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

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  • Florian Thibord
  • Ci Song
  • Jack Pattee
  • Benjamin A T Rodriguez
  • Christopher J O'Donnell
  • Marcus E Kleber
  • Graciela E Delgado
  • Xiuqing Guo
  • Jie Yao
  • Kent D Taylor
  • Ayse Bilge Ozel
  • Jennifer A Brody
  • Barbara McKnight
  • Beata Gyorgy
  • Eleanor Simonsick
  • Hampton L Leonard
  • Germán D Carrasquilla
  • Marta Guindo-Martinez
  • Angela Silveira
  • Gerard Temprano-Sagrera
  • Lisa R Yanek
  • Diane M Becker
  • Rasika A Mathias
  • Lewis C Becker
  • Laura M Raffield
  • Tuomas O Kilpeläinen
  • Niels Grarup
  • Oluf Pedersen
  • Torben Hansen
  • Allan Linneberg
  • Anders Hamsten
  • Hugh Watkins
  • Maria Sabater-Lleal
  • Mike A Nalls
  • David-Alexandre Trégouët
  • Pierre-Emmanuel Morange
  • Bruce M Psaty
  • Russel P Tracy
  • Nicholas L Smith
  • Karl C Desch
  • Mary Cushman
  • Jerome I Rotter
  • Paul S de Vries
  • Nathan D Pankratz
  • Aaron R Folsom
  • Alanna C Morrison
  • Winfried März
  • Weihong Tang
  • Andrew D Johnson
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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 = 6,876) 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 3 out of the 5 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.

OriginalsprogEngelsk
TidsskriftJournal of thrombosis and haemostasis : JTH
Vol/bind19
Udgave nummer8
Sider (fra-til)2019-2028
Antal sider10
ISSN1538-7933
DOI
StatusUdgivet - aug. 2021

ID: 65156046