TY - JOUR
T1 - FGL1 as a modulator of plasma D-dimer levels
T2 - exome-wide marker analysis of plasma tPA, PAI-1 and D-dimer
AU - Thibord, Florian
AU - Song, Ci
AU - Pattee, Jack
AU - Rodriguez, Benjamin A T
AU - Chen, Ming-Huei
AU - O'Donnell, Christopher J
AU - Kleber, Marcus E
AU - Delgado, Graciela E
AU - Guo, Xiuqing
AU - Yao, Jie
AU - Taylor, Kent D
AU - Ozel, Ayse Bilge
AU - Brody, Jennifer A
AU - McKnight, Barbara
AU - Gyorgy, Beata
AU - Simonsick, Eleanor
AU - Leonard, Hampton L
AU - Carrasquilla, Germán D
AU - Guindo-Martinez, Marta
AU - Silveira, Angela
AU - Temprano-Sagrera, Gerard
AU - Yanek, Lisa R
AU - Becker, Diane M
AU - Mathias, Rasika A
AU - Becker, Lewis C
AU - Raffield, Laura M
AU - Kilpeläinen, Tuomas O
AU - Grarup, Niels
AU - Pedersen, Oluf
AU - Hansen, Torben
AU - Linneberg, Allan
AU - Hamsten, Anders
AU - Watkins, Hugh
AU - Sabater-Lleal, Maria
AU - Nalls, Mike A
AU - Trégouët, David-Alexandre
AU - Morange, Pierre-Emmanuel
AU - Psaty, Bruce M
AU - Tracy, Russel P
AU - Smith, Nicholas L
AU - Desch, Karl C
AU - Cushman, Mary
AU - Rotter, Jerome I
AU - de Vries, Paul S
AU - Pankratz, Nathan D
AU - Folsom, Aaron R
AU - Morrison, Alanna C
AU - März, Winfried
AU - Tang, Weihong
AU - Johnson, Andrew D
N1 - This article is protected by copyright. All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1111/jth.15345
DO - 10.1111/jth.15345
M3 - Journal article
C2 - 33876560
VL - 19
SP - 2019
EP - 2028
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
SN - 1538-7933
IS - 8
ER -