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 -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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2019-2028 |
| Number of pages | 10 |
| Journal | Journal of Thrombosis and Haemostasis |
| Volume | 19 |
| Issue number | 8 |
| Early online date | Apr 20 2021 |
| DOIs | |
| State | Published - Aug 2021 |
Bibliographical note
Funding Information:Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL068986, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS‐NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Atherosclerosis Risk in Communities study (ARIC) has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. Funding support for “Building on GWAS for NHLBI‐diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). The Precocious Coronary Artery DISease (PROCARDIS) study project was funded with 10 million Euros through the 6th Framework Program of the European Union (LSH‐2005‐2.1.1‐1). It started in April 2007 and funding lasted until September 2011. After the funding ended, PROCARDIS is still actively doing research in the field of coronary artery disease genetics. Maria Sabater‐Lleal is supported by a contract from the ISCIII Spanish Health Institute (CP17/00142) and co‐financed by the European Social Fund. Stockholm Coronary Artery Risk Factors (SCARF): The authors would like to thank all participants in this study. The study was funded by the Foundation for Strategic Research, the Swedish Heart‐Lung Foundation, the Swedish Research Council (8691, 12660, 20653), the European Commission (LSHM‐CT‐2007‐037273), the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Söderberg Foundation, the Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and the Stockholm County Council, and the Stockholm County Council (560183). MARTHA genetic investigations were financially supported by the GENMED Laboratory of Excellence on Medical Genomics (ANR‐10‐LABX‐0013). GENESTAR: This research was supported by grants HL59684 and HL112064 from the National Institutes of Health/National Heart, Lung, and Blood Institute, Bethesda, Maryland, and the Johns Hopkins University School of Medicine General Clinical Research Center, National Institutes of Health grant M01 RR00052. Genotyping services were provided through the RS&G Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under U.S. federal government contract number HHSN268201100037C from the National Heart, Lung, and Blood Institute. The Genes and Blood Clotting Study is supported by funds from HL135793 and HL141399 from the National Institutes of Health/National Heart, Lung, and Blood Institute, Bethesda, Maryland. The CHARGE Hemostasis Working Group is supported by funds from HL134894 and HL139553. Provision of exome chip genotyping was provided in part by support of NHLBI contract N02‐HL‐64278 and UCLA CTSI UL1‐TR001881, and the S. Calif DRC DK063491. DAT was supported by the «EPIDEMIOM‐VTE» Senior Chair from the Initiative of Excellence of the University of Bordeaux. Germán D. Carrasquilla was supported by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406. Tuomas O. Kilpeläinen was supported by the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848, NNF15CC0018486). Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center, based at the University of Copenhagen, Denmark, and partially funded by an unconditional donation from the Novo Nordisk Foundation ( www.cbmr.ku.dk ; grant number NNF18CC0034900). Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Miguel Servet
Funding Information:
The Inter99 study was funded by the Danish Research Councils, the Health Foundation in Denmark, Danish Centre for Evaluation and Health Technology Assessment, Copenhagen County, Danish Heart Foundation, Ministry of Health and Prevention in Denmark, Association of Danish Pharmacies, Augustinus Foundation, Novo Nordisk, Velux Foundation, Becket Foundation, and Ib Henriksens Foundation. The Framingham Heart Study was supported by the National Heart, Lung, and Blood Institute contracts NO1‐HL 25195 and HHSN268201500001I. Florian Thibord and Andrew Johnson were supported by NHLBI Intramural funds. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01‐HC‐95159, 75N92020D00005, N01‐HC‐95160, 75N92020D00002, N01‐HC‐95161, 75N92020D00003, N01‐HC‐95162, 75N92020D00006, N01‐HC‐95163, 75N92020D00004, N01‐HC‐95164, 75N92020D00007, N01‐HC‐95165, N01‐HC‐95166, N01‐HC‐95167, N01‐HC‐95168, N01‐HC‐95169, UL1‐TR‐000040, UL1‐TR‐001079, UL1‐TR‐001420. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center.
Funding Information:
The Inter99 study was funded by the Danish Research Councils, the Health Foundation in Denmark, Danish Centre for Evaluation and Health Technology Assessment, Copenhagen County, Danish Heart Foundation, Ministry of Health and Prevention in Denmark, Association of Danish Pharmacies, Augustinus Foundation, Novo Nordisk, Velux Foundation, Becket Foundation, and Ib Henriksens Foundation. The Framingham Heart Study was supported by the National Heart, Lung, and Blood Institute contracts NO1-HL 25195 and HHSN268201500001I. Florian Thibord and Andrew Johnson were supported by NHLBI Intramural funds. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Cardiovascular Health Study: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL068986, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Atherosclerosis Risk in Communities study (ARIC) has been funded in whole or in part with federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. Funding support for ?Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium? was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). The Precocious Coronary Artery DISease (PROCARDIS) study project was funded with 10 million Euros through the 6th Framework Program of the European Union (LSH-2005-2.1.1-1). It started in April 2007 and funding lasted until September 2011. After the funding ended, PROCARDIS is still actively doing research in the field of coronary artery disease genetics. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Stockholm Coronary Artery Risk Factors (SCARF): The authors would like to thank all participants in this study. The study was funded by the Foundation for Strategic Research, the Swedish Heart-Lung Foundation, the Swedish Research Council (8691, 12660, 20653), the European Commission (LSHM-CT-2007-037273), the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar S?derberg Foundation, the Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and the Stockholm County Council, and the Stockholm County Council (560183). MARTHA genetic investigations were financially supported by the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013). GENESTAR: This research was supported by grants HL59684 and HL112064 from the National Institutes of Health/National Heart, Lung, and Blood Institute, Bethesda, Maryland, and the Johns Hopkins University School of Medicine General Clinical Research Center, National Institutes of Health grant M01 RR00052. Genotyping services were provided through the RS&G Service by the Northwest Genomics Center at the University of Washington, Department of Genome Sciences, under U.S. federal government contract number HHSN268201100037C from the National Heart, Lung, and Blood Institute. The Genes and Blood Clotting Study is supported by funds from HL135793 and HL141399 from the National Institutes of Health/National Heart, Lung, and Blood Institute, Bethesda, Maryland. The CHARGE Hemostasis Working Group is supported by funds from HL134894 and HL139553. Provision of exome chip genotyping was provided in part by support of NHLBI contract N02-HL-64278 and UCLA CTSI UL1-TR001881, and the S. Calif DRC DK063491. DAT was supported by the ?EPIDEMIOM-VTE? Senior Chair from the Initiative of Excellence of the University of Bordeaux. Germ?n D. Carrasquilla was supported by the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406. Tuomas O. Kilpel?inen was supported by the Novo Nordisk Foundation (NNF18CC0034900, NNF17OC0026848, NNF15CC0018486). Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research center, based at the University of Copenhagen, Denmark, and partially funded by an unconditional donation from the Novo Nordisk Foundation (www.cbmr.ku.dk; grant number NNF18CC0034900). Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116.
Publisher Copyright:
© 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.
Keywords
- computational biology
- exome
- fibrinogen
- fibrinolysis
- genetic association study
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, N.I.H., Intramural
- Research Support, Non-U.S. Gov't