Antithrombin, protein C, and protein S : genome and transcriptome-wide association studies identify 7 novel loci regulating plasma levels
Ji, Yuekai (University of Minnesota. Department of Medicine)
Temprano Sagrera, Gerard (Institut d'Investigació Biomèdica Sant Pau)
Holle, Lori (University of North Carolina at Chapel Hill. Department of Pathology)
Bebo, Allison (The University of Texas Health Science Center at Houston. Department of Epidemiology)
Brody, Jennifer A. (University of Washington. Department of Medicine)
Le, Ngoc-Quynh (Institut d'Investigació Biomèdica Sant Pau)
Kangro, Kadri (University of North Carolina at Chapel Hill. Department of Pathology)
Brown, Michael R. (The University of Texas Health Science Center at Houston. Department of Epidemiology)
Martinez-Perez, Angel (Institut d'Investigació Biomèdica Sant Pau)
Sitlani, Collen M. (University of Washington. Department of Medicine)
Suchon, Pierre (La Timone Hospital. Laboratory of Haematology)
Kleber, Marcus E. (SYNLAB MVZ für Humangenetik Mannheim)
Emmert, David B. (Eurac Research)
Ozel, Ayse Bilge (University of Michigan. Department of Human Genetics)
Dobson, DreVon (University of North Carolina at Chapel Hill. Department of Pathology)
Tang, Weihong (University of Minnesota. Division of Epidemiology and Community Health)
Llobet, Dolors (Institut d'Investigació Biomèdica Sant Pau)
Tracy, Russell (University of Vermont. Department of Pathology)
Deleuze, Jean-François (Fondation Jean Dausset. Centre d'Etude du Polymorphisme Humain)
Delgado, Graciela E. (Heidelberg University. Medical Faculty Heidelberg)
Gögele, Martin (Eurac Research)
Wiggins, Kerri L. (University of Washington. Department of Medicine)
Souto, Juan Carlos (Institut d'Investigació Biomèdica Sant Pau)
Pankow, James S. (University of Minnesota. Division of Epidemiology and Community Health)
Taylor, Kent (Friedrich Schiller University Jena)
Trégouët, David-Alexandre (Laboratory of Excellence on Medical Genomics)
Moissl, Angela Patricia (Heidelberg University. Medical Faculty Mannheim)
Fuchsberger, Christian (Eurac Research)
Rosendaal, Frits (Leiden University Medical Center. Department of Clinical Epidemiology)
Morrison, Alanna (The University of Texas Health Science Center at Houston. Department of Epidemiology)
Soria Fernández, José Manuel (Institut d'Investigació Biomèdica Sant Pau)
Cushman, Mary (University of Vermont. Larner College of Medicine)
Morange, Pierre-Emmanuel (Aix-Marseille Université)
März, Winfried (Heidelberg University. Medical Faculty Mannheim)
Hicks, Andrew A. (Eurac Research)
Desch, Karl C. (University of Michigan. Department of Pediatrics)
Johnson, Andrew (National Heart Lung and Blood Institute)
de Vries, Paul S. (Human Genetics Center (Texas, Estats Units d'Amèrica))
Wolberg, Alisa S. (University of North Carolina at Chapel Hill. Department of Pathology)
Sabater-Lleal, Maria (Institut d'Investigació Biomèdica Sant Pau)

Data:	2023
Resum:	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.
Ajuts:	Instituto de Salud Carlos III CP17/00142
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Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Matèria:	Anticoagulant ; Antithrombin ; Genome-wide association study ; Genotype ; Hemostasis ; Protein C ; Protein S
Publicat a:	Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 43, issue 7 (July 2023) , p. E254-E269, ISSN 1524-4636

DOI: 10.1161/ATVBAHA.122.318213
PMID: 37128921

Postprint 41 p, 302.3 KB

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