical endpoints are planned.

Results: Top loci at which conditionally independent and replicated variants were identified in the low TF condition were ARHGAP1, ABO, LOC102724474, and SLC34A1 (endogenous thrombin potential, ETP); ORM1, F7, F5, and PROCR (lag time); ABO, LOC102724474, SLC34A1, and F5 (peak height). Top loci in the high TF condition were F2, ORM2 (ETP); ORM2, F5, F10, and ABCC1 (lag time); ARHGAP1, ABO, LOC102724474, PLXDC2 and F5 (peak height). Among the identified variants were genome-wide significant monocyte and whole blood eQTLs for ORM1 and F5 expression, and plasma pQTLs for F7, ABO, and ORM1 concentrations.

Conclusion(s): This study identified new loci for TG. Distinct loci for each parameter indicated complementary information. Genetic differences between the low and high reagent conditions suggested activation of distinct pathways depending on the amount of tissue factor.