Dataset Information

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

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.

SUBMITTER: Thibord F

PROVIDER: S-EPMC9946195 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Thibord Florian F Song Ci C Pattee Jack J Rodriguez Benjamin A T BAT Chen Ming-Huei MH O'Donnell Christopher J CJ Kleber Marcus E ME Delgado Graciela E GE Guo Xiuqing X Yao Jie J Taylor Kent D KD Ozel Ayse Bilge AB Brody Jennifer A JA McKnight Barbara B Gyorgy Beata B Simonsick Eleanor E Leonard Hampton L HL Carrasquilla Germán D GD Guindo-Martinez Marta M Silveira Angela A Temprano-Sagrera Gerard G Yanek Lisa R LR Becker Diane M DM Mathias Rasika A RA Becker Lewis C LC Raffield Laura M LM Kilpeläinen Tuomas O TO Grarup Niels N Pedersen Oluf O Hansen Torben T Linneberg Allan A Hamsten Anders A Watkins Hugh H Sabater-Lleal Maria M Nalls Mike A MA Trégouët David-Alexandre DA Morange Pierre-Emmanuel PE Psaty Bruce M BM Tracy Russel P RP Smith Nicholas L NL Desch Karl C KC Cushman Mary M Rotter Jerome I JI de Vries Paul S PS Pankratz Nathan D ND Folsom Aaron R AR Morrison Alanna C AC März Winfried W Tang Weihong W Johnson Andrew D AD

Journal of thrombosis and haemostasis : JTH 20210530 8

<h4>Background</h4>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.<h4>Objectives</h4>We sought to discover new ...[more]

PMID: 33876560

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Project description:The fibrin clot is gelatinous matter formed upon injury to stop blood loss and is later destroyed by fibrinolysis, an enzymatic cascade with feedback. Pharmacological fibrinolysis stimulation is also used to destroy pathological, life-threatening clots and thrombi (thrombolysis). The regulation of the nonlinear spatially nonuniform fibrinolytic process in thrombolysis is not currently well understood. We developed a reaction-diffusion-advection model of thrombolysis by tissue plasminogen activator (TPA) in an occluded vessel with a pressure gradient. Sensitivity-analysis-based model reduction was used to reveal the critical processes controlling different steps of thrombolysis. The propagation of thrombolysis in the system without flow was predominantly controlled by TPA diffusion, whereas transport of other active components was rendered nonessential either by their high fibrin-binding parameters and short lifetimes or their initial uniform distribution. The concentration of the main TPA inhibitor plasminogen activator inhibitor 1 (PAI-1) controlled both the extent of lysis propagation and the shape of fibrin spatial distribution during lysis. Interestingly, PAI-1 remained important even when its concentration was an order of magnitude below that of TPA because of its role at the edge of the diffusing TPA front. The system was robust to reaction rate constant perturbations. Using these data, a reduced model of thrombolysis was proposed. In the presence of flow, convection of TPA was the critical controlling process; although the role of PAI-1 concentration was much less in the presence of flow, its influence became greater in the presence of collateral bypassing vessels, which sufficiently reduced TPA flux through the thrombus. Flow bypass through the collateral vessel caused a decrease in TPA flux in the clotted vessel, which increased the PAI-1/TPA ratio, thus making PAI-1-induced inhibition relevant for the regulation of spatial lysis up to its arrest.

Dataset Information

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

Background

Objectives

Methods

Results

Conclusion

Publications

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

Similar Datasets

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