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

TitleFGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.
Publication TypeManuscript
Year of Publication2021
AuthorsThibord F, Song C, Pattee J, Rodriguez BAT, Chen M-H, O'Donnell CJ, Kleber ME, Delgado GE, Guo X, Yao J, Taylor KD, Ozel ABilge, 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, Tregouet 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
Collection TitleJ Thromb Haemost
Volume/Storage Container19
Pagination2019-2028
Date Published2021 08
KeywordsExome, Fibrin Fibrinogen Degradation Products, Fibrinogen, Fibrinolysis, Humans, Plasminogen Activator Inhibitor 1, Tissue Plasminogen Activator
Abstract

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 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 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.

DOI10.1111/jth.15345
AbbreviationJ Thromb Haemost
PubMed ID33876560
Grant List5RC2HL102419 / GF / NIH HHS / United States
N01-HC-95163 / / MESA /
N01HC85082 / HB / NHLBI NIH HHS / United States
8691 / / Foundation for Strategic Research /
/ / Johns Hopkins University School of Medicine General Clinical Research Center /
/ / Novo Nordisk /
UCLA CTSI UL1-TR001881 / HB / NHLBI NIH HHS / United States
N01HC8508 / HB / NHLBI NIH HHS / United States
LSHM-CT-2007-037273 / / European Commission /
UL1TR001881 / TR / NCATS NIH HHS / United States
HL135793 / / National Institutes of Health/National Heart, Lung, and Blood Institute /
UL1-TR-001079 / / MESA /
HHSN268201500001I / HL / NHLBI NIH HHS / United States
NNF17SA0031406 / / Novo Nordisk Foundation /
N01-HC-95164 / / MESA /
18CDA34110116 / / American Heart Association /
/ / Health Foundation in Denmark /
NNF15CC0018486 / / Novo Nordisk Foundation /
/ / European Social Fund /
20653 / / Swedish Research Council /
75N92020D00004 / / MESA /
N01-HC-95169 / / MESA /
R01 HL139553 / HL / NHLBI NIH HHS / United States
75N92020D00007 / / MESA /
LSH-2005-2.1.1-1 / / 6th Framework Program of the European Union /
U01 HL130114 / HL / NHLBI NIH HHS / United States
/ / Association of Danish Pharmacies /
U01HL130114 / HB / NHLBI NIH HHS / United States
CP17/00142 / / ISCIII Spanish Health Institute /
/ / Copenhagen County /
NNF17OC0026848 / / Novo Nordisk Foundation /
N01HC55222 / HB / NHLBI NIH HHS / United States
/ / Augustinus Foundation /
UL1-TR-000040 / / MESA /
HHSN268201700002I / HH / HHS / United States
N01-HC-95168 / / MESA /
N01-HC-95167 / / MESA /
ANR-10-LABX-0013 / / GENMED Laboratory of Excellence on Medical Genomics /
75N92020D00003 / / MESA /
HL59684 / / National Institutes of Health/National Heart, Lung, and Blood Institute /
R01 HL105756 / HL / NHLBI NIH HHS / United States
HHSN268201500003I / HL / NHLBI NIH HHS / United States
N01HC85083 / HB / NHLBI NIH HHS / United States
HHSN268201700005I / HH / HHS / United States
HHSN268201700001I / HH / HHS / United States
HHSN268201800001C / HB / NHLBI NIH HHS / United States
R01HL103612 / HB / NHLBI NIH HHS / United States
/ / Velux Foundation /
/ / U.S. /
/ / Knut and Alice Wallenberg Foundation /
/ / Danish Heart Foundation /
HL134894 / / CHARGE Hemostasis Working Group /
/ / Danish Research Councils /
N02-HL-64278 / HB / NHLBI NIH HHS / United States
75N92020D00006 / / MESA /
HL141399 / / National Institutes of Health/National Heart, Lung, and Blood Institute /
N01-HC-95162 / / MESA /
DK063491 / / National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) /
HL112064 / / National Institutes of Health/National Heart, Lung, and Blood Institute /
HHSN268201700003I / HH / HHS / United States
N01-HC-95166 / / MESA /
N01HC85079 / HB / NHLBI NIH HHS / United States
/ NH / NIH HHS / United States
N01HC85086 / HB / NHLBI NIH HHS / United States
R01HL068986 / HB / NHLBI NIH HHS / United States
N01-HC-95159 / / MESA /
75N92020D00002 / / MESA /
N01-HC-95161 / / MESA /
HHSN268200800007C / HB / NHLBI NIH HHS / United States
N01-HC-95160 / / MESA /
HHSN268201700004I / HH / HHS / United States
75N92020D00001 / / MESA /
N01HC85080 / HB / NHLBI NIH HHS / United States
R01HL087652 / HB / NHLBI NIH HHS / United States
/ / Ministry of Health and Prevention in Denmark /
/ / Becket Foundation /
/ / Stockholm County Council /
/ / National Institute of Neurological Disorders and Stroke (NINDS) /
560183 / / Stockholm County Council /
N01-HC-95165 / / MESA /
/ / Danish Centre for Evaluation and Health Technology Assessment /
/ / NHLBI Intramural funds /
U01HL080295 / HB / NHLBI NIH HHS / United States
UL1-TR-001420 / / MESA /
R01AG023629 / / National Institute on Aging (NIA) /
M01 RR00052 / NH / NIH HHS / United States
R01HL120393 / HB / NHLBI NIH HHS / United States
HL139553 / / CHARGE Hemostasis Working Group /
12660 / / Swedish Heart-Lung Foundation /
R01HL105756 / HB / NHLBI NIH HHS / United States
/ / Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet /
75N92020D00005 / / MESA /
/ / Torsten and Ragnar Söderberg Foundation /
HHSN268201200036C / HB / NHLBI NIH HHS / United States
R01 HL134894 / HL / NHLBI NIH HHS / United States
NO1-HL 25195 / / National Heart, Lung, and Blood Institute contracts /
NNF18CC0034900 / / Novo Nordisk Foundation /
DRC DK063491 / / S. Calif /
HHSN268201100037C / HL / NHLBI NIH HHS / United States
/ / Ib Henriksens Foundation /