Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels-Reference-Cited by-全球学者库

Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels

Published:2023-07 Issue:7 Volume:43 Page:
ISSN:1079-5642
Container-title:Arteriosclerosis, Thrombosis, and Vascular Biology
language:en
Short-container-title:ATVB

Author:

Ji Yuekai¹,Temprano-Sagrera Gerard²^ORCID,Holle Lori A.³^ORCID,Bebo Allison⁴,Brody Jennifer A.⁵^ORCID,Le Ngoc-Quynh²,Kangro Kadri³^ORCID,Brown Michael R.⁴^ORCID,Martinez-Perez Angel²^ORCID,Sitlani Colleen M.⁶^ORCID,Suchon Pierre⁷⁸,Kleber Marcus E.⁹¹⁰,Emmert David B.¹¹,Bilge Ozel Ayse¹²,Dobson Dre’Von A.³^ORCID,Tang Weihong¹³^ORCID,Llobet Dolors¹⁴,Tracy Russell P.¹⁵^ORCID,Deleuze Jean-François¹⁶¹⁷¹⁸,Delgado Graciela E.¹⁰,Gögele Martin¹¹^ORCID,Wiggins Kerri L.⁵^ORCID,Souto Juan Carlos²¹⁴^ORCID,Pankow James S.¹³^ORCID,Taylor Kent D.¹⁹^ORCID,Trégouët David-Alexandre¹⁸²⁰^ORCID,Moissl Angela P.¹⁰²¹²²^ORCID,Fuchsberger Christian¹¹,Rosendaal Frits R.²³^ORCID,Morrison Alanna C.⁴^ORCID,Soria Jose Manuel²^ORCID,Cushman Mary²⁴^ORCID,Morange Pierre-Emmanuel⁷⁸,März Winfried¹⁰²⁵,Hicks Andrew A.¹¹^ORCID,Desch Karl C.²⁶,Johnson Andrew D.²⁷^ORCID,de Vries Paul S.⁴^ORCID,Wolberg Alisa S.³^ORCID,Smith Nicholas L.²⁸²⁹³⁰^ORCID,Sabater-Lleal Maria²³¹^ORCID,

Affiliation:

1. Cardiovascular Division, Department of Medicine, University of Minnesota, MN (Y.J.).

2. Unit of genomics of Complex Disease, Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Barcelona, Spain (G.T.-S., N.-Q.L., A.M.-P., J.C.S., J.M.S., M.S.-L.).

3. Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina at Chapel Hill (L.A.H., K.K., D.A.D., A.S.W.).

4. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston (A.B., M.R.B., A.C.M., P.S.d.V.).

5. Department of Medicine, University of Washington (J.A.B., K.L.W.).

6. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle (C.M.S.).

7. C2VN, INSERM, INRAE, Aix Marseille Univ, France (P.S., P.-E.M.).

8. Laboratory of Haematology, La Timone Hospital, France (P.S., P.-E.M.).

9. SYNLAB MVZ für Humangenetik Mannheim, Germany (M.E.K.).

10. Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Germany (M.E.K., G.E.D., A.P.M., W.M.).

11. Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Italy (D.B.E., M.G., C.F., A.A.H.).

12. Department of Human Genetics, University of Michigan, C.S. Mott Children’s Hospital, Ann Arbor (A.B.O.).

13. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, MN (W.T., J.S.P.).

14. Unit of Thrombosis and Hemostasis, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (D.L., J.C.S.).

15. Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington (R.P.T.).

16. Centre National de Recherche en Génomique Humaine, CEA, France (J.-F.D.).

17. Centre d’Etude du Polymorphisme Humain, Fondation Jean Dausset, France (J.-F.D.).

18. Laboratory of Excellence on Medical Genomics (GenMed), France (J.-F.D., D.-A.T.).

19. The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, CA (K.D.T.).

20. INSERM UMR 1219, Bordeaux Population Health Research Center, France (D.-A.T.).

21. Institute of Nutritional Sciences, Friedrich Schiller University Jena, Germany (A.P.M.).

22. Competence Cluster for Nutrition and Cardiovascular Health(nutriCARD) Halle-Jena-Leipzig, Germany (A.P.M.).

23. Department of Clinical Epidemiology, Leiden University Medical Center, the Netherlands (F.R.R.).

24. Larner College of Medicine, University of Vermont, Burlington (M.C.).

25. Synlab Academy, Synlab Holding Deutschland GmbH, Germany (W.M.).

26. Department of Pediatrics, University of Michigan, C.S. Mott Children’s Hospital, Ann Arbor (K.C.D.).

27. National Heart Lung and Blood Institute, Division of Intramural Research, Population Sciences Branch, The Framingham Heart Study, MA (A.D.J.).

28. Department of Epidemiology, University of Washington, Seattle (N.L.S.).

29. Kaiser Permanente Washington Health Research Institute (N.L.S.).

30. Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, WA (N.L.S.).

31. Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden (M.S.-L.).

Abstract

Background: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total. Methods: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes. Results: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels ( GCKR , BAZ1B , and HP-TXNL4B ) and 1 with PS levels ( ORM1 - ORM2 ). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level ( FCGRT ), 1 with PC ( GOLM2 ), and 1 with PS ( MYL7 ). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of GCKR , SNX17 , and HP genes in antithrombin regulation. Conclusions: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

Reference115 articles.

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1. Genetic Modifiers of Antihrombin, Protein C, and Protein S Plasma Levels;Arteriosclerosis, Thrombosis, and Vascular Biology;2023-07