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

Autor: Thibord F; The Framingham Heart Study, National Heart Lung and Blood Institute, Framingham, Massachusetts, USA., Song C; The Framingham Heart Study, National Heart Lung and Blood Institute, Framingham, Massachusetts, USA., Pattee J; Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA., Rodriguez BAT; The Framingham Heart Study, National Heart Lung and Blood Institute, Framingham, Massachusetts, USA., Chen MH; The Framingham Heart Study, National Heart Lung and Blood Institute, Framingham, Massachusetts, USA., O'Donnell CJ; The Framingham Heart Study, National Heart Lung and Blood Institute, Framingham, Massachusetts, USA.; U.S. Department of Veterans Affairs, Boston, Massachusetts, USA., Kleber ME; Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; SYNLAB MVZ Humangenetik Mannheim GmbH, Mannheim, Germany., Delgado GE; Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Guo X; Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA., Yao J; Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA., Taylor KD; Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA., Ozel AB; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA., Brody JA; Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA., McKnight B; Department of Biostatistics, University of Washington, Seattle, Washington, USA., Gyorgy B; INSERM UMRS1166, ICAN - Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France., Simonsick E; National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA., Leonard HL; National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA., Carrasquilla GD; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Guindo-Martinez M; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Silveira A; Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Center for Molecular Medicine and Karolinska University Hospital Solna, Stockholm, Sweden., Temprano-Sagrera G; Genomics of Complex Diseases, Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain., Yanek LR; GeneSTAR Research Program, Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Becker DM; GeneSTAR Research Program, Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Mathias RA; GeneSTAR Research Program, Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.; Division of Allergy and Clinical Immunology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Becker LC; GeneSTAR Research Program, Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Raffield LM; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Kilpeläinen TO; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Grarup N; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Pedersen O; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Hansen T; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Linneberg A; Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark., Hamsten A; Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Center for Molecular Medicine and Karolinska University Hospital Solna, Stockholm, Sweden., Watkins H; Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Sabater-Lleal M; Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Center for Molecular Medicine and Karolinska University Hospital Solna, Stockholm, Sweden.; Genomics of Complex Diseases, Research Institute of Hospital de la Santa Creu i Sant Pau, IIB Sant Pau, Barcelona, Spain., Nalls MA; National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA., Trégouët DA; INSERM UMRS1166, ICAN - Institute of CardioMetabolism and Nutrition, Sorbonne Université, Paris, France.; INSERM, BPH, Univ. Bordeaux, Bordeaux, France., Morange PE; INSERM, INRAE, Aix-Marseille Univ, Marseille, France., Psaty BM; Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA., Tracy RP; Department of Pathology and Laboratory Medicine & Department of Medicine, Vermont Center on Cardiovascular and Brain Health, Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA., Smith NL; Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA.; Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, Washington, USA.; Department of Epidemiology, University of Washington, Seattle, Washington, USA.; Department of Veterans Affairs Office of Research and Development, Seattle Epidemiologic Research and Information Center, Seattle,, Washington, USA., Desch KC; Department of Pediatrics, Cell and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, USA., Cushman M; Department of Pathology and Laboratory Medicine & Department of Medicine, Vermont Center on Cardiovascular and Brain Health, Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA., Rotter JI; Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA., de Vries PS; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Pankratz ND; Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA., Folsom AR; Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA., Morrison AC; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA., März W; Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany., Tang W; Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA., Johnson AD; The Framingham Heart Study, National Heart Lung and Blood Institute, Framingham, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2021 Aug; Vol. 19 (8), pp. 2019-2028. Date of Electronic Publication: 2021 May 30.
DOI: 10.1111/jth.15345
Abstrakt: 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.
(© 2021 International Society on Thrombosis and Haemostasis. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)
Databáze: MEDLINE
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