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 -