You are here
FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.
Tuesday,2021-07-20 19:11 America/Los_Angeles — ecterry
| Title | FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer. |
| Publication Type | Journal Article |
| Year of Publication | 2021 |
| Authors | 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, 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, 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 |
| Journal | J Thromb Haemost |
| Date Published | 2021 Apr 20 |
| ISSN | 1538-7836 |
| Abstract | <p><b>BACKGROUND: </b>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.</p><p><b>OBJECTIVES: </b>We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.</p><p><b>METHODS: </b>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.</p><p><b>RESULTS: </b>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.</p><p><b>CONCLUSION: </b>This work provides new evidence for a role of FGL1 in hemostasis.</p> |
| DOI | 10.1111/jth.15345 |
| Alternate Journal | J Thromb Haemost |
| PubMed ID | 33876560 |
| Grant List | 5RC2HL102419 / 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 / 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 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 / |
ePub date:
21/04