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

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...

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Authors: Thibord, F; Song, C; Pattee, J; Rodriguez, BAT; Chen, MH; O'Donnell, CJ; Kleber, ME; Delgado, GE; Guo, XQ; Yao, J; Taylor, KD; Ozel, AB; Brody, JA; McKnight, B; Gyorgy, B; Simonsick, E; Leonard, HL; Carrasquilla, GD; Guindo-Martinez, M; Silveira, A; Temprano-Sagrera, G; Yanek, LR; Becker, DM; Mathias, RA; Becker, LC; Raffield, LM; Kilpelainen, TO; Grarup, N; Pedersen, O; Hansen, T; Linneberg, A; Hamsten, A; Watkins, H; Sabater-Lleal, M; Nalls, MA; Tregouet, DA; Morange, PE; Psaty, BM; Tracy, RP; Smith, NL; Desch, KC; Cushman, M; Rotter, JI; de Vries, PS; Pankratz, ND; Folsom, AR; Morrison, AC; Marz, W; Tang, WH; Johnson, AD
Format: Article
Status:Published version
Publication date:2021
Country:España
Institution:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repository:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p4676
Online Access:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=4676
https://hdl.handle.net/2027.42/168475
Access Level:Open access
Keyword:computational biology
exome
fibrinogen
fibrinolysis
genetic association study
Summary: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 x 10(-8)). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 x 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.

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