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

Abstract

BackgroundUse 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.ObjectivesWe sought to discover new genetic loci contributing to variation in these traits using an exome- array approach.MethodsCohort- 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.ResultsFive variants located in NME7, FGL1, and the fibrinogen locus, all associated with D- dimer levels, achieved genome- wide significance (P < 5 à  10- 8). Replication was sought for these 5 variants, as well as 45 well- imputed variants with P < 1 à  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.ConclusionThis work provides new evidence for a role of FGL1 in hemostasis.