FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer

J Thromb Haemost. 2021 Aug;19(8):2019-2028. doi: 10.1111/jth.15345. Epub 2021 May 30.

Abstract

Background: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.

Objectives: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.

Methods: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.

Results: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10-8 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10-4 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.

Conclusion: This work provides new evidence for a role of FGL1 in hemostasis.

Keywords: computational biology; exome; fibrinogen; fibrinolysis; genetic association study.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Exome
  • Fibrin Fibrinogen Degradation Products
  • Fibrinogen / genetics
  • Fibrinolysis
  • Humans
  • Plasminogen Activator Inhibitor 1* / genetics
  • Tissue Plasminogen Activator* / genetics

Substances

  • FGL1 protein, human
  • Fibrin Fibrinogen Degradation Products
  • Plasminogen Activator Inhibitor 1
  • fibrin fragment D
  • Fibrinogen
  • Tissue Plasminogen Activator

Grant support