FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.
Thibord F., Song C., Pattee J., Rodriguez BAT., Chen M-H., O'Donnell CJ., Kleber ME., Delgado GE., Guo X., 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., Kilpeläinen TO., Grarup N., Pedersen O., Hansen T., Linneberg A., Hamsten A., Watkins H., Sabater-Lleal M., Nalls MA., Trégouët D-A., Morange P-E., Psaty BM., Tracy RP., Smith NL., Desch KC., Cushman M., Rotter JI., de Vries PS., Pankratz ND., Folsom AR., Morrison AC., März W., Tang W., Johnson AD.
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