Abstract Number: PB0500
Meeting: ISTH 2020 Congress
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) and tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system.
Aims: There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA and D-dimer. We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.
Methods: Cohort level analysis and fixed effects meta-analysis of PAI-1 (n=15,063), tPA (n=6,605) and D-dimer (n=15,306) from 12 cohorts of European ancestry were conducted using the seqMeta package.
Results: Twelve variants (7 for D-dimer, 5 for tPA) achieved genome-wide significance (P< 5E-08) including 9 rare variants (allele frequency < 1%). Replication was sought for 57 well-imputed variants with P< 1E-4 in the discovery using an independent cohort. Replication was observed for 6 variants including one SNP in the known Factor V locus (F5) and 2 SNPs in the fibrinogen coding locus, all for D-dimer association. We observed and replicated association of an uncommon (0.013 allele frequency) coding variant Trp256Leu in FGL1 (fibrinogen like 1) with increased plasma D-dimer levels, replicating a prior study. Novel signals were replicated for a rare coding variant (rs201393961-T) in MTFR1L associated with increased tPA, and for an intronic SNP (rs11057830-A) in SCARB1 associated with increased D-dimer levels. Mouse models of Scarb1 deficiency previously showed roughly doubled plasma cholesterol levels, increased platelet reactivity, arterial occlusion and venous thrombosis. Human GWAS studies showed association of the same SCARB1 variant allele rs11057830-A with increased coronary artery disease risk.
Conclusions: Utilizing a targeted exome approach, we found common and rare variation associated with tPA and D-dimer plasma levels, including newly discovered and replicated loci linked to thrombosis.
To cite this abstract in AMA style:Thibord F, Song C, Chen M-, Rodriguez BAT, Yanek LR, Sabater-Lleal M, Carrasquilla GD, Hampton L, Rotter JI, Desch KC, Morange P, Kleber ME, Smith NL, Morrison AC, Johnson AD. Exome-array Analysis of Plasma Hemostatic Factors D-dimer, tPA and PAI-1 Identifies Novel Genes [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/exome-array-analysis-of-plasma-hemostatic-factors-d-dimer-tpa-and-pai-1-identifies-novel-genes/. Accessed January 27, 2022.
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