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    Oral Communication

    Diagnostics and OMICs

    High Throughput Methods for Improved Understanding of Coagulation and Bleeding

    OC 57.3 - Genome-wide identification of loci controlling plasma coagulation factor IX activity

    Tuesday, June 27, 2023
    11:15 – 11:30 ET
    Room: 518
    Session Available As: On-Demand

      Presenting Author(s)

    • Jihee Han, MS

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

      • Co-Author(s)

    • Ruifang Li-Gao, PhD (she/her/hers)

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

    • Rd

      Renée de Mutsert

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

    • FR

      Frits R. R. Rosendaal

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

    • Alejandro Pallares Robles

      PhD student
      Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz (UMCM), Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • Vt

      Vincent ten Cate

      Postdoc
      Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz (UMCM), Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • PS

      Philipp S. S. Wild

      Professor
      Clinical Epidemiology and Systems Medicine, Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz (UMCM), Mainz, Germany
      Mainz, Rheinland-Pfalz, Germany

    • Astrid van Hylckama Vlieg, PhD

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

    Background: Elevated coagulation factor (F) IX activity is associated with cardiometabolic diseases including venous thrombosis. Factor IX activity may be affected by environmental and genetic factors. However, genetic factors affecting FIX activity remain elusive.

    Aims: We aimed to identify novel genetic loci affecting plasma FIX activity.

    Methods: We performed a genome-wide association study (GWAS) using the Netherlands Epidemiology of Obesity study, including 6,671 individuals. We excluded participants who used anticoagulants (n=130), had missing information for any needed variables (n=163), or who did not pass individual level quality control for GWAS (n=927). Genotype data were imputed to the 1000 Genomes reference panel phase III. FIX activity was measured with a coagulometric clot detection method. We performed linear regression analysis for FIX activity in the original unit using an additive genetic model adjusted for age, sex, hormone therapy, menopausal status, and the first 5 principal components. The genome-wide significance threshold was defined as 5 x 10-8. An additional GWAS and meta-analysis of the results are planned based on the German population-based Gutenberg Health Study.

    Results: In total, 5,581 participants were included with a mean (SD) plasma FIX activity of 123.4 % (20.2). We identified 6 novel genetic loci associated with plasma FIX activity, i.e. GCKR (rs1260326), NRP2 (rs143629900), KNG1 (rs698078), F12 (rs2731674), ABO (rs597974) and CDH4 (rs145541636). The identified associations ranged between -3.28 and 20.70%. Of the associated genetic loci, ABO (rs597974), located in chromosome 9, showed the most significant association with plasma FIX activity (β-estimate = 4.39 %, p-value = 4.01E-25).

    Conclusion(s): We identified novel genetic loci affecting plasma FIX activity. Our results aid in a better understanding of the biological mechanism regulating plasma FIX activity and shed light on potential preventive and therapeutic targets of cardiometabolic diseases associated with FIX activity.

    Learning Objectives:

    • Upon completion, participants will be able to identify genetic loci controlling plasma coagulation factor IX activity
    • Upon completion, participants will be able to describe genes associated with plasma coagulation factor IX activity
    • Upon completion, participants will be able to explain how to perform a genome-wide association study and meta-analysis